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Learn how Celegence has successfully supported global medical device organizations in navigating critical regulatory challenges and more.

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Medical device and sufficient clinical evidence: case studies examples of clinical investigation and survey.

In recent years, following the entry into force of Regulation (EU) 2017/745 (MDR), more and more medical device manufacturers had to assess, for each of their legacy devices, the strength and completeness of the available clinical data. This, in order to establish whether or not their medical devices evidence of safety and clinical effectiveness was sufficient to prove compliance with the MDR General Safety and Performance Requirements ( Medical Devices and Sufficient Clinical Evidence ).

PRINEOS, as a Life Sciences consulting company, had the opportunity to work together with several medical device manufacturers  assessing the sufficiency of available clinical data on their legacy devices, and to support them in making the most correct choice for how to collect and submit such data to Notified Bodies (NBs), in order to obtain the MDR EC certification.

As reported in the MDCG 2020-6 , it is important for a manufacturer to identify all available sources of clinical data from both the pre-market and post-market phases. This will include all of the clinical data which is generated and held by the manufacturer as well as clinical data for equivalent or similar devices.

For the purpose of legacy devices, pre-market sources of clinical data may include: 

• Clinical investigation reports of the device concerned; 
• Clinical investigation reports or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated in accordance with the MDR; 
• Reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated; 
• Other pre-market data, e.g. case reports on experience with the use of the device in question, such as compassionate or humanitarian exceptional use reports. 

Instead, post-market sources of clinical data refer to data collected following the initial EC marking under the Directives 93/42 EEC (MDD). This may include: 

• PMS clinical data, complaint and incident reports; 
• PMCF studies, including post-market clinical investigations; 
• Independent clinical studies conducted using the device37; 
• Device registries; 
• Data retrieved from the literature

The Appendix III of MDCG 2020-6 suggests a hierarchy of clinical evidence (listed in decreasing hierarchical order, ranging from 1 - most robust evidence - to 12 - least robust evidence) used to demonstrate device compliance with the relevant General Safety and Performance Requirements of the MDR Regulations. The results of high-quality clinical investigations covering all device variants, indications, patient populations, duration of treatment effect, etc. are on top of the hierarchy, as most robust evidence. Surveys are positioned almost in the middle of this hierarchy, with a rank of 8 and are referred to as an example of proactive Post Market Surveillance. Clinical data obtained from surveys fall within the definition of clinical data under MDR Article 2(48), but is not generally considered a high quality source of data due limitations associated with sources of bias and quality of data collection. It may be useful for identifying safety concerns or performance issues. Finally, pre-clinical and bench testing are reported at the bottom of this hierarchy.

To date, the most common scenarios PRINEOS has faced are:

• manufacturers of EC-marked medical devices under the MDD Directive (legacy devices), who did not have clinical data on their products, as defined by Article 2(48) of the MDR;
• manufacturers of EC-marked medical devices under the MDD Directive (legacy devices), who already had sufficient clinical data on their products, but for whom it was still necessary to put in place proactive post-market surveillance activities, in order to verify the medical device safety and performance for its entire life cycle.

In the first case, PRINEOS  prepared a proper post-market clinical investigation for manufacturers, in accordance with the requirements of UNI EN ISO 14155:2020 and MDR Regulation Articles from 62 to 82. In the second case, PRINEOS  prepared surveys activities, using manual data collection in some cases, and electronic database collection in other cases.  

Clinical Investigation The MDR Regulation Article 2 (45) defines a clinical investigation as “any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device”. Clinical investigations shall be designed and conducted in such a way that the rights, safety, dignity and well-being of the subjects participating in a clinical investigation are protected and prevail over all other interests and the clinical data generated are scientifically valid, reliable and robust. In compliance with the requirements of the MDR Regulations, PRINEOS prepared post-market clinical investigations by supporting legacy medical device manufacturers from the drafting of the Clinical Investigation Protocol (CIP) to the drafting of the Clinical Investigation Report (CIR).  PRINEOS developed the study synopsis and its methodology, calculated the sample size, provided the CIP submission to the Ethics Committee - to obtain approval to initiate the clinical investigation - and finally managed, collected, and analyzed the obtained results at the end of the investigation. An example of such an activity is that of a retrospective observational clinical investigation - Post-Market Clinical follow-up - that PRINEOS planned and executed for a legacy, sterile, ophthalmic, non-innovative, non-diagnostic medical device, class IIa according to the MDD Directive and placed on the market since 2017. The device for MDR EC certification will undergo a classification upgrade -Annex VIII MDR Regulation - to class IIb.

The clinical investigation synopsis included a collection of data registered in medical records from 1st May 2019 to 1st May 2022. Data were extracted from the medical records at the selected investigation center between January 2023 and March 2023, identifying relevant inclusion and exclusion criteria, planning the appropriate sample size and the performance and safety outcomes to be measured, and describing the statistical methodology and the analysis performed. The clinical investigation outcomes provided sufficient clinical data (valid, reliable, and robust) on the clinical safety and efficacy of the medical device when used as intended by the manufacturer.

Survey The survey is a means by which a medical device manufacturer can collect proactive Post-Market Surveillance data on its products. Survey involves the preparation of questionnaires useful for collecting information related to the performance and safety of a medical device already EC-marked and placed on the market. The questionnaires should be addressed and delivered directly to the medical device user or to the distributors or healthcare professionals (physicians, pharmacists, etc.) who respectively convey or prescribe the medical device use. An example of survey activities, managed by PRINEOS, involved the development of a questionnaire to be given to the users of a legacy device, EC marked according to the MDD Directive, intended to be use by lay users in the home environment. The questionnaires were written in several languages so that the manufacturer could distribute and fill them out in most countries where the product is sold. Some questionnaires were filled out by physicians, on behalf of the user, others directly by users. Upon completion of the collection of the completed questionnaires, PRINEOS performed a manual Data Entry activity , which allowed, based on careful analysis of the questionnaire responses, to gain statistically information to confirm the safety, performance, and usability of the product. Based on client needs, PRINEOS also conducted survey activities in which the questionnaires access and completion, by end users, was via a link on the medical device manufacturer's website. After electronic completion, the various questionnaires were collected into an electronic database for the results analysis. Finally, for an active medical device used for the monitoring and delivery of therapeutic gases to hospitalized patients, EC-marked according to the MDD Directive, and intended to be used in a hospital setting by qualified health care personnel appropriately trained in its use, the survey activity was set up by taking advantage of the device's operating data, recorded by the software on the device itself, without involving the patients or the health care personnel assigned to its use.  The data collected by the software were then analyzed by PRINEOS to obtain statistically relevant information related to the device effectiveness and safe operation.

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Medical Device Clinical Trials: Regulatory Pathways & Study Types Explained

In both the US and the EU, medical devices may be required to undergo a clinical trial before they can be placed on the market. A clinical trial is a systematic assessment of the device’s safety and/or efficacy that uses human participants, and it’s a requirement for certain risk classes:

In the EU, all Class III and Class IIb implantable devices must undergo clinical investigations according to EU MDR. 

In the US, all Class III devices are required by FDA to undergo clinical investigations as part of premarket approval (PMA).

With that in mind, let’s take a look at the different stages and designs of medical device clinical trials and the regulations surrounding them. 

NOTE: You may see clinical trials referred to as “clinical studies” or, more commonly in the medical device industry, “clinical investigations.” These terms are all synonymous and can be used interchangeably.

BONUS RESOURCE: Click here to download our 15-in-1 clinical investigations content bundle to help you run studies and collect clinical data more efficiently.

How are medical device clinical trials initiated?

Because clinical trials involve human participants, medical device companies must perform preclinical testing and research on their product before even applying for a clinical trial.

Preclinical activities determine whether a device is safe and effective enough for use with human subjects, and include steps like:

Bench testing

Technical testing

Computer simulations

Animal studies

Once the manufacturer believes their device is ready for clinical trials, they must first get approval for their proposed investigation. The processes for getting approval and initiating a clinical trial in the EU and US are different, so let’s take a look at each.

Clinical trial regulatory pathways in the US

In the US, medical device manufacturers that want to pursue a clinical trial must obtain an Investigational Device Exemption (IDE). Only once the IDE has been approved can a device that has not yet received market approval be tested on human subjects. 

There are exceptions to the IDE submission, which include certain low-risk diagnostic devices as well as devices that are determined to be non-significant risk (NSR).

If a device is granted an IDE, the clinical investigation must still be reviewed by an Institutional Review Board (IRB). Clinical trials are generally performed within an institution, such as a hospital, and an IRB is an additional layer of scrutiny that the institution provides to ensure the study meets its standards. The study may begin only once the IRB has approved it and FDA has approved the IDE application.

Clinical trial regulatory pathways in the EU

EU MDR has 20 articles outlining the requirements for clinical investigations of medical devices, spanning articles 62 through 82. Within these articles, the regulation lays out three regulatory pathways manufacturers can take:

Article 62 covers investigations that are performed in order to demonstrate conformity and obtain a CE marking. This is the pathway medical device companies will use if their device classification (for Class III or Class IIb implantables ) requires a clinical investigation.

Article 74(1) covers the regulatory pathway for devices that already have a CE marking if the parameters of the investigation are within the device’s intended purpose. In other words, if you are conducting a clinical investigation as part of your Post-Market Clinical Follow-Up (PMCF) , then you will be guided by Article 74(1).

Article 82 covers clinical investigations that are not being performed in order to demonstrate conformity. Additionally, the Member State in which you hold your study may have relevant national provisions for you to follow.

Before initiating a clinical trial in the EU, you’ll also need a CIV-ID and approval from the relevant competent authority. The CIV-ID is an EU specific tracking number that competent authorities in any Member State can use to identify and track your clinical investigation. 

Keep in mind that once the EUDAMED database is fully functional, now scheduled for spring of 2024 , the CIV-ID will be replaced by a Single Identification Number tracked through EUDAMED.

What are the different stages and types of medical device clinical trials?

Clinical trials may be carried out during both the premarket and postmarket phases of the device lifecycle. The graphic below includes the many different types of clinical activities, including clinical trials, medical device manufacturers may carry out during the pre-market and post-market phases.

Clinical trials may occur during the pilot stage, the pivotal stage, or during post-market surveillance. As I mentioned earlier, pre-clinical activities do not use human subjects.

As we dig in here, don’t get too hung up on the study descriptors in this graphic. Many of these terms are interchangeable, and different descriptors are often used in different markets to describe the same thing. For now, let’s focus on the general types and stages of studies and their burden to human subjects.

What are pilot studies?

Pilot studies occur early in device development, often before the device design has been finalized. Pilot studies are used when nonclinical testing is unable to provide preliminary information on device functionality and clinical safety. These will be conducted with a very small number of patients—often 10 or fewer. 

The purpose of pilot studies is to gain a broad range of information that may be used to:

Identify modifications to the device or procedure

Optimize operator technique

Refine the intended use population

Refine nonclinical test plans or methodologies

Develop subsequent clinical study protocols

The data you gain from a pilot study may then be used to help you design a pivotal study later on. 

What are pivotal studies?

A pivotal study is used to gather definitive evidence of the safety and effectiveness of your medical device for a specific intended use. These studies generally use a larger number of subjects than pilot studies, and you’ll use the results of your pivotal study to gain regulatory approval for your device. 

Keep in mind, a pivotal study does not necessarily need to be preceded by a pilot study. The types of clinical activities you carry out will depend on your device and the regulatory pathway you’re taking.

Do clinical trials happen during post-market surveillance?

As you can see from the graphic, the post-market surveillance stage includes both confirmatory and observational types of clinical activities. 

While it may seem odd that you would need to perform a confirmatory study after receiving approval to place your device on the market, this is not an irregular occurrence. For example, EU MDR includes a distinct regulatory pathway—Article 74(1)—for conducting a clinical investigation as part of your PMCF.

These post-market surveillance studies may be conducted for a number of reasons, including to confirm the safety and efficacy of the device once it’s on the market or to answer questions about the long-term safety or performance of the device. 

How are observational clinical activities conducted?

Many post-market clinical activities are categorized as “observational” and they use non-interventional methods to collect data. 

In interventional studies , such as a pivotal study, someone is actively recruiting participants. For example, a physician may ask a patient who may benefit from a certain device if they would like to volunteer for that study. In other words, they are intervening in the normal clinical pathway the patient would follow.

In non-interventional studies , there is no intervention in the clinical pathway—merely observation. For example, a physician prescribes a treatment they believe the patient needs (the normal clinical pathway), and then asks the patient if they would agree to share the data related to their treatment as part of an observational study.

Remember, some devices may need clinical data from all of these categories, but many will not. For example, low risk devices relying on well-known technology may not require any clinical investigations on your part. 

Greenlight Guru Clinical helps you streamline clinical data collection for your medical device

This may seem like a complicated topic, but if you break it down by the stages of the device lifecycle and the type of clinical activity, you have a roadmap for how you’ll obtain the necessary clinical data for your device.

And when it comes time to begin collecting that data, you’ll need a flexible, modern platform that can streamline data collection from any and all of your clinical activities. 

Greenlight Guru Clinical is that platform. Whether you’re gathering data in clinical studies, performance studies, PMCF/PMPF studies, surveys, registries, cohorts, or case series, our Electronic Data Capture solution allows you to collect and manage it all with ease. Even better, it comes fully validated out of the box per ISO 14155:2020 .

Ready to learn more? Contact us today for a customized demo →

Jon Bergsteinsson

Jón Ingi Bergsteinsson, M.Sc. in Biomedical Engineering, is the co-founder of Greenlight Guru Clinical (formerly SMART-TRIAL). He was also the technical founder of Greenlight Guru Clinical where he paved the way for the platform’s quality standards, data security, and compliance.

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Navigating the Regulatory Pathway for Medical Devices—a Conversation with the FDA, Clinicians, Researchers, and Industry Experts

• Published: 14 March 2022
• Volume 15 , pages 927–943, ( 2022 )

Cite this article

• Aaron E. Lottes 1 ,
• Kenneth J. Cavanaugh 2 ,
• Yvonne Yu-Feng Chan 3 ,
• Vincent J. Devlin 2 ,
• Craig J. Goergen 1 ,
• Ronald Jean 2 ,
• Jacqueline C. Linnes 1 ,
• Misti Malone 2 ,
• Raquel Peat 2 ,
• David G. Reuter 4 ,
• Kay Taylor 5 &
• George R. Wodicka 1  

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Successful translation of new and innovative medical products from concept to clinical use is a complex endeavor that requires understanding and overcoming a variety of challenges. In particular, regulatory pathways and processes are often unfamiliar to academic researchers and start-ups, and even larger companies. Growing evidence suggests that the successful translation of ideas to products requires collaboration and cooperation between clinicians, researchers, industry, and regulators. A multi-stakeholder group developed this review to enhance regulatory knowledge and thereby improve translational success for medical devices. Communication between and among stakeholders is identified as a critical factor. Current regulatory programs and processes to facilitate communication and translation of innovative devices are described and discussed. Case studies are used to highlight the importance of flexibility when considering evidence requirements. We provide a review of emerging strategies, opportunities, and best practices to increase the regulatory knowledge base and facilitate medical device translation by all stakeholders.

Graphical abstract

Clinicians, regulators, industry, and researchers require regulatory knowledge and collaboration for successful translation of innovative medical devices

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Introduction

The translation of novel medical devices from discovery through development, testing, and regulatory review, and finally to clinical use, is well known to contain a metaphorical “valley of death” in which products fail to advance from the development and testing phases to successful clinical use [ 1 ]. To bring new and innovative medical devices to market efficiently and effectively, a greater understanding of challenges faced and how to overcome those challenges is needed. One area, for academic researchers, start-ups, and small companies in particular, is understanding the various regulatory processes that must be navigated before most products can be used in patients or commercially marketed [ 2 , 3 , 4 ]. A multi-stakeholder group representing a cross-section of the medical device field, including clinicians, academic researchers, industry professionals, and regulators from the United States Food and Drug Administration (FDA), all of whom play critical roles in maintaining a vibrant and productive network for the development of medical devices, prepared this review of salient points and best practices toward a goal of increasing knowledge and advancing medical device translation through the regulatory process from concept to clinic [ 5 ].

Role of FDA Center for Devices and Radiological Health (CDRH)

As the FDA center responsible for the regulatory oversight of medical devices, CDRH plays a crucial role in facilitating device development by interacting with all stakeholder groups in the medical device ecosystem. CDRH activities relevant to improving translational processes include engaging with patients and the community to bring a product to market, the work of the FDA Office of Science and Engineering Laboratories (OSEL), special considerations related to pediatric populations, the Breakthrough Devices Program, Early Feasibility Studies (EFS), Q-submissions, current initiatives related to National Evaluation System for health Technology (NEST) and real-world evidence (RWE), evolution of regulatory pathways, global harmonization, and training.

Early engagement with key stakeholders including patients, clinicians, and payers is critical for regulatory and commercial success given the many pitfalls on the path from product concept to marketing, adoption, and reimbursement. In particular, patients are at the heart of CDRH activities and patient input, preference, and benefit-risk decisions are important parts of product development and regulatory decision-making. Involvement of patient advocacy groups and FDA as part of a patient-caregiver collaborative community can provide expert input from the patient perspective, bring together key stakeholder groups to solve shared problems, and provide community-driven solutions that may be accepted by FDA [ 6 ]. Systems and solutions identified and developed by collaborative communities are often designed not just for use by FDA, but also to meet the needs of industry and other stakeholders such as patients, caregivers, healthcare providers, and payers. Communicating with FDA, innovation hubs, and regional consortiums throughout the development process builds connections to stakeholders who can help address various scientific and regulatory issues to accelerate innovation.

As new technologies are rapidly developed, FDA expertise must also advance. To address this challenge, OSEL supports pre-market reviews and post-market surveillance requirements by engaging in practical research and problem solving, and developing tools to better assess and understand new and cross-cutting technologies. Research areas include in silico clinical trials that can be completed in days rather than years, identification of early biomarkers for age-related conditions, and additive manufacturing, among many others. Through OSEL, FDA can align common research interests and goals with academia and other partners and provide expertise and laboratory capabilities that can help enable optimal review of novel products.

The use of innovative regulatory pathways such as the Breakthrough Devices Program, Safer Technologies Program (STeP), and EFS Program has rapidly expanded over time [ 7 ]. These programs and other efforts to de-risk the product development process for innovative technologies help attract investment and continue to drive innovative product development efforts in the USA. The Breakthrough Devices Program is intended to improve timely access to novel and innovative technologies that provide more effective treatment or diagnosis of a life-threatening or irreversibly debilitating disease or condition, often in areas of unmet clinical need, whereas STeP is intended for devices that do not meet the breakthrough criteria but still provide important safety advantages over existing technologies [ 8 ]. Both programs offer opportunities to engage early and frequently with FDA. To consider the suitability of a device for the Breakthrough Program, the product design should be developed at least to the point of understanding specific risks and key performance characteristics. Additionally, the intended use, patient population to be treated, and existing treatment options should be known, along with information to support why the proposed treatment would be more effective than existing options. Demonstration of expected effectiveness could include clinical data, bench or animal data, or a scientifically supported theoretical argument, depending on the technology. At that point, one approach may be to reach out to the assistant director for the relevant review team at FDA and have a brief informal conversation to help determine if there is enough information for a more formal discussion and/or breakthrough designation request.

The Q-Submission process is a helpful and popular pathway for communicating with FDA [ 9 ]. Gaining a clearer understanding of regulatory requirements early in the development process can help de-risk the business aspects of projects, which can be especially important for small innovators. A sponsor can share information and obtain FDA’s feedback on a particular question(s) to keep a product moving forward on the translational pathway. Q-Submissions, including Informational Meetings and Pre-Submissions, can be especially helpful for complex products such as indwelling or implantable devices, new technology, or innovative non-clinical or clinical testing strategies. Very early in the development process, an Informational Meeting can help FDA gain a deeper understanding of new technology by providing an overview of the device and optionally demonstrating a prototype; having an opportunity for FDA personnel to interact with a device in a hands-on environment, or in a video-conference setting, can be extremely beneficial. Working with an expert who understands the Q-Submission process and can provide guidance may help optimize the benefit of the program.

In addition to allowing more concrete feedback from FDA, Pre-Submissions also provide an opportunity to engage with both FDA and payors, including CMS and private payors, together as part of the Early Payor Feedback Program [ 10 ]. A clinically successful device that makes it through the regulatory process can still fail to be integrated into medical practice if there is no or poor reimbursement. Therefore, it is often important to develop a reimbursement strategy early during product development and clinical planning. Including payors in a Pre-Submission meeting allows payors to consider and provide feedback on the type of clinical evidence that could support payment for a technology (e.g., reasonable and necessary criteria for CMS) along with FDA feedback on clinical evidence that can potentially demonstrate a reasonable assurance of safety and effectiveness.

Real-world evidence is an increasingly important concept to support device development and evaluation. Continuing improvements in infrastructure, data completeness, definitions, and harmonization may provide increased opportunities for RWE to support regulatory and clinical decision-making. FDA has identified numerous cases where RWE has been accepted to support pre-market authorizations and fulfill post-market requirements [ 11 ]. RWE can be leveraged not only to support regulatory decisions, but also to facilitate hypothesis generation or finding appropriate patients. When using RWE, it is important to understand not just the device and clinical space, but also the data source quality and the relevance and reliability of the data. NEST is working to help advance the use of RWE to support regulatory decision-making and has drafted data quality and methods frameworks. Discussing RWE use in advance with FDA, again potentially as part of a Pre-Submission, is highly encouraged.

The role of post-market surveillance has evolved over time beyond merely serving as a regulatory requirement to also helping answer important clinical questions that may not have been fully addressed in pre-market studies. For example, post-market surveillance offers an opportunity to fill in evidence gaps in the patient population being treated or to collect information on how a device could be used in a real-world setting. This multi-purpose use provides a potential role for patient registries or coordinated registry networks that in a total product lifecycle environment can then be used as RWE to support expanding a device indication and identify unmet clinical needs.

The mission of CDRH is not just to protect the public health, but also to promote the public health. This includes facilitating medical device innovation by advancing regulatory science and providing efficient regulatory pathways. The vision and values supporting this mission include being a leader in regulatory science and medical device innovation by challenging the status quo and testing and adopting new approaches to foster positive change and more effectively and efficiently accomplish the CDRH mission. As a future consideration to support innovation, additional flexibility could be considered in regulations to allow a more agile regulatory process; for example, leveraging of individual building blocks as appropriate to meet requirements. A risk-based and least-burdensome approach would remain at the core, but regulatory processes may be tailored to a specific technology. This more agile approach could be particularly relevant for innovative, rapidly changing technologies, such as digital health, as well as small, underserved patient populations and rare diseases. As one example, the current ecosystem is not well-designed to support development of innovative products for small and complex patient populations, such as pediatrics, due to high risks and limited investment incentives. As a result, physicians often must attempt to leverage technology designed for adults for use in children. For devices designed to treat or diagnose a disease or condition that affects not more than 8000 individuals in the USA on an annual basis, the Humanitarian Device Exemption (HDE) program provides a regulatory pathway based on demonstration of safety and probable benefit, but there remain numerous additional requirements tied to the program such as institutional review board (IRB) reviews, profit limitations, and other challenges that have limited widespread use of this pathway [ 12 ]. For larger patient populations, the pre-market approval (PMA) pathway may still be too difficult for pediatric devices to be commercially viable. A hypothetical future hybrid approach could envision a device coming to market with the HDE standard of safety and probable benefit, but without all of the currently associated requirements, and then developing additional evidence of a reasonable assurance of safety and effectiveness (PMA standard) in a streamlined manner. While this approach would require changes to US law, it may ultimately provide a more effective pathway to market along with greater confidence in the technology.

Similarly, efforts are ongoing within the International Medical Device Regulators Forum (IMDRF) to develop globally harmonized essential principles for pre-market review, which could potentially be used as building blocks to support a multi-national single review program [ 13 ]. A number of challenges remain, including differences in the current US regulatory framework compared to many other regions and the need to ensure confidence in whichever entities would conduct pre-market review for a new technology. The Medical Device Single Audit Program provides one example of success for international harmonization [ 14 ]. An effective single review program that allows for near-simultaneous entry of technology to multiple marketplaces could better drive innovation and boost global health.

Providing regulatory training to new scientists and engineers is an important facet for maintaining a robust innovation ecosystem for translation. Programs around medical device development provide an opportunity to walk trainees through the entire life cycle of a product, including regulatory components such as practical applications of regulatory science to develop and evaluate innovative technologies. Use cases, including those developed by FDA, can provide examples of how regulatory principles integrate into the medical device development process. Having students engaged in regulatory science working in the field with developers, FDA, and other stakeholders such as patients, providers, and payers would be a robust opportunity to develop skills and provide an investment for the future. Recent reports indicate a large gap is expected between the supply and demand for skilled regulatory professionals, highlighting the need for expanding educational opportunities and pathways [ 15 ]. It is hoped that ongoing discussions will serve to motivate further development of regulatory-focused training programs for scientists, engineers, and other stakeholders.

Translational Pathways

Medical device development—from academic discovery to regulatory review to patient access.

One starting point for device development is to consider the question: “How do we start with a breakthrough idea from an inventor’s mind and translate that idea to a product that actually reaches patients?” Three critical pieces are necessary to be successful in medical device translation: people, processes, and product selection. Additionally, one of the biggest current challenges to success is the increasing cost of medical device development due to regulatory burdens, dilution of capital by project failures and inefficient management, and falling product prices and reimbursement. Together, these factors result in decreased margins for innovation and drive the need to further optimize the pathway.

The first critical piece for success is people. Stakeholders that understand the medical device ecosystem and with the experience to provide leadership and knowledge on where to focus limited resources must be included. These leaders can assemble the right team of scientific experts, financial experts, clinicians, and supply chain necessary to guide development and source capital. Examples of collaborative efforts to develop this leadership within the translational ecosystem include the CTSIs, International Society of Cardiovascular and Translational Research (ISCTR), standards organizations, and international harmonization efforts such as Harmonization By Doing (HBD).

The next piece is having the right processes in place to accelerate the product development stages (Fig.  1 ). A good process will eliminate wasted effort from inexperience and mistakes, carefully coordinate to identify efficiencies and avoid pitfalls, and accelerate development by maximizing parallel processes to achieve the most efficient project plan. Combining the right people with the right process leads to development of successful engineering, testing, clinical, and regulatory strategies. This includes developing strategies around user needs, test models, simulations, and acceptance criteria, and planning and performing bench and animal testing. Developing a clinical and regulatory plan early, simultaneous with product development, allows feeding requirements and findings back into the development process to create a more efficient overall path.

Components of an accelerated product development sequence; careful coordination can identify efficiencies and maximize parallel development processes to achieve the most efficient path to market; figure used with permission from MED Institute, Inc

The third piece for success is the product itself. The patient/clinical need comes first, and the best product is the one that best meets this need. Many great ideas do not pass this initial test, and trying to force a product to fit a need often ends in failure, regardless of how interesting or innovative the technology. Adapting the intended use and claims for a product to best fit the available data and clinical results is one approach to consider. In addition to being scientifically feasible, a successful product must also be economically feasible and commercially viable. Product ideas and the pros and cons of different strategies (e.g., regulatory path, intellectual property arrangements, development costs, reimbursement and payor strategies) should be considered from this perspective. Products that meet these initial requirements still require long-term dedication to succeed from an idea to patient use.

Early Feasibility Studies—a First Step Into Clinical Studies

The EFS process provides opportunities for rapid and efficient data collection to guide further product development activities [ 16 ]. These early studies can be integral to the device development process by obtaining insights into proof of concept related to various factors, including safety, performance, usability, or identification of the optimal patient population, and may form the basis for further device iteration and improvement. One benefit of EFS is the opportunity to enhance collaborations among all stakeholders, including developers, industry, investigators, and regulators.

Appropriate devices for EFS are those still in the development stage where the design has not yet been finalized and further development or evaluation is not available or adequate via non-clinical testing. The EFS pathway may reduce delays to device access for patients with limited alternatives and help device developers better understand the underlying clinical condition and unmet clinical need. Devices may be used in a few patients followed by making modifications to the device and enrolling a few additional patients in an iterative process that can help refine device design. The EFS process is uniquely beneficial to first-in-class therapies where innovators may have no choice but to extrapolate from animal studies to predict design requirements for human devices. Clinical data either allow confirmation of boundary conditions used during development or provide tangible data to guide iteration. Outcomes during the EFS phase also aid in designing a subsequent pivotal study. EFS are expected to incorporate risk mitigation strategies, monitoring, and informed consent that includes general and specific information for early feasibility studies.

A Pre-Submission to discuss strategy for an EFS can help ensure the EFS submission is complete and has the best chance of being approved in the first 30-day review as well as allowing FDA an opportunity to provide feedback on progressing toward an Investigational Device Exemption (IDE) pivotal study. Depending on the device and intended use, there may be flexibility in the level and timing of information necessary to support an EFS. In some cases, a leaner testing approach may be adequate to initiate an EFS depending on the potential benefits and risks associated with the device and indications, but that could mean that more comprehensive studies may still need to be completed later (e.g., in parallel with or prior to initiating the pivotal study). The sponsor can consider if a staged approach is more efficient or if it may be preferred to perform a more rigorous study to start with.

Medical devices are often continually modified over time. As a result, the EFS process provides for facilitated review and approval of device or procedure modifications during the study. A concept of “contingent approval” can allow FDA to be interactive and work with sponsors to incorporate iterative changes into the clinical environment more quickly. For example, this approach may allow a sponsor to implement a device design or manufacturing change without prior FDA approval and with additional data provided later in the process, provided FDA prospectively concurs with the evaluation methods and acceptance criteria. A “just in time” testing approach focuses on completing the right test at the right time, which may include deferring some testing until after the device design is finalized.

The EFS process also provides the opportunity to involve regulators earlier so they can gain experience with a device during the development phase. Ideally, this leads to reaching a consensus with sponsors about what data are needed to proceed through the clinical study phase, from a first-in-human experience to a larger feasibility study to a pivotal trial leading to FDA approval. These discussions typically involve long-term strategic planning supported by initial safety and effectiveness evidence supporting clinical use of the device, and can entail frequent interactions during the IDE review itself. These issues may be intimidating for less experienced device developers with academic backgrounds, and in addition to preliminary discussions with FDA it may be helpful to take advantage of industry-wide resources to facilitate these projects. For example, the Medical Device Innovation Consortium (MDIC) has an EFS initiative to achieve a 60/60/60 goal: FDA and IRB approval in the first 60 days, site contract executed in the next 60 days, and patient enrollment within the next 60 days. As of 2021, the approval and enrollment goals are close, but there remain challenges with site contracting and budgeting [ 17 ]. There are also efforts to begin engaging more directly with patient advocacy groups and industry trade organizations to encourage the use of EFS in more disease and device areas.

The EFS process has become increasingly popular, with a doubling of IDEs for EFS over the last 7 years. There are now more than 200 EFS IDEs approved with more than 2500 patients enrolled. As FDA has gained more experience, approximately 80% of EFS IDEs are now approved in the first review cycle. Future efforts include facilitating transitions from EFS to pivotal studies, working closer with the Centers for Medicare & Medicaid Services (CMS) on EFS coverage decisions, continuing to advance synergies between the EFS and Breakthrough Device programs, and enhancing collaboration with all stakeholders to drive sustainable growth in EFS.

EFS-type programs are also being considered outside the USA, for example, in Japan, through initiatives such as Harmonization By Doing [ 18 ]. Although Japan does not have a formal EFS program, there are opportunities to have consultations with the Japan Pharmaceuticals and Medical Devices Agency (PMDA) to discuss early phase clinical research opportunities. While the start-up culture is different in Japan compared to the USA, there are many opportunities for development of novel products through academic centers and openness within PMDA to discuss regulatory and clinical pathways for initiating clinical studies, particularly for clinical strategies that include a non-Japanese component.

Medical Device Development—Building a Productive Innovation Ecosystem Through De-risking

A primary step toward building a productive innovation ecosystem is to enable de-risking the product development process to the extent possible. This applies not just to product technical factors, but just as importantly to non-technical factors such as regulatory pathway, reimbursement, intellectual property coverage, and existence of an addressable market. Continuing funding challenges due to regulatory requirements and market uncertainties threaten to stall a product’s advancement from development to commercialization. Hence, regulatory de-risking is critical, and the regulatory path must be determined early; a great idea without a good regulatory path will not succeed. Additional de-risking from a payer perspective is also a necessity for long-term success.

De-risking can also enhance the likelihood of success for a start-up engaging with a large company; differences in culture, standards, expertise, and risk tolerance may be a source of friction in partnerships when risk is often shared. Often, there is not a high level of interest in acquisition until the product is near or at the end of development, e.g., in a pivotal trial or even ready to go to market. Higher risk may be acceptable for truly novel technologies that can clearly differentiate and be considered superior to products available on the market; the greater potential benefit allows for a greater potential risk.

Another important aspect of de-risking is having adequate supporting resources available such as innovation communities and a start-up environment infrastructure that includes maker space, office space, mentorship, and a venture studio model. As one example, the Indiana CTSI, including Purdue University, Indiana University, and the University of Notre Dame, has established Think Tanks to provide feedback and advice to academic innovators at various stages of drug and device development to help further de-risk the development process and drive advancements [ 19 ].

Pediatric Medical Devices

Recommended best practices for development of pediatric devices, case studies describing clinical and regulatory pathways to support pediatric indications, and FDA programs to promote and encourage development and marketing of pediatric devices are discussed in this section. Pediatric patients are defined in the Federal Food, Drug, and Cosmetic (FD&C) Act (Sect. 520(m)(6)(E)(i)) as persons aged 21 or younger at the time of their diagnosis or treatment; pediatric subpopulations for medical devices are neonates (from birth through the first 28 days of life), infants (29 days to less than 2 years), children (2 years to less than 12 years), and adolescents (aged 12 through 21, up to but not including the 22nd birthday). The development of a pediatric medical device from conception through regulatory approval can be considered through four key phases of development, namely (1) understanding the relationship between pediatric and adult pathology, (2) analysis, (3) iteration, and (4) testing. Details for each phase are provided in Table 1 .

Due to the small size of many pediatric disease populations, the Humanitarian Device Exemption (HDE) program is one regulatory pathway sometimes considered for pediatric devices as it requires that a device must exhibit safety and probable benefit, but is exempt from the effectiveness requirements of Sects. 514 and 515 of the FD&C Act, if certain criteria are met [ 20 ]. Table 2 provides a further comparison of the HDE, Premarket Approval (PMA), and De Novo Classification Request programs. As mentioned previously, there are limitations with the HDE Program such as restrictions on patient population size, need for IRB approval, and other requirements. However, the HDE Program also includes monitoring of the benefit-risk profile of an approved device in the post-market setting with additional requirements such as oversight by an IRB or appropriate local committee, and annual review of safety signals with FDA’s Pediatric Advisory Committee.

Leveraging or extrapolating adult data to support pediatric use may be a relevant strategy when the disease course or condition and the effects of the device are sufficiently similar in adults and pediatric patients, and the existing data are determined to be valid scientific evidence [ 22 ]. If there are different risks or adverse events expected for a pediatric population, FDA may request supplemental clinical data to support safety in the pediatric setting. Additionally, pediatric populations are heterogenous and comprised of numerous sub-populations with many factors to consider (e.g., differences in disease presentation, severity, and impact across different life stages) to appropriately leverage data from adults to pediatrics or from one pediatric sub-population to another.

The concept of pre- and post-market balance considers shifting some of the evidence requirements to the post-market phase to accept a greater degree of pre-market uncertainty if this uncertainty is sufficiently balanced by other factors, including the probable benefits of the device and the extent of post-market controls. In some cases, the probable benefit of having earlier access to a particular device outweighs the associated risks because there may be no alternatives available. Both pre-market and post-market studies should be properly designed to be small enough to complete, yet impactful enough to collect the necessary information to support approval and clinical use.

Cases studies described in Table 3 illustrate some of the points discussed above, particularly the potential for leveraging data from one patient population to another.

Three case studies of pediatric orthopedic devices highlighted the importance of flexibility in the development and review of pediatric devices and the different marketing pathways available in the USA. These cases and the lessons learned are described in Table 4 . One clear message is that it is important to maintain good communication with FDA throughout the device life cycle, from early development to post-market.

In some cases, FDA has encouraged companies to consider an HDE as a stepping stone while continuing to work toward a PMA or De Novo submission. As two examples, the Berlin Heart EXCOR® device and the Medtronic Melody™ Valve both started with small studies to support safety and probable benefit for an HDE. Additional studies were then designed with input from FDA and data collected via post-approval requirements and other data collection pathways to support safety and effectiveness for a PMA [ 23 , 24 ]. Similar efforts are underway in the orthopedic space. This more holistic milestone-based approach to establishing a reasonable assurance of safety and effectiveness can make these important devices available to patients sooner. In addition, there may be a more favorable reimbursement process for devices that continue down a more traditional regulatory pathway.

HDE devices require approval by an IRB or an appropriate local committee prior to use. This requirement is intended to provide additional oversight and ensure institutions are aware of what data are available since these devices, by definition, may not yet have established a reasonable assurance of effectiveness. One long-time IRB member shared that in their experience this function of the IRB does not add value and wondered if this HDE requirement should be eliminated as it may serve as a barrier to use of HDE devices. There has also often been confusion from the hospital side about the purpose and requirement of IRB oversight. The process can be particularly confusing for hospitals when there is also an FDA-mandated post-approval study required as a condition of HDE approval, resulting in separate IRB approvals—one simply to use the device and a second for the post-market clinical study. One option to consider is a central IRB rather than multiple local IRBs. Initiatives to further educate IRBs on HDEs and the purpose and process of their reviews could also be helpful. However, it was also noted that from a non-FDA perspective, the IRB review process for HDEs may not be fulfilling the original intent of the requirement and alternative approaches may be worth considering. The different stakeholders agreed this is an important issue and should be further examined, and could possibly be discussed as part of the next Medical Device User Fee Amendments (MDUFA) reauthorization process.

How to best leverage existing partnerships to generate innovation related to pediatric devices is an important consideration. Within Indiana there is a recent alliance focused on pediatrics between the Weldon School of Biomedical Engineering at Purdue, Riley Hospital for Children, and Cook Medical to leverage complementary expertise and build synergies. Also, the IU School of Medicine in collaboration with Purdue Biomedical Engineering has a robust MD/PhD program that is a strong resource to develop pediatric devices. In early medical school training, a student can identify a clinical need in collaboration with Riley, start working at Purdue on a technical solution during their PhD, and then continue collaborating with Cook to help mature the technology and consider what clinical data are necessary while completing their MD. Keeping momentum going and building on different expertise throughout the process will be important. A similar program is in place at the University of Minnesota as part of a local pediatric consortium and Earl Bakken fellows program [ 25 ]. A limited number of FDA-funded pediatric consortia also act as hubs located around pediatric medical centers of excellence to provide support and assistance for multiple pediatric device projects during all stages of development [ 26 ].

Incentives or mandates could be considered to help accelerate or encourage pediatric device development, similar to what occurs with drugs for pediatric use. However, one key difference out of many between drug and device development is that the active ingredient in a drug is the same for adults and children. On the device side, a total redesign may be needed for pediatric use, resulting in a very different device to treat adults compared to children, which would make any sort of mandate a difficult concept to consider. However, evaluating pediatric needs when starting to develop a device for adults remains a critical concept, and FDA encourages sponsors to consider this as part of a marketing submission. It is also important to remember there are multiple potential pathways by which clinical evidence can support a submission to FDA. Different programs and tools are available for pediatric drugs and devices and these should continue to be improved and better utilized to move the development of pediatric devices forward.

Diagnostic Devices, IVDs, and Disease Detection

Academic researchers and start-ups in the diagnostics space often have a lack of understanding around when and how to reach out to FDA. This was highlighted during the COVID-19 pandemic when numerous academic researchers and private start-ups with extremely limited regulatory background rapidly entered the diagnostics space. Good communication with FDA is key and there is no differentiation in FDA’s willingness to work with small start-ups, academics, or large companies. Some FDA communication pathways and programs applicable to all devices, not just diagnostics, include the following:

Q-submission Program that provides various mechanisms for interacting with FDA, including receiving feedback prior to an intended premarket submission

Breakthrough Devices program to help encourage and speed novel device development

FDA’s Division of Industry and Consumer Education (DICE) can provide technical and regulatory assistance, help answer questions, and provide direction, particularly for small businesses and academic and research organizations

In addition to considering when and how to communicate with FDA, it is also important to have regulatory scientists involved very early in diagnostics development to help guide the intended use and indications for use. The intended use should be clearly defined and can strongly influence the regulatory path and consequently the design and development of the test or device. This decision drives what analytical testing needs to be performed and what clinical testing should be considered. Understanding how the result or outcome from the test will be used clinically is also a key factor in determining the appropriate intended use. One theoretical example considers a carcinoembryonic antigen (CEA) test with a very general use “to measure CEA” compared to a more specific use “to measure CEA to monitor and aid in the diagnosis of a potential metastasis”; these two uses could lead to different regulatory paths and test requirements. While the general use would only require evidence of accurate CEA measurement, the specific use would require more extensive evidence to support that this measure can also be used for diagnosis; the diagnosis component could result in a higher classification due to increased risk around misdiagnosis.

Of particular importance to the diagnostics industry is that there be rigorous and scientifically sound data, testing, and documentation to support a technology. Additionally, manufacturability and scale-up can be vital considerations that are sometimes overlooked. For example, molecular assays to detect COVID-19 were developed in parallel to the manufacturing process rather than sequentially, resulting in numerous manufacturing challenges and increased risk that was necessary due to the time-critical situation.

Another industry challenge is the development and evaluation of novel diagnostic tests that do not have a clear predicate to successfully use the 510(k) process. In this case, a sponsor could consider a Pre-Submission to initiate conversation with FDA. The submission typically provides details of the device and how it will be validated, followed by specific questions to FDA about the proposed testing. Particular development steps will depend on the device, what it does, and how it can be validated, but in general it is helpful to include some way to compare to a reference standard, reference device, or reference test. FDA remains very open and willing to work with test developers on advancing novel technologies.

The integration of smartphones and similar devices into the performance, interpretation, or reporting of a diagnostic test is a topic of high interest. Understanding the regulation of these products can be challenging and specific examples or questions can be discussed with FDA to obtain feedback on the topic, if not identified in a final guidance document. One hypothetical example provided in Fig.  2 considers some of the decision points for an ancillary device or app that receives readings from a sensor; additional examples are included in FDA guidance [ 27 ].

Hypothetical regulation of ancillary device or app

COVID-19 has catalyzed changes in development, regulatory, and clinical activities related to diagnostic devices, and some of these changes may be carried forward beyond the pandemic. For example, there is increased demand for testing in non-traditional settings, such as self-testing at home, and continuing innovation in this space may result in low-priced over-the-counter test kits for in-home testing for various diseases far beyond just COVID-19. This will provide new opportunities for improving patient care and disease management and promoting health. While the compressed pace of test development from years to just months is not expected to become standard, there are opportunities to improve efficiencies and accelerate the traditionally slower pace of development. These include an increased awareness to be proactive, considering alternative approaches throughout the development process, and potentially accepting a higher level of risk tolerance during development such as performing steps concurrently rather than sequentially.

Increased access to FDA’s current thinking via guidance or Pre-Submission feedback has allowed industry to effectively develop new products and move products efficiently through the regulatory review process. Weekly open townhall meetings offered by the Office of In Vitro Diagnostics and Radiological Health to discuss COVID-19 test development have been valuable and there is consideration to continue offering some sort of similar forum on a regular basis (e.g., monthly). For new technologies that FDA realizes may be particularly important to public health, there is an effort to develop draft recommendations (e.g., rapid tests for COVID-19 diagnosis). Additionally, FDA submission templates for various technologies have helped clarify regulatory expectations, especially for new developers. FDA submission templates may continue to be developed, particularly for common technologies, to help democratize access.

Digital Health and Wearable Devices

The beginning of this section describes recent FDA initiatives involving digital health, shares recent FDA authorizations for digital health products including orthopedic products, and provides a look at the future of the digital health field. Digital health can be viewed as the convergence of connectivity, data, and computing power for healthcare and related uses across the life of an individual or a patient. Equally, digital technologies can help consumers make informed decisions, enable moving care from the traditional care setting such as a clinic to the patient, and facilitate better understanding of patient behavior and physiology to help prevent disease or change the course of disease via earlier and smaller interventions. FDA has expectations for different aspects of digital health technologies, including when used as a medical product, incorporated into a medical product, used to develop or study a medical product, and when used as a companion or adjunct to a medical product. FDA’s goal continues to be to enhance patients’ access to high-quality, safe, and effective digital health products; this should be accomplished in a least burdensome manner while continuing to provide a reasonable assurance of safety and effectiveness in a field with a rapidly evolving pace of development. Within the FDA Digital Health Center of Excellence, the goal is to empower digital health stakeholders to advance healthcare by fostering responsible and high-quality digital health innovation. This is a broader focus on responsible innovation, not just regulations, and includes connecting and building partnerships to accelerate digital health advancements and sharing knowledge to increase awareness and advance best practices, in addition to pursuing innovative regulatory approaches. There are a number of focus areas within the Center that span the total product lifecycle. In particular, interoperability and cybersecurity are becoming increasingly important to consider.

Consumer technology has continued to move into the medical area as technology used in day-to-day life becomes part of healthcare, leading to the development of novel and innovative products. We should understand and have appropriate expectations for bringing these products to market when they are used for preventing, mitigating, diagnosing, or curing disease. One initial factor to evaluate when considering FDA regulation of a digital health technology is the benefit and risk profile. This assessment can help determine how or if the product will be regulated. Recent products include electronics that provide augmented reality as well as novel therapeutic technologies. Looking ahead to coming products, technologies such as energy harvesting are being connected with sensors to provide a holistic real-time view of an individual’s physiology. Based on the evolution of these products, as a community of academia, government organizations, device manufacturers, small start-ups, regulatory affairs professionals, clinicians, patients, and the general public, we should think about how to prepare for a digital revolution in healthcare.

Digital health technologies undergo rapid development, iteration, and innovation compared to traditional medical devices, resulting in a potentially exponential increase in submission volume as a result. The current regulatory paradigm may not be fit for purpose in this space and a more holistic ongoing and continuous oversight approach that depends upon not just the product, but also the manufacturer/developer and how the product is performing in the marketplace, may be appropriate. At the core of this thinking are principles of patient safety, product quality, clinical responsibility, cybersecurity responsibility, and a proactive culture. A pre-certification concept of excellence appraisal, review pathway determination, streamlined pre-market review process, and real-world performance has been used to develop a working model with artificial intelligence (AI) and machine learning (ML) as a use case to test this program. FDA received many comments and published a plan in January 2021 for moving forward in a total product lifecycle approach rather than an episodic manner [ 28 ]. The plan includes many aspects specifically intended to facilitate the appropriate development of devices incorporating AI/ML, including the potential for a “pre-determined change control plan” that would permit iterative changes to device algorithms after marketing. The plan also calls for additional public engagement and partnerships with stakeholders in this space, as recently evidenced by the joint development and publication of guiding principles for Good Machine Learning Practices (GMLP) by regulators in the USA, Canada, and the UK [ 29 ].

In many cases, digital health products may already be outdated as soon as they are approved or cleared because of iterative changes that continue to be developed. The concept of having a pre-determined change control plan could allow a company to work with FDA on discussing how a product or algorithm may evolve over time and what guardrails should be in place to allow a more agile regulatory framework that will continue to allow these products on the market for patients while also continuing to provide a reasonable assurance of safety and effectiveness. Within FDA there are ongoing conversations across offices (e.g., Digital Health Center of Excellence, Office of Science and Engineering Labs, Offices of Health Technology) to develop best practices and ensure consistency in reviews and feedback.

The following case study provides an example industry experience bringing a digital technology to market. Many digital products started as consumer wellness products and have transitioned over time into medical products. In many cases, the claims or intended use for the product determines if it is a general wellness product or a medical device, e.g., measuring heart rate for exercise feedback vs. to detect bradycardia. This case study, described in Fig.  3 , reviewed the use of digital technologies to enhance the role of a stethoscope as a cardiac screening tool. As a result, algorithms to diagnose irregular heart sounds have been cleared through the 510(k) process and deployed via apps into the market [ 30 ]. The technology also enables remote examination and sharing of information with other healthcare providers.

Example of digital health technology to enhance patient care

Additional algorithms can be developed by leveraging the vast amount of information collected from digital devices. For example, low ejection fraction is currently measured and diagnosed by an echocardiogram and is undetectable by a traditional electrocardiogram (ECG). However, by analyzing a very large number of concurrent ECG and echocardiogram measurements, an algorithm can be built as a screening tool to allow a single lead ECG to predict who should undergo further testing for low ejection fraction [ 31 ]. This development of software as a medical device has received breakthrough designation with FDA to help bring the technology to market.

During clinical trials of digital health products, there are often questions around making and documenting changes to the technology being studied. Traditionally, the preferred approach in clinical trials has been to minimize any changes once a study has been initiated. However, this is not always possible for digital health; e.g., there may be software changes that occur over time. Starting with a risk-based assessment and considering the potential impact of a change on the study endpoints continues to be appropriate. Changes to critical aspects of a product, unless absolutely necessary, are not desirable, but changes that would not be expected to impact endpoints may be reasonable. Documentation is important to explain and justify how the change will be managed and/or why the change will not affect the results of the study.

An important consideration when developing new technologies of any sort, and in particular digital technologies and artificial intelligence that often interact directly with the patient, is how users and/or patients will interact with and benefit from the product. Industry should focus on identifying and meeting user needs and considering usability and value of the product to the user throughout the development process. As one example, considering how a product fits within the current workflow to make transition to the technology as seamless, intuitive, and user-friendly as possible is an important consideration for digital stethoscope technology. Involving users throughout product development can help achieve this objective. Continuing to engage and train physicians and patients on use of new technology is also important, and providing education around upcoming new developments in the digital health space will increase acceptance.

Having hands-on demonstrations and discussions of novel digital health technologies with FDA can also be very helpful. Bringing FDA experts together with product developers and end users may enable FDA to achieve a greater understanding of the technology and function of the device; how it fits in clinical practice, relevant patient-reported outcomes, and patient preferences; and what the benefits and risks may be when compared to only a paper-based review. This interactive process can lead to a more effective and efficient overall review process for a product, and the enhanced communication is beneficial for many novel products, not just those in digital health.

The Pressing Need for Enhanced Communication

Throughout this review, there is a consistent emphasis on the critical importance of communication with FDA. One initial barrier for many academics and small start-ups is simply knowing how and when to initiate contact. FDA encourages early communication through the Q-Submission process, both via Informational Meetings to start a general dialog with FDA regarding technology under development to ensure the technology is sufficiently well-understood, and via Pre-Submissions to obtain FDA feedback on specific regulatory and technical questions to guide device development and strategic planning. FDA feedback can also be obtained less formally via email, either from the relevant review team or from the Office of Communication and Education’s Division of Industry and Consumer Education regarding general questions about medical device regulation. Within digital health specifically, many questions relate to if a technology falls under FDA regulation or not and the Digital Health Center of Excellence will try to provide feedback if similar technologies have or have not been regulated. In some Pre-Submission discussions, FDA may be able to provide feedback regarding potential predicates for the 510(k) pathway or discuss the appropriateness of the De Novo pathway to market for a particular device. FDA has internal discussions across offices around new and upcoming technologies to help identify best practices and provide consistent and effective feedback to innovators. In emerging fields, there will be a need for FDA, industry, and innovators to learn together, and clear communication from all parties is necessary.

The question of how early to engage with FDA was also considered. While there remains variability in preferred approaches, some potential prerequisites to consider for a productive Pre-Submission discussion include understanding the device, the intended use, the patient population and clinical setting, and the relative benefits and risks, as well as having a basic strategy for evaluating the device. While some innovators may feel they are not ready for a full Pre-Submission early in the development stage, if a question is too complex for an informal email or query, it is important to consider that Pre-Submissions can be narrowly focused on a single topic.

For new start-ups and small companies in particular, there can be many unknowns around how and when to start interacting with FDA and, in some cases, a persistent fear of sharing information, especially information regarding early prototype failures. From FDA’s perspective, it is often helpful to understand the history of development of a device, such as understanding previous failures, iterations, and improvements, which demonstrate the robustness of risk assessment and the current design. Similar to device developers, FDA is excited and interested to see novel devices brought forward to help patients and there is no need to fear sharing information.

By the same token, FDA also recognizes the value in broader proactive communication with the medical device ecosystem to demystify the regulatory process and gain further insight into device evaluation and access considerations. For example, FDA regularly convenes public advisory committee meetings to gain external expert recommendations on how to address new questions of safety and effectiveness as they arise, either as part of specific file reviews or to more generally inform the device evaluation landscape in a given topic area. FDA also convenes workshops during which FDA along with other stakeholders can discuss potential best practices in a given technical area, and routinely participates in scientific and clinical symposia to maintain currency in these fields. This multifaced approach to engagement supports FDA’s mission to enhance the development of novel devices via collaboration and mutual learning.

In conclusion, collaboration and cooperation between clinicians, researchers, industry, and regulators is important for successful translation of laboratory and clinical observations and ideas into products and interventions that improve patient and public health. The criticality of good communication includes not only early and often communication with FDA, but also with patients, end-users, and other stakeholders. Numerous regulatory programs and processes are in place or being developed to help facilitate communication and translation of innovative products including the Pre-Submission, Breakthrough Devices, and Early Feasibility Study programs. Flexibility is an important consideration as evidence requirements may vary dependent upon technology, the benefit-risk ratio, and what is best for the patient. By sharing this review, we hope to highlight current strategies, opportunities, and best practices and thereby increase the regulatory knowledge base for all stakeholders as one step toward improving medical product translation.

Abbreviations

Artificial intelligence

Center for Devices and Radiological Health

Centers for Medicare & Medicaid Services

Clinical and Translational Science Institutes

Division of Industry and Consumer Education

Electrocardiogram

Early Feasibility Study

United States Food and Drug Administration

Harmonization By Doing

Humanitarian Device Exemption

Humanitarian Use Device

Investigational Device Exemption

International Medical Device Regulators Forum

International Society of Cardiovascular and Translational Research

In Vitro Diagnostics

Machine learning

Medical Device Innovation Consortium

Medical Device User Fee Amendments

National Evaluation System for health Technology

Office of Science and Engineering Laboratories

Pre-market approval

Pharmaceuticals and Medical Devices Agency

Real-world evidence

Safer Technologies Program

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Acknowledgements

Participants in the 2021 Indiana CTSI Virtual Retreat ( https://purdue.link/CTSI_Retreat_2021 ) contributed to the content of this article.

This article was prepared with support from the Indiana CTSI funded in part by Award Number UL1TR002529 from the National Institutes of Health (NIH), National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. This article reflects the views of the authors and should not be construed to represent FDA’s views or policies nor those of the NIH.

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Lottes, A.E., Cavanaugh, K.J., Chan, Y.YF. et al. Navigating the Regulatory Pathway for Medical Devices—a Conversation with the FDA, Clinicians, Researchers, and Industry Experts. J. of Cardiovasc. Trans. Res. 15 , 927–943 (2022). https://doi.org/10.1007/s12265-022-10232-1

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Case studies of innovative medical device companies from India: barriers and enablers to development

• Szymon Jarosławski 1 &
• Gayatri Saberwal 1  

BMC Health Services Research volume  13 , Article number:  199 ( 2013 ) Cite this article

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Over 75% of the medical devices used in India are imported. Often, they are costly and maladapted to low-resource settings. We have prepared case studies of six firms in Bangalore that could contribute to solving this problem. They have developed (or are developing) innovative health care products and therefore are pioneers in the Indian health care sector, better known for its reverse engineering skills. We have sought to understand what enablers and barriers they encountered.

Information for the case studies was collected through semi-structured interviews. Initially, over 40 stakeholders of the diagnostics sector in India were interviewed to understand the sector. However the focus here is on the six featured companies. Further information was obtained from company material and other published resources.

In all cases, product innovation has been enabled by close interaction with local medical practitioners, links to global science and technology and global regulatory requirements. The major challenges were the lack of guidance on product specifications from the national regulatory agency, paucity of institutionalized health care payers and lack of transparency and formalized Health Technology Assessment in coverage decision-making. The absence of national evidence-based guidelines and of compulsory continuous education for medical practitioners were key obstacles in accessing the poorly regulated and fragmented private market.

Conclusions

Innovative Indian companies would benefit from a strengthened capacity and interdisciplinary work culture of the national device regulatory body, institutionalized health care payers and medical councils and associations. Continuous medical education and national medical guidelines for medical practitioners would facilitate market access for innovative products.

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In the case of drugs, due to its strong reverse engineering skills, India is virtually self-sufficient. In contrast, 75% of the annual purchase of devices and diagnostics comes from imports [ 1 ]. A WHO report on medical devices pointed out that: “almost all devices present in developing countries have been designed for use in industrialized countries” [ 2 ]. Consequently, they are often unaffordable and are maladapted to low resource settings.

Whereas rural health care providers are a documented source of grassroots technical innovation on a micro scale [ 3 ] the private industry world-wide has valuable expertise in the development of medical devices for mass use [ 2 ]. However, the industry has traditionally perceived that developing-world markets are too small to justify the development of new products [ 2 , 4 ]. Thus, over the past decade, a number of push and pull incentives have been proposed by international public health organizations, non-governmental organizations (NGOs) and donors in order to incentivize the western industry to undertake research and development (R&D) addressing the specific needs of the developing world [ 4 , 5 ], although market access challenges of this industry in such markets have been well-documented [ 6 ]. More recent is health technology innovation, largely by young companies located in developing countries, where the companies perceive local markets as the main focus of their R&D strategy [ 7 , 8 ].

Important to health technology innovation is Health Technology Assessment (HTA), defined as the “systematic evaluation of the properties and effects of a health technology, addressing the direct and intended effects of this technology, as well as its indirect and unintended consequences, and aimed mainly at informing decision making regarding health technologies” ( http://htaglossary.net ). In industrialized countries, there is a growing interest in interactions among bodies concerned with HTA, coverage (institutional purchasing or reimbursement), and regulation with whom the industry needs to engage in order to develop novel products that can reach patients [ 9 ]. Improving such interactions is believed “to speed patient access to valuable products” and “to remove unnecessary barriers to successful development and appropriate market access for innovative products” [ 9 ].

In contrast, India doesn’t have a formalized national HTA process and the public financing of new technologies is very limited [ 10 ]. Whereas 60-80% of health care is delivered in the private sector, only 3-5% of the population has health insurance [ 11 ] so coverage decisions by insurers have negligible impact on the market uptake. Further, medical practitioners in the private sector are not obliged to follow any official evidence-based guidelines, and continuous medical education is not mandatory [ 12 – 14 ]. Finally, the regulation of medical devices is minimal: in the case of in-vitro tests, only those for HIV, hepatitis B and C and blood typing are considered 'critical’ by the Indian regulator and only these tests must be clinically validated before receiving a license. In this context, our study aimed to provide qualitative insights into the frugal innovation experience of companies that function in an environment that doesn’t have a tradition of indigenous novel bio-medical product development.

Here we present case studies of six private companies in Bangalore, India, that have developed and launched (four cases) or are expecting to soon launch (two cases) devices for the Indian market. These firms belong to a new wave of intellectual property (IP)-based product ventures in the country. We study (i) the evolution of the firms and their approaches to product development; (ii) their funding and human resource challenges; (iii) their access to global science and technology (S&T); (iv) their use of global regulatory requirements, and finally (v) the market challenges that must be overcome in order to access patients with their products. We believe that insights from this study will be of interest to many young companies, regulators and policy makers in the world.

We adopted a qualitative case study research methodology that has been used by others to study medical innovation in developing countries [ 8 , 15 – 17 ]. The innovative medical device industry in India is only emerging today and a quantitative study would not be feasible with such a small sample size. Further, as explained below, the firms have gone through very different paths since their inception and the case study methodology is better suited to capture this heterogeneity. The study protocol was approved by the Ethics Committee of IBAB. Written informed consent was obtained from participants by asking them to positively reply to an interview invitation e-mail. Initially more than 40 private and government doctors, diagnostic labs, manufacturers and distributors of diagnostic tests, NGOs and academics were interviewed about the diagnostics’ business in India. The interviews concerned local innovation versus imported products, delivery of devices to patients in public and government sectors, regulatory issues and doctors’ prescription behaviour. Informants were chosen by purposeful sampling and were chiefly located in metropolitan cities although their experience extended to rural areas as well. Results of these interviews are not presented here, but served to select the six companies located in Bangalore that were the basis for this study. Additionally, the following sources were used: the BioSpectrum India Life Sciences Resource Guide 2010 which is one of the most comprehensive repositories of information on the Indian life science industry ( http://www.newindigo.eu/biotech/main/index.htm ) and a published review of the Indian biotech industry [ 18 ]. Since none of the firms had achieved significant sales at the time of our research, financial measures such as profit, volumes or return on investment could not be used as criteria for selection. Nor were details of debt or equity available for the (largely) privately held companies. We selected medical device firms located in Bangalore, arguably the most innovative biomedical hub in India, that were developing innovative, IP-based products for the Indian market, and low-resource settings in particular. Finally, in the one situation where two companies with similar profiles were identified (that is, inception or origin, type of product and development path) the company that was further in the product development process was chosen. The company-specific interviews sought to understand the inception of the firm and the origin of the key personnel; the path of product development and target product profiles; sources of funding; issues related to clinical validation; regulatory approval and market access in private and government settings. Interviews were not recorded but detailed notes were made during and immediately after each interview. The analysis presented here is based on multiple interviews with the founders of five of the companies. In the case of GE Healthcare India (GEH) the informant was the senior product manager who led the development of MAC400 and MACi. Consequently, the perspective of his own R&D centre may not fully reflect the history of General Electric (GE) in India. In each case there was one interview at the company, followed by a few more conversations in person, by phone or by e-mail. Further information was obtained from company material and other published interviews of the founders. After all the interviews, the write up on each of the six companies was verified by the concerned firm. However the final manuscript was not submitted to them for their verification. All interviews were semi-structured and were conducted between March and December 2011, inclusive.

The companies and their products

The firms profiled are XCyton Diagnostics (XCyton), Bigtec Labs (Bigtec), GEH, ReaMetrix India (ReaMetrix), Embrace Global (Embrace) and Achira Labs (Achira). The companies were founded from 2 to 18 years ago (Table  1 ). Interestingly the founders of these six firms came from six of the nine categories of biotech founders in India, identified previously [ 18 ]. The earlier study had pointed out a low rate of company formation by local academics, and that is reflected here, where none is a scientist from local academia (Additional file 1 ). In terms of the companies’ evolution GEH started as a manufacturing support unit of GE Healthcare Worldwide's Indian manufacturing facility and then evolved into an R&D centre. The remaining ventures started as R&D firms and this has remained unchanged (Additional file 2 ). Most of the firms were able to take their products from concept to clinical validation in two to three years. The exception was Bigtec where the founders operated in a field that was unfamiliar to them, and where – when the product launches later this year – it will have taken 12 years from the firm’s founding.

Each firm wanted its products to be appropriate for use in low-resource settings which constitute the bulk of the Indian market both in volume and in overall value. Thus, each company undertook an independent assessment of the needs of health-care providers in such settings. It went on to construct product profiles according to its own market- and consumer-research without guidance from national health-care payers or regulators. Low-cost was therefore a common criterion, although other specifications varied with the company (Additional file 3 ). Each firm’s route to its product(s) is outlined below.

XCyton develops diagnostic kits for infectious diseases. It has relied on (i) an invention sourced from the local R&D centre of a multinational company (MNC) (one case), or (ii) science sourced from or products developed in collaboration with Indian public or private research institutions (11 cases). These scientific collaborations were enabled by the personal contacts and informal links of the founder to local scientists. They were unofficial collaborations with low administrative burden and great flexibility in negotiation. Initially, XCyton developed ELISA-based kits (CheX) which require a generic reader but are relatively easy to perform even by untrained manpower. Later, the company developed polymerase chain reaction (PCR)-based kits (XCyto Screen) which call for skilled staff and dedicated laboratory facilities. This shift from rapid kits to high-resource technology was partially motivated by fading confidence in the public health-care market.

ReaMetrix started out as a contract research organization (CRO) offering services to Western clients. This led to a gradual build up of its capabilities and capacity. Subsequently the firm changed track and developed a proprietary dried reagent tailored to the needs of the National AIDS Control Organization (NACO) program which covers approximately 50% of the patients on anti-retroviral treatment in India. This reagent is used for a flow-cytometer-based test which monitors the patient’s absolute CD4+ and CD8+ T-cell counts and can replace a more expensive product supplied to NACO by an MNC. Also, it (i) removes the necessity of both cold-chain distribution (storage and transport) and on-bench refrigeration and (ii) reduces the possibility of procedural errors by supplying the pre-weighed reagent in ready-to-use disposable tubes. The company went on to develop a cheaper, simpler and more robust fluorescence reader that can replace the flow-cytometer that was supplied to NACO by the MNC. The company estimates that the currently used instrument costs $20,000–90,000 and it is willing to offer its reader at $15,000–20,000. In resource-limited settings it would offer a reagent rental scheme wherein the cost of ownership of the machine is zero. However, disappointed with the government market, the company is considering re-inventing itself yet again to build advanced R&D instruments for Western markets.

Initially Bigtec worked on a recombinant insulin for the Indian market. Subsequently it shifted to an innovative PCR-based microfluidics platform for the detection of infectious diseases specific to India. Notably, the founders were not microfluidics’ specialists. They were nevertheless attracted to this technology because it offers the automation and short sample processing times necessary in point-of-care settings. The diagnostic device allows sample preparation and mixing, bio-chemical reactions and sample screening and detection to be performed on a single chip. The diagnosis takes 45 minutes rather than several hours, and can be performed in harsh environmental conditions by an untrained person. The technology has been clinically validated for several diseases. Bigtec is planning to price the device below the cost of a real-time PCR machine. The cost of running a test would be similar to that with a currently available in-vitro diagnostic (IVD) kit for the concerned infection.

GEH started as a low cost, off-shored manufacturing unit of the mother MNC. Subsequently, it developed the MAC400 electrocardiogram (ECG) device for emerging markets by removing some features from an existing GE model. It was the first product released for the Brazil, Russia, India and China (BRIC) markets and was priced at $800, compared with GE’s other hospital-class ECG units that had a price tag between $2,000 and $10,000. However, the development of the next ECG device, MACi, was specific to the Indian market. The needs of rural health-care practitioners were surveyed by engineers from several Indian states. This was felt to be a necessity in a country with a multitude of local languages, a range of geographies and wide disparities in income-levels. It featured a fast-charging, long-life battery and was robust and portable. Also, the company realized that the poorly-regulated local market was dominated by very low-cost ECG machines, which was rather unique among BRIC countries. MACi was therefore priced at $500. It was released on the market just one year after product conceptualization. The emergence of GEH as an innovative product development centre capable of the entire design, development and manufacturing of a product was enabled by two key factors: extensive supervision and deliberate technology transfer from GE R&D units located in Germany and the US, as well as the initiative and corporate advocacy of a team at GEH for the development of a product tailored to the Indian market.

Embrace was set up to develop and commercialize a portable and safe warmer for low-birth infants. Although initially based in the US, it relocated to India, where the core R&D team made field trips to rural and urban settings in order to consult with potential end-users. One version of the warmer has been developed for use in hospitals and clinics. In the former setting it facilitates the inter-ward transfers of infants which might take up to 40 minutes. It is available for less than $300 compared to $580–$1900 for currently used radiant warmers. Another version is being developed for use at home and in rural settings. In all settings, Embrace’s warmers would replace potentially dangerous electric radiators which can accidentally catch fire.

Achira was set-up to capitalize on the founder’s academic expertise in microfluidics. Although it started out intending to provide such services to large global pharmaceutical companies, it soon shifted focus to developing a lab-on-chip platform for low-resource health-care providers in India. Achira is developing two immunoassay-based platforms: (i) microfluidic chips with a dedicated fluorescence reader for quantitative assays and (ii) device-free silk fibre-based chips for qualitative assays, which can be read by the naked eye. The former technology generates results in less than 30 minutes and can be used with minimal technical training. It has been internally validated by the company and external validation is planned. The latter technology is currently being optimized. It is superior to the currently available lateral-flow technology because multiple types of tests can be performed on a single chip. Its large-scale manufacture requires only low-cost physical infrastructure and therefore it will be sold at a lower price than the first platform.

In order to protect their inventions, all the firms filed patents, in India and in other countries. There was a general tendency to first file the applications in India and then in the US and Europe. However, we formed the impression that the young companies did not have an established IP policy.

Human resources

The Indian medical industry has traditionally been based on reverse-engineering, and therefore many skills required for the development of entirely novel products are rare in the country today [ 19 ]. Consequently the companies faced a few challenges related to the recruitment and retention of appropriately skilled personnel. (i) Indians returning from Western nations, with postgraduate academic degrees or industry experience, played an important role in most of the firms (Additional file 1 ). The process has been accelerated by both the recent economic growth in urban India and the economic stagnation of Western economies. (ii) All the firms have found that neither candidates with experience in the local pharmaceutical industry nor graduates of local academic institutions have the right skill sets to work on the design and marketing of innovative products. Whereas senior scientific staff in the companies are able to train new employees in technical skills, finding experienced candidates for market access activities has been a key challenge. (iii) XCyton and Achira, which employ Indian biologists with postgraduate experience, have found that there are cultural issues related to retaining their staff for long periods. As elsewhere, many biologists in India are women, and there is high attrition due to the relocation of those who follow their spouses to other cities. This churn has serious costs for young firms, in terms of both time and money.

Funding of the companies

The studied companies managed to engage with both local and international investors to fund their R&D programs, without having to forgo majority equity. It turns out that half of the firms were primarily funded from Indian sources and the other half from foreign ones, as detailed below (more details in Additional file 4 ).

Primarily Indian sources

Among the indigenous start-ups, XCyton and Bigtec benefitted from soft loans and small grants for young R&D firms from the Government of India, and this funding was vital. Both companies have had difficulty finding investors who would be willing to fund marketing and distribution activities without taking a majority share. They perceive such offers as unfair since their products have already been clinically validated and therefore the investment would carry relatively low risk. However, XCyton has very recently obtained an equity investment from a US-based entity which will be used mainly for marketing its XCyto Screen services and also to establish new laboratories across the country. Interestingly, this forced the company to discontinue the two approved CheX tests (for HIV and hepatitis C). This was necessary to avoid being classified as a pharmaceutical company under Indian law and it enabled XCyton to finalize the foreign investment deal without government pre-approval.

Primarily Western sources

In contrast to the cases above, ReaMetrix was almost entirely dependent on the private money of the founder who has been a serial entrepreneur in the US, and on international private investors. Although GEH is a division of a global corporation, funds for the development of an ECG for the local market were not granted automatically. After the India-based team of engineers took the initiative, their ideas received financial support first from global headquarters and later from a locally created budget. Finally, Embrace was established as a social enterprise and was funded by US-based donors. The founders are now planning to split the enterprise into a non-profit and a for-profit entity, the latter in order to secure the substantial international investment necessary to enable large-scale manufacturing and global marketing.

Overall, the firms’ major struggle was in raising substantial funds for marketing as well as scaling-up manufacture. Apart from Bigtec which formed a product marketing joint-venture with a major Indian diagnostics manufacturer, the companies needed to rely on foreign investment to finance such activities. Some of the firms fear that an investment by an MNC would result in a loss of control of the pricing strategy, and force them to price their products higher than they would wish even in low-resource settings.

Globalization of science and technology

Overall, the companies value being located in India. It has allowed them to organize frequent field surveys, construct meaningful product specifications and experiment with market access strategies, all with respect to low resource settings. Notably, however, each firm's ability to develop such appropriate technologies was enabled by the founders’ or other key persons’ experience in Western academia or industry (Table  2 and Additional file 1 ). Contact with global S&T occurred in the local divisions of MNCs (XCyton and GEH) or through returning Indians (the other firms). Also, for some of the firms, pre-existing international links were instrumental in accessing Western clients and/or funding sources, which were essential in the early days (Table  2 ). Since the availability of manufacturers and suppliers of advanced services and components in India is limited, this posed a challenge to several of the companies. Being a division of an MNC, GEH has an international network of accredited providers which facilitated sourcing of specific components. However other companies had to establish partnerships with industry located in Europe or the US. These were often initiated during global charity or industry meetings or through international academic collaborations (Additional file 5 ). Thus, medical technology innovation in a developing country can require outsourcing to the West due to the lack of local facilities or expertise.

Experience with international regulatory authorities

The companies’ international reach concerns not only S&T but also regulatory approval for their products. This is mainly because the regulation of medical devices in India is rudimentary. Further, the regulatory body is not accustomed to licensing innovative products that have not been approved in a developed country. Some firms were dissatisfied with the limited regulation in the country primarily for two reasons: (a) the lack of dialogue and guidance on what specifications a product should meet and (b) unfair competition from manufacturers offering sub-standard and cheaper versions of their innovative products.

In the absence of local regulation, the companies pursued WHO pre-qualification, US Food and Drug Administration (FDA) approval or the CE mark (Additional file 4 ). It was considered necessary to engage with foreign regulatory agencies not only for their guidance and to distinguish the companies’ innovative products from substandard ones, but also for accessing global markets, including those of low-income countries. Surprisingly, as exemplified by the struggle of XCyton, even WHO pre-qualification involves mobilizing significant resources. Thus, whereas the company’s HIV CheX test was compliant with WHO guidelines, pre-qualification came only after a two-year effort to attract the attention of the relevant officer who was based in Geneva. Notably, this contract gave XCyton global visibility. Subsequently, international organizations have helped the firm obtain accreditation abroad for other tests.

The firms have also pursued international certifications due to the high uncertainty related to the Indian public market, that is discussed further below. The companies that have tried to sell to the Indian government have failed to do so. Therefore, the companies have accessed, or have considered accessing, the local market via funding from foreign donor organizations. For this, international accreditation of their products would be required.

Accessing the market

Health-care providers in India range from high-end private hospitals manned by highly qualified personnel and equipped with the latest technologies, to public and private rural health-care centres lacking trained staff and with serious shortcomings in basic facilities such as the availability of uninterrupted power and water. This has large implications for the product planning process since there is significant uncertainty regarding the kind of end users and their sample throughput needs, as well as the target price range. The companies’ perception is that whereas high-end settings require high throughput capacity of an instrument and national or international accreditation, other settings primarily require (i) low capital investment and maintenance costs, (ii) low costs to the patient, (iii) resistance to adverse operating conditions and (iv) the equipment should be explicitly designed to facilitate task shifting to lower cadres of workers. Consequently, the companies have found that reaching such complex markets requires more time than product R&D. Notably, the experience of GEH in marketing to high-resource settings in India proved insufficient to access low-resource settings with the MACi. Thus, for the Indian market, the key obstacles to reaching the customer have been: (a) an underfunded and non-transparent government health-care market and (b) a highly fragmented and poorly regulated for-profit private market. In the case of diagnostics, soaring competition among diagnostic labs has increased the occurrence of referral fees that are paid to doctors on a per patient basis. It is also complex and costly to access African countries, even via the WHO purchasing process. XCyton and Embrace said that the largest funding rounds in their existence would be used in large part for marketing and distribution. These obstacles are discussed in Additional file 6 .

Five of the six companies discussed here took their products from concept to validation in two to three years. This compares well to the average product lifecycle of 18–24 months estimated by Eucomed, the medical technology industry body in Europe ( http://www.eucomed.org ). However, the availability of both funding and the human resources necessary to access the market with finished products has been one of the major impediments to the companies. Whereas advanced technological knowledge could be accessed via links to global academic and industry communities, the lack of local regulatory guidance posed a major challenge for product development. Although FDA, CE and WHO certifications are an alternative, the interviewed companies assert that the high cost of such procedures and/or distant location of these agencies are serious obstacles and result in delays. Whereas there is scarcity of literature on the innovative health care industry in India, some of these issues have been reported previously [ 17 , 20 ]. Further, the paucity of institutional health care payers, the fragmentation of private health-care providers and the lack of national consensus guidelines meant that the companies had to use their own resources to educate the doctors and laboratories about their technologies. Notably, the for-profit nature of the private sector demands that when pricing their products, firms must consider both the affordability for the patient and the provider’s desire to generate profits from the provision of a technology [ 12 , 21 – 23 ]. This market complexity implies that the commercial success and survival of such companies will depend on their ability to develop ground-breaking strategies in the post-R&D phase also.

We believe that the future of India’s innovative biomedical industry will depend on the upgradation of several national policies. Whereas this study was not designed to inform such policies, and tools such as stakeholder analysis are better suited for this purpose than the case study method adopted here, we would like to make three recommendations for the development of an innovative medical device sector in India: First, the national regulatory bodies need to offer guidance to industry about product development as the FDA, European Medicines Agency and WHO do. Currently, the scientific capabilities of the relevant agencies are inadequate to do this. Second, government procurement of innovative devices needs to be increased. Also, the process to do so should be made more transparent through the incorporation of explicit evidence-based decision making. The UK’s National Institute for Health and Clinical Excellence and similar government agencies in many other European and some Asian countries, such as Japan, Singapore and Malaysia, appraise medical technologies and advise on their financing from public sources. Third, the private healthcare sector requires more regulation. This implies tackling the issue of referral fees and the production of national guidelines for diagnosis and treatment. In many countries that have nationalised health systems this is achieved through close collaboration between the HTA bodies, medical councils that control doctors’ practice and the national health funds or insurers that directly employ most health care professionals. However, it remains to be seen whether such centralized control can or should be achieved in a large and diverse country such as India, that has a health care sector that is highly fragmented and largely private.

Abbreviations

Achira labs

Bigtec labs

Brazil Russia, India and China

Contract research organization

Electrocardiogram device

Embrace global

General electric

GE Healthcare India

Health technology assessment

In-vitro diagnostic

Multinational company

National AIDS Control Organization

Non-governmental organization

Polymerase chain reaction

ReaMetrix India

Science and technology

XCyton Diagnostics

Intellectual property

Research and development.

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Acknowledgements

We are grateful to all the interviewees from the studied companies who generously contributed their time. We are also very grateful to the Institut Merieux (IM), Lyon, which funded this study as part of support to several of GS’s projects. SJ is supported financially by France Volontaires, Ivry-sur-Seine.

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GS’s research is funded by Institut Merieux (IM) which has financial interests in the medical technology industry. However IM did not play any role in designing this study, or in any other aspect related to it other than general funding, as indicated below.

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GS proposed the study. SJ performed and analysed the interviews. SJ and GS wrote the manuscript. Both authors read and approved the final manuscript.

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Additional file 1: detailed profiles and origins of the founders and key people in the studied companies.(doc 38 kb), additional file 2: key events in the evolution of each company and sources of innovation.(doc 34 kb), 12913_2012_2626_moesm3_esm.doc.

Additional file 3: Key criteria considered by the companies when constructing product profiles for their devices and other issues of product development.(DOC 36 KB)

Additional file 4: Sources of funding for the studied companies.(DOC 33 KB)

12913_2012_2626_moesm5_esm.doc.

Additional file 5: Details of the six companies’ pursuit of global (i) science and technology and (ii) regulatory requirements.(DOC 34 KB)

12913_2012_2626_MOESM6_ESM.doc

Additional file 6: Challenges faced by each company in accessing the Government and private markets in India or other developing countries.(DOC 36 KB)

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Jarosławski, S., Saberwal, G. Case studies of innovative medical device companies from India: barriers and enablers to development. BMC Health Serv Res 13 , 199 (2013). https://doi.org/10.1186/1472-6963-13-199

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Telehealth and Mobile Health: Case Study for Understanding and Anticipating Emerging Science and Technology

Introduction

This case study was developed as one of a set of three studies, focusing on somewhat mature but rapidly evolving technologies. These case studies are intended to draw out lessons for the development of a cross-sectoral governance framework for emerging technologies in health and medicine. The focus of the case studies is the governance ecosystem in the United States, though where appropriate, the international landscape is included to provide context. Each of these case studies:

• describes how governance of the technology has developed within and across sectors and how it has succeeded, created challenges, or fallen down;
• outlines ethical, legal, and social issues that arise within and across sectors;
• considers a multitude of factors (market incentives, intellectual property, etc.) that shape the evolution of emerging technologies; and
• identifies key stakeholders.

Each case study begins with two short vignettes designed to highlight and make concrete a subset of the ethical issues raised by the case (see Box 1 and Box 2 ). These vignettes are not intended to be comprehensive but rather to provide a sense of the kinds of ethical issues being raised today by the technology in question.

The cases are structured by a set of guiding questions, outlined subsequently. These questions are followed by the historical context for the case to allow for clearer understanding of the trajectory and impact of the technology over time, and the current status (status quo) of the technology. The bulk of the case consists of a cross-sectoral analysis organized according to the following sectors: academia, health care/nonprofit, government, private sector, and volunteer/consumer. Of note, no system of dividing up the world will be perfect—there will inevitably be overlap and imperfect fits. For example, “government” could be broken into many categories, including international, national, tribal, sovereign, regional, state, city, civilian, or military. The sectoral analysis is further organized into the following domains: science and technology, governance and enforcement, affordability and reimbursement, private companies, and social and ethical considerations. Following the cross-sectoral analysis is a broad, nonsectoral list of additional questions regarding the ethical and societal implications raised by the technology.

The next section of the case is designed to broaden the lens beyond the history and current status of the technology at the center of the case. The “Beyond” section highlights additional technologies in the broad area the focal technology occupies (e.g., neurotechnology), as well as facilitating technologies that can expand the capacity or reach of the focal technology. The “Visioning” section is designed to stretch the imagination to envision the future development of the technology (and society), highlighting potential hopes and fears for one possible evolutionary trajectory that a governance framework should take into account.

Finally, lessons learned from the case are identified—including both the core case and the visioning exercise. These lessons will be used, along with the cases themselves, to help inform the development of a cross-sectoral governance framework, intended to be shaped and guided by a set of overarching principles. This governance framework will be created by a committee of the National Academies of Sciences, Engineering, and Medicine (https://www.nationalacademies.org/our-work/creating-a-framework-for-emerging-science-technology-and-innovation-in-health-and-medicine).

Case Study: Telehealth

As far back as the Civil War, the United States has used electronic means (in this early example, telegraphs) to communicate patient health information. After a long, slow ramp-up, there has been steady evolution and growth in electronic health data and communication since 1990, pulled by advances in technology and pushed by changes in regulation.

Prior to the COVID-19 pandemic, which began in March 2020, three broad trends were under way in the evolution of telehealth: first, a shift in application from efforts to expand health care access that motivated early use to the use of telehealth to control costs; second, the expansion of telehealth use from the context of acute care to the management of chronic conditions; and third, a transition of the site of care from health care institutions to patients’ homes and mobile devices (Dorsey and Topol, 2016). The recent exponential increase in mobile health applications and physical distancing requirements that accompanied the pandemic have dramatically accelerated the evolution and adoption of telehealth (Olla and Shimskey, 2014).

It is important to note that “telehealth” and “mobile health (mHealth)” do not have consensus definitions, nor do many other terms used in this space, such as “electronic health (eHealth),” “telemedicine,” and “digital health” (HealthIT.gov, 2019; Doarn et al., 2014; WHO, 2010). From a regulatory perspective, definitions are important because countries and states must describe what they do and do not regulate and how (Hashiguchi, 2020). In the United States, telehealth is generally the umbrella term covering telemedicine (defined as provider-based medical care at a distance); telemedicine within medical specialties such as telepsychiatry, telestroke, and teledermatology; and mHealth (initially used to describe care provision through text messaging, but now includes the use of wearable and ambient sensors, mobile apps, social media, and location-tracking technology in service of health and wellness) (APAa, 2020; Sim, 2019; CMS, 2011).

One widely used definition of telemedicine—the component of telehealth with the longest history—is from the World Health Organization (WHO), which defines it as, “The delivery of health care services, where distance is a critical factor, by all health care professionals using information and communication technologies for the exchange of valid information for diagnosis, treatment and prevention of disease and injuries, research and evaluation, and for the continuing education of health care providers, all in the interest of advancing the health of individuals and their communities” (WHO, 2010).

In Norway, an early adopter and regulator of telemedicine, “telemedicine” is defined by law as “the use of videoconferencing to perform an outpatient consultation, examination, or treatment at a distance” (Zanaboni et al., 2014). In South Africa, by contrast, telemedicine is defined not by statute but by the Health Professions Council of South Africa as “using electronic communications, information technology or other electronic means between a health care practitioner in one location and a health care practitioner in another location for the purpose of facilitating, improving and enhancing clinical, educational and scientific health care and research” (HPCSA, 2020).

Telehealth can include everything from medical websites (e.g., the Mayo Clinic, WebMD) to remotely controlled surgical robots. Telehealth can also be categorized into groups of technologies, including interactive telemedicine (including video visits and electronic consults between providers), telemonitoring, store-and-forward technology (the collection and use of non-urgent medical information), and mHealth.

Early applications of telehealth were designed to expand access, and in fact, telehealth has been critical (if not entirely successful) in this regard. There are, of course, long-standing and persistent concerns about the number and geographic distribution of health care providers, and telehealth has improved access to those in remote and historically underserved populations in states such as Alaska and Texas, as well as for those in the military (e.g., those at sea or in a combat zone), prisons, and astronauts (NRHA, n.d.). Telehealth has also expanded access to language interpreters and specialists for patients with rare disease.

Telehealth, as it is traditionally construed, offers significant benefits, but it also raises a number of concerns. These concerns pertain to the use of telehealth in and of itself and the ways in which availability has been exponentially and almost instantaneously expanded in response to the COVID-19 pandemic and in recent years by mHealth. One broad issue, at least in the United States prior to the COVID-19 pandemic, is the shift mentioned previously from a focus on the use of telehealth to expand access to health care to the use of this technology to cut health care costs (Dorsey and Topol, 2016). In addition, and despite the dramatic expansion in telehealth, many of those most in need remain without access to high-quality health care (Park et al., 2018). On the individual level, telehealth raises concerns not only about privacy, both due to the site of care and the transmission, storage, and sharing of data, but also about both concrete and intangible losses related to physical distancing from the care relationship and ‘the healing touch’ (Bauer, 2001).

Guiding Questions

(derived from global neuroethics summit delegates, 2018; mathews, 2017).

The following guiding questions were used to frame and develop this case study.

• Historical context: What are the key scientific antecedents and ethics touchstones?
• Status quo: What are the key questions, research areas, and products/applications today?
• Cross-sectoral footprint: Which individuals, groups, and institutions have an interest or role in emerging biomedical technology?
• Ethical and societal implications: What is morally at stake? What are the sources of ethical controversy? Does this technology or application raise different and unique equity concerns?

Additional guiding questions to consider include the following:

• Key assumptions around technology: What are the key assumptions of both the scientists around the technology and the other stakeholders that may impede communication and understanding or illuminate attitudes?
• International context and relevant international comparisons: How are the technology and associated ethics and governance landscape evolving internationally?
• Legal and regulatory landscape: What are the laws and policies that currently apply, and what are the holes or challenges in current oversight?
• Social goals of the research: What are the goals that are oriented toward improving the human condition? Are there other goals?

Historical Context

What are the key scientific antecedents and ethics touchstones.

Despite its association for most people with the last decade or even just with the COVID-19 pandemic, telehealth was first employed in the United States more than 100 years ago—one of the first health-related telephone calls was described in 1874 (Nesbitt and Katz-Bell, 2018). In 1905, the first “telecardiogram” was recorded and sent by telephone wire from a laboratory to a hospital (IOM, 2012). By the 1920s, Norwegian providers began giving medical advice to clinics on ships over radio, a use that quickly spread to other parts of the world (Ryu, 2010).

Over time, technology and applications expanded to include transmission of images and video. Teleradiology has been used for more than 60 years in the United States, with some of the first radiologic images transmitted by telephone between West Chester, Pennsylvania and Philadelphia, Pennsylvania, in 1948 (Gershon-Cohen and Cooley, 1950). Similar use in Canada soon followed.

The first use of interactive video in health care communications in the United States likely occurred at the University of Nebraska in 1959, through the transmission of neurological exams (Wittson and Benschoter, 1972). In an early and famous use of telemedicine, Norfolk State Hospital employees provided psychiatric consultations for the Nebraska Psychiatric Institute in the 1950s and 1960s (IOM, 1996). Wireless transfers of electrocardiogram and X-rays became prominent around this time as well (IOM, 1996).

In collaboration with the state of Arizona, the National Aeronautics and Space Administration (NASA) advanced satellite-based telemedicine in order to provide future care to astronauts, while also benefiting the Papago Indians in Arizona through a demonstration project called the STARPAHC (Space Technology Applied to Rural Papago Advanced Health Care) project (Freiburger et al., 2007). During the 1970s, the use of this technology spread to other parts of the United States, serving remote and historically underserved communities, such as those in Alaska (Nesbitt and Katz-Bell, 2018). However, without private-sector investment, such projects were not sustainable, leaving the populations they were designed help without the capacity to maintain the expanded access (Greene, 2020).

Following slow growth in the 1980s, the 1990s saw a great expansion of telehealth use and services through the development of statewide telemedicine projects, passage of state and federal legislation making telemedicine services reimbursable, and increasing affordability of telemedicine (Nesbitt and Katz-Bell, 2018). The hub-and-spoke model emerged in which multiple distant care sites were connected to a larger specialty health center. These programs were often funded through legislative appropriations or grants and focused on increasing outpatient access to specialty care (particularly for patients in remote or historically underserved areas) and provision of continuing provider education. Many health systems, which have traditionally operated as competitors, formed telehealth alliances, such as the New Mexico American Telemedicine Association, in order to decrease barriers to health care (Nesbitt and Katz-Bell, 2018).

Research on the efficacy of telehealth also dramatically increased in the 1990s. Publications from the Veterans Health Administration (VHA) and Kaiser Permanente added to the telehealth evidence base and suggested that home telehealth may benefit some patients (Darkins, 2014; Johnston et al., 2000). Telehealth also became more common in correctional facilities due to the costs and significant risks in transporting patients to physically see health care providers (Nesbitt and Katz-Bell, 2018).

Throughout the early 2000s, telemedicine platforms multiplied across states (every state had a platform by 2010) and around the world (Nesbitt and Katz-Bell, 2018). The Medicare, Medicaid, and SCHIP Benefits Improvement and Protection Act, enacted in 2001, lowered barriers to telehealth in a number of ways, including requiring payment parity (equivalent payment for in-person and telemedicine visits) by Medicare, requiring Medicare to pay a $24 facility fee payment to the originating site for each telehealth visit, and expanding the range of telehealth services covered under Medicare (Gilman and Stensland, 2013; 106th Congress, 1999). In addition, Teladoc Health, now the world’s largest telemedicine company, was launched in 2002 (Teladoc Health, 2022).

Inpatient and emergency care telehealth services then started to become more common. teleICU care increased and began to incorporate interactive video conferencing and smart alarms in intensive care units (ICUs) (Lilly et al., 2011). The Department of Veterans Affairs (VA) led the way in adapting telehealth to care for patients with chronic health conditions (Nesbitt and Katz-Bell, 2018).

In 2008, the Medicare Improvements for Patients and Providers Act further expanded both covered services and eligible providers, including community mental health centers (Gilman and Stensland, 2013). As internet speed and affordability improved, the Federal Communications Commission (FCC) provided grants to expand broadband to rural areas, further increasing the number of Americans who could access telehealth. In addition, the American Recovery and Reinvestment Act of 2009 helped expand telehealth services, with a focus on disaster preparedness (Nesbitt and Katz-Bell, 2018). The Office for the Advancement of Telehealth, within Health Resources and Services Administration (HRSA), part of the Department of Health and Human Services (HHS), helped start state clinical telehealth networks and funded telehealth research (Nesbitt and Katz-Bell, 2018).

By 2010, 11 states (California, Colorado, Georgia, Hawaii, Kentucky, Louisiana, Maine, New Hampshire, Oklahoma, Oregon, and Texas) had mandated that insurance payers cover telemedicine services (although each state’s rules varied) (Nesbitt and Katz-Bell, 2018). In addition, 36 states covered telehealth services under Medicaid (CCHP, 2018). In 2011, CMS approved proxy credentialing of providers for telehealth services, greatly decreasing barriers to access. Although some state Medicaid programs began to reimburse for more telehealth services, there was tremendous variation across states (Nesbitt and Katz-Bell, 2018). In 2016, 48 states and Washington, DC, reimbursed for live video telemedicine services, and 19 reimbursed for remote patient monitoring (CCHP, 2021). However, despite significant improvements in access for many, telehealth has increasingly received more attention from venture capital than from the sort of government and nonprofit actors that might deliver on the original promise of telehealth for the expansion of health care access to low-income and rural populations (Greene, 2020).

By 2016, 46 percent of health care providers reported using multiple forms of telehealth technology in practice (HIMSS Analytics, 2016). At this time, the top seven diagnoses for Medicare beneficiaries receiving telehealth services were related to mental health (CMS, 2018). In 2020, 85.8 percent of Americans had access to the internet, suggesting that a greater proportion of people in the United States might be able to access telehealth services (Johnson, 2022). However, access to the internet is far from the only barrier to accessing telehealth, while it is a major barrier—others include language barriers between patients and providers, digital literacy, and access to equipment (more on this subsequently) (Park et al., 2018).

What are the key questions, research areas, and products or applications today?

Telehealth and telemedicine occupy a rapidly evolving evidence development and regulatory space. While the literature on telehealth effectiveness is limited, it is expanding rapidly. A 2019 Agency for Healthcare Research and Quality (AHRQ) evidence review included 106 studies of telehealth effectiveness (Seehusen and Azrak, 2019). While evidence was insufficient or low for many specialties, moderate strength of evidence was found for telehealth effectiveness in wound care, psychiatric care, and chronic disease management. Furthermore, patient satisfaction with telehealth services has been consistently found to be high (Orlando et al., 2019; Kruse et al., 2017).

International regulation of telemedicine varies widely. In contrast to other areas of complex regulation, there have been to date no generally applicable treaties governing telemedicine or attempts at legally harmonizing the practice across jurisdictions. This even includes an absence of general laws across countries that are otherwise bound together by supranational organizations like the European Union (EU) (Callens, 2010). Where specific regulations do exist governing telemedicine apart from traditional medicine, almost all countries broadly regulate telemedicine on a national or supranational level in contrast the United States’ federalist (i.e., subnational) approach. Exceptions to this general observation include countries with similarly robust federalist structures like Spain, Australia, Canada, and, to a lesser extent, Germany, which, like the United States, allows subnational jurisdictions to implement their own regulations governing telemedicine (Hashiguchi, 2020). Countries that have specific broad, national legislation implementing a permissive approach to telemedicine include the Netherlands, Finland, Iceland, and Norway (Hashiguchi, 2020). Hungary stands, to date, as a major exception among countries with explicit telemedicine policy, with national legislation restricting (rather than permitting) the practice of telemedicine beyond what would be afforded absent the law (Hashiguchi, 2020).

In the United States, telehealth options for Medicare Advantage patients expanded in January 2020 with the enactment of the 2018 Bipartisan Budget Act, which removed requirements with respect to the originating (patient) and distant (physician) sites, allowing patients to access telehealth services from home (Contreras et al., 2020). In response to the COVID-19 pandemic, the U.S. federal government has relaxed many telehealth regulations and increased telehealth funding. The number of telemedicine visits dramatically increased across the country during the pandemic (Mehrotra et al., 2020). The CMS 1135 waiver and the Coronavirus Preparedness and Response Supplemental Appropriations Act, enacted in March 2020, expanded telehealth benefits for Medicare Advantage patients to patients with standard Medicare by removing requirements that patients be physically located within a health care facility in order to participate in telemedicine (116th Congress, 2020; CMS, 2020). CMS also established equivalent reimbursement (parity) for video telemedicine visits and traditional in-person visits (CMS, 2020). Furthermore, the HHS Office for Civil Rights relaxed the enforcement of software-based violations of the Health Insurance Portability and Accountability Act (HIPAA), enabling flexibility in platforms through which telemedicine is delivered, as huge amounts of health care shifted to telemedicine in a matter of days following the onset of the COVID-19 pandemic (HHS, 2020).

Medicaid has always allowed states the flexibility to reimburse telemedicine visits in whatever way they deemed best, and although many states already required private health insurance and Medicaid plans to cover telehealth, many more expanded these policies in response to the COVID-19 pandemic (APAb, 2022). Some states also relaxed state-specific licensure requirements, allowing providers to conduct telehealth (and teletherapy) services more easily across state lines, although as the pandemic wanes in the United States, states have begun rolling back such measures (PSYPACT, n.d.; Richardson et al., 2022).

Relaxed requirements and reduced barriers to access do not necessarily mean uniform increased utilization, however. A 2018 study found that from 2013 to 2016, though overall telehealth use increased dramatically, this increased use was largely driven by higher-income populations and younger Medicare beneficiaries (Park et al., 2018). Telehealth was less likely to be used by Medicaid beneficiaries and low-income and rural populations, even in states with less restrictive state telehealth policies (Park et al., 2018).

mHealth is much newer than telehealth, and its evidence base is smaller, but it is rapidly growing, seeing $8.1 billion in investments in 2018, aided tremendously by the high-powered computers the vast majority of us carry on our persons, the smartphone, which is designed to track our motion and position in three-dimensional space (Day and Zweig, 2019). mHealth app and device developers have taken advantage of this capacity to turn smartphones into fall detectors, spirometers, heart-rate sensors, and much more, not only expanding diagnostic and treatment options but also generating new kinds of health data and evidence (Sim, 2019). The Apple Health app can combine data collected from the iPhone or Apple watch with a consumer/patient’s electronic health record. The lucrative segment of mHealth focused on concierge care for those with means does expand access to care, but not in the way originally envisioned in the 1970s (Greene, 2020).

Apps specific to COVID-19 have also proliferated in the mHealth space. A survey of iOS and Android apps available between April 27 and May 2, 2020, identified 114 COVID-related apps, 84 (74%) of which were categorized as either health and well-being/fitness or medicine apps. About half of all apps were developed by regional or national governments, and all but one was free (Collado-Borrell et al., 2020).

As alluded to previously, access to the full range of telehealth services is dependent on access to high-speed internet (“broadband”), although it is important to note that a great deal of telehealth still happens by phone. According to the 2018 American Communities Survey (ACS), 18 million U.S. households lacked access to broadband, 60 percent of which had household incomes below $35,000/year (Siefer and Callahan, 2020). Additionally, the substantial racial disparities present in access to broadband can exacerbate racial disparities in use of telehealth (Singh et al., 2020). Internationally, it has been suggested that a 10 percent increase in internet access yields 1–2 percent increase in GDP (DeLaTorre, 2022). Policies aiming to address the “digital divide” are often targeted at building internet infrastructure in rural areas, but many Americans who lack access to broadband actually live in urban regions and are simply unable to afford all but the slowest internet speeds—a fact that has been made clear by stories of children and parents doing their schooling and jobs from the parking lots of public libraries and fast food restaurants during the COVID-19 pandemic (Greene, 2020; Kang, 2020). More inclusive efforts to close the digital divide have emerged, particularly in response to the growing need for broadband in the era of COVID-19. The HEROES Act, a COVID-19 relief bill passed by the U.S. House of Representatives in May 2020, included significant funding to help low-income households pay for broadband and acquire internet-capable devices, as well as funding to expand broadband access to urban health care providers left out of previous efforts to reach rural providers, though it did not receive a vote in the Senate (116th Congress, 2020; Cochrane, 2020). Versions of many of these provisions were maintained in the $900 billion stimulus bill that was signed into law in December 2020 (Montague, 2020).

Currently, the regulation of telehealth in the United States is at a major inflection point. The COVID-19 pandemic has dramatically altered the way that health care is sought and provided, and it is unlikely that the practice of medicine will return to the pre-COVID-19 status quo after the pandemic recedes. The rapid expansion in use of, and reimbursement for, telehealth services in the face of a global pandemic has accelerated the shift from traditional in-person medicine to a normalization of telemedicine. Similarly, the use of (largely non-evidence-based) health and wellness apps, as well as apps that enable digital contact tracing, has expanded over the course of the pandemic. How these products will be used and regulated in a post-COVID-19 world remains to be seen (Figueroa and Aguilera, 2020; JHU, 2020; Lagasse, 2020).

Cross-Sectoral Footprint

The cross-sectoral analysis is structured according to sectors (academia, health care, private sector, government, and volunteer/consumer—see Figure 1 ) and domains (science and technology, governance and enforcement, end-user affordability and insurance reimbursement [affordability and reimbursement], private companies, and social and ethical considerations). The sectors described subsequently are intended to be sufficiently broad to encompass a number of individuals, groups, and institutions that have an interest or role in telehealth. Health care is the primary nonprofit actor of interest, and so in this structure, ‘health care’ has replaced ‘nonprofit’, though other nonprofit actors may have a role in this and other emerging technologies, and, of course, not all health care institutions are nonprofits.

Today, many telehealth technologies are researched, developed, and promoted by a scientific-industrial complex largely driven by market-oriented goals. The development of various components of telehealth may be altered by differing IP regimes. This larger ecosystem is also embedded in a broad geopolitical context, in which the political and the economic are deeply intertwined, shaping national and regional investment and regulation. The political economy of emerging technologies involves and affects not only global markets and regulatory systems across different levels of government but also non-state actors and international governance bodies. Individuals and societies subsequently adopt emerging technologies, adjusting their own values, attitudes, and norms as necessary, even as these technologies begin to shape the environments where they are deployed or adopted. Furthermore, individual and collective interests may change as the “hype cycle” of an emerging technology evolves (Gartner, n.d.). Stakeholders in this process may include researchers, technologists, business firms and industry associations, government officials, civil society groups, worker safety groups, privacy advocates, and environmental protection groups, as well as economic and social justice-focused stakeholders (Marchant et al., 2014).

This intricate ecosystem of stakeholders and interests may be further complicated by the simultaneous introduction of other technologies and platforms with different constellations of ethical issues, modes of governance, and political economy contexts. In contrast to the development of therapeutics or, to a lesser extent, medical devices, the development of telehealth technologies and platforms has not appeared to be controlled by the availability of intellectual property (McGowan et al., 2012). Subsequently, this ecosystem is disaggregated and organized for ease of presentation. This section will address both telehealth and mHealth but will endeavor to address telehealth first and then mHealth in the subsections. It is important to keep in mind that there are entanglements and feedback loops between and among the different sectors, such that pulling on a single thread in one sector often affects multiple areas and actors across the broader ecosystem.

Cross-Sectoral Analysis

For the purposes of this case study, the primary actors within the academic sector interested are those engaging in cost-effectiveness, comparative effectiveness, health services, basic and translational device, and mHealth research; and scholars working in bioethics.

Science and technology: Research on telemedicine has been conducted for decades, primarily focusing on effectiveness and cost relative to traditional in-person care (Torre-Diez et al., 2015). While the literature on telehealth effectiveness is limited, it is expanding rapidly. A 2019 AHRQ evidence review included 106 studies of telehealth effectiveness (Seehusen and Azrak, 2019). While evidence was insufficient or low for many specialties, moderate strength of evidence was found for telehealth effectiveness in wound care, psychiatric care, and chronic disease management. Furthermore, patient satisfaction with telehealth services has been consistently found to be high (Orlando et al., 2019). The evidence base for the use of telehealth and wellness apps (mHealth) is small, and more research is needed, particularly on the effects these technologies may have on reducing or exacerbating existing health disparities.

Governance and enforcement: Within the research context, governance is primarily through institutional human subject research review boards and research ethics boards, research funding bodies, academic publication standards, and scientific and professional societies (i.e., self-regulation).

Affordability and reimbursement: N/A

Private companies: N/A

Social and ethical considerations: There has been some academic research on social factors related to telehealth adoption and use, as well as ethical issues associated with telehealth adoption. There are related, growing literatures on the privacy and other implications of persistent data collection, big data, digital phenotyping, and so forth, with direct relevance to mHealth.

Health Care

Given the focus of CESTI on health and medicine, for the purpose of this case study, the primary actors within the nonprofit sector are those involved in health care.

Science and technology: As noted previously, research on efficacy across specialties is ongoing but limited.

Governance and enforcement: Health care systems are the main hubs for telemedicine. Their use of these technologies is subject to HIPAA regulation, as well as the licensing requirements of the state in which they operate. Proposals related to licensing for practicing across state lines could potentially change the reach of health systems (e.g., a proposal that licensing requirements only apply for the location of the telemedicine provider would enable a provider in a health system located in only one state to reach patients across the country) (Lee et al., 2020).

Physicians are governed by their respective state licensing boards. In general—and with the exception of psychiatry—state licensing boards do not grant their physicians blanket permissions or prohibitions to practice telemedicine, requiring only (again, in general) that physicians provide their patients “competent care” (APAb, 2022).

Professional bodies have also developed position papers regarding telehealth, including in the context of the pandemic (AHA, 2020). In Europe, there are cross-sectoral committees that include academics, industry/technology representatives, and regulators; similarly cross-sectoral committees were established in the United States to address the COVID-19 pandemic (NIH, 2020). These committees could potentially serve as a model for coordination of cross-sectoral governance of emerging technologies.

Affordability and reimbursement: The United States’ multimodal payer system makes reimbursement and payment for medical services in the United States difficult to summarize. Federally organized public payers (e.g., Medicare, Medicaid, the VHA) are largely governed by federal law, while strictures on state-level public and private payers are governed by state law. Each payer—including administrative agencies—sets different rates and schedules for each service, including those pertaining to telemedicine. Beyond this, states may have additional laws in place governing which services must be covered by private insurers.

Parity in reimbursement between in-person and telemedicine-based services remains an issue, and laws in some states require insurers to reimburse telemedicine visits at the same rate as in-person visits. From a health system perspective, this might make telemedicine an attractive option, as it is often less expensive to provide relative to traditional face-to-face care, though state medical boards have often required an in-person consultation before allowing for telehealth services (Lee et al., 2020). Furthermore, the traditional reimbursement model does not incentivize physicians to use telemedicine because they get paid more for in-person services and procedures (Goldberg et al., 2022). There are also basic questions related to implementation of telemedicine more broadly: What are the clinical workflows for telehealth care? How can physicians/health systems leverage and utilize remote monitoring effectively? How does data flow into the health system? Should these data be integrated with the medical record, and if so, how? Who is responsible for understanding and analyzing a potentially near-real-time stream of patient data? What are the shared expectations and liability concerns around these new platforms?

Private companies: Health care institutions partner with private companies that provide many enabling technologies for telehealth, including telemedicine care delivery platforms, monitoring and management technologies, mHealth apps, and more. While some of these technologies may be protected by trade secrets (e.g., confidential algorithms), few are robustly protected by patents given the difficulties in patenting software applications (Price, 2015). Furthermore, there have been calls for more rigorous testing of many of these technologies for clinical effectiveness (Sim, 2019).

Social and ethical considerations: While health data in the United States is regulated by HIPAA, there is no blanket data privacy law (104th Congress, 1996). Data privacy, like medical consent, is largely an issue of contract and tort. Data privacy is arguably the principal international issue concerning telemedicine regulation. Most significantly, the European Union’s General Data Protection Regulation (GDPR) provides a robust set of rights to individuals’ “personal data,” that is, “any information relating to an identified or identifiable natural person” (European Parliament, 2016). This includes the right to forbid its collection; to demand a third party destroy it; and, if electronic, to download it where it resides. Health data, specifically, receives further protections under the GDPR (although there are public health exceptions). The GDPR’s reach is not only cabined within the European Union but extends to anywhere in the world where the processing of European citizens’ data occurs. Penalties for noncompliance can be stiff (European Parliament, 2016). While other countries invested in telemedicine—including Colombia, Costa Rica, and Peru—have data privacy laws, the GDPR seems unique in its global reach and effect on data transmission practices.

In most countries, patient consent for telemedicine tracks with each respective country’s model for other forms of health care delivery. For example, where delivery operates at the physician level, patients’ consent typically is obtained through their physicians. Notable exceptions include Japan and Greece, which require explicit consent from patients before physicians can conduct treatment through telemedicine (Hashiguchi, 2020).

Physicians, particularly in subspecialties conducive to telemedicine (e.g., dermatology and psychiatry) may have workforce concerns as restrictions on cross-jurisdictional medical practice are relaxed. Providers may resist lowering licensing barriers as this could allow for competition from other states’ telehealth services (IOM, 2012).

As mentioned previously, the digital divide has significant equity implications for telehealth access, in addition to other challenges, including language barriers between patients and providers, digital literacy, and access to necessary equipment (Park et al., 2018). There are special issues related to safety, efficacy, and privacy/data security when mHealth devices/toys are used in the treatment of children (Comscore, 2014).

Private Sector

For the purposes of this case study, the primary actors within the private sector are digital health platform providers, startups, and app developers.

Science and technology: Telehealth startups are currently targeting large, self-insured employers with strong incentives to keep costs low (Dorsey and Topol, 2016). mHealth apps have been developed for a wide array of purposes, including tracking fertility and exercise; diabetes management; medication adherence; treating depression, anxiety, and traumatic brain injury; and preventing suicide.

Governance and enforcement: Many companies in the telemedicine space offer services designed to help physicians do their jobs and so fall under the umbrella of “physician practice,” which is not regulated by the U.S. Food and Drug Administration (FDA). Telemedicine platforms used by health systems are subject to stronger scrutiny, but in the interest of expanding access to telemedicine during the COVID-19 pandemic, the HHS Office for Civil Rights has “waived penalties for HIPAA violations against health care providers that serve patients through everyday communications technologies” during the public health emergency (HHS, 2020). There are thousands of health- and wellness-focused apps available for smartphones, some of which make dubious or unproven claims about their effectiveness. In addition to a shallow evidence base about the effectiveness of many health and wellness apps, they also raise significant privacy concerns because they are not all governed by the same privacy laws (like HIPAA) that protect sensitive patient information in traditional care settings (Singer, 2019). While some companies may be required or choose to engage third-party compliance services to monitor their data security, this is not a legal requirement for all.

The FDA’s Digital Health Software Precertification (Pre-Cert) Program has piloted new ways of regulating software-based medical devices, but this regulatory innovation has faced pushback from the U.S. Congress, suggesting that such innovation will be challenging (FDA, 2021; Warren et al., 2018).

Affordability and reimbursement: As described in more detail subsequently, states can and have mandated that commercial insurance plans offer parity for telemedicine visits (Yang, 2016). Historically, concern about medical liability has been a persistent barrier to the broader adoption of telemedicine (WHO, 2010). The United States, which has a robust medical practice tort system, appears to assign liability in much the same way for errors in telemedicine as it does for traditional practice. There is frequently lack of clarity about who should pay for mHealth technology, in particular when prescribed by a physician. Many mHealth apps are free or low-cost to download, though the safety and efficacy of many of these apps are unclear, and there are significant associated data privacy concerns.

As noted previously, an explicit goal of telehealth has long been expanded access in rural and remote areas. There are a number of companies that seek to address barriers to health and health care beyond geographic barriers and are focused squarely on improving equity in health care, such as ConsejoSano (SameSky Health), Hazel Health, and CareMessage (CareMessage, n.d., Hazel, n.d.; SameSky Health, n.d.).

At the same time, another major driver of telehealth is lowering the cost of health care. Insurers are motivated by the low cost of telehealth compared to the high cost of in-person care and self-insured employers also highly motivated to reduce costs and maintain a healthy workforce.

Private companies: One assessment of digital health startups highlighted 150 companies that had collectively raised more than $20 billion, and which had among them established partnerships with the American Heart Association, Sanofi, Cigna, Mount Sinai Health System, Mercy Health, and Arizona Care Network, demonstrating tremendous interest and growth in this space (CBInsights, 2021). Apple has partnered with both Aetna and the government of Singapore to incentivize individuals to engage in health-promoting behaviors. Fitbit has a similar partnership with United Health (Aetna, n.d.; Elegant, 2020; Gurdus, 2017).

Social and ethical considerations: Significant concerns about privacy, transparency, and accountability with regard to the algorithms and data generation by commercial devices and apps. As noted previously, there have been calls for more rigorous testing of many of these technologies for clinical effectiveness (Sim, 2019). The is often a wide range of third parties involved in telehealth delivery, some of which will be outside the “covered entity” and be governed by different (or few) rules (Gerke et al., 2020). Equity concerns are raised by algorithms trained on the healthy, well-off, and White.

For the purposes of this case study, the primary actors within the government sector are both the federal government and the states, which play critical gatekeeping (or facilitating) roles in the development and evolution of telehealth.

Science and technology: As noted previously, NASA and the VA have been leaders in telehealth research and development. The federal government also partners with tribal governments to administer the Indian Health Service (IHS), which provides care to American Indian/Alaska Native (AI/AN) people across the country. Telemedicine is particularly important to the work of the IHS due to the rurality of many AI/AN communities, which has led to innovation in telehealth systems (Hays et al., 2014). The IHS also has a Telebehavioral Health Center of Excellence, which offers behavioral health care and mental health care through multiple telehealth modalities (IHS, n.d.).

Governance and enforcement: U.S. federal and state governments have significant interests in the governance of telehealth. Prime among these is their interest in requiring public and private insurers to provide reimbursement for telemedicine services. As a result of the COVID-19 pandemic, CMS has waived reimbursement requirements that patients be physically located within a health center when receiving telemedicine services, making it possible for millions to access care safely from their homes. Every state has different reimbursement requirements for their state Medicaid plan, and states also have the power to control reimbursement parity for commercial insurance, which has led to the development of essentially 50 different reimbursement policies across the country.

As noted, the VA has been a leader in telehealth adoption and implementation, as they retain significant control over telemedicine and telehealth offered within the VHA, including control over licensure requirements and copay amounts (CRS, 2019). Since 2012, the VA secretary has had the ability to waive copays for telemedicine provided to veterans in their homes, and VA-employed providers can practice telemedicine across state lines with any patients within the VHA (CRS, 2019).

Another key role for the government is the protection of protected health information (PHI)—personally identifiable information that relates to a medical condition, the provision of care, or payment—which is regulated via HIPAA (104th Congress, 1996). HIPAA establishes restrictions on the dissemination of PHI by “covered entities”—providers, plans, clearinghouses, or business—without the express consent of the patient.

HIPAA is of particular concern in telemedicine because PHI is necessarily generated in telemonitoring and store-and-forward technologies. In addition, the nature of telemedicine is such that users of telemonitoring and store-and-forward technologies are almost certainly “covered entities” under the statute, that is, providers, businesses, or health care plans. In addition, HIPAA demands extra precautions from covered entities for most telemedicine applications under the HIPAA Security Rule, a regulation promulgated by HHS that concerns electronic PHI (CFR, 2011). Prior to the COVID-19 pandemic, the HIPAA Security Rule limited the types of platforms that could be used for the transmission of electronic PHI. In March 2020, the HHS Office for Civil Rights issued a Notification of Enforcement Discretion indicating that providers who engage in telemedicine using non-public-facing communication technologies in good faith will not be subject to penalties for noncompliance with HIPAA rules (HHS, 2021).

With respect to medical devices used in telemedicine, these are typically regulated at the federal level by the FDA (94th Congress, 1976). For example, the Da Vinci Xi Surgical System, a robotic surgical assistant and a form of interactive telemedicine, is regulated by the FDA as a Class II device (Stevenson, 2017).

Telemedicine encompasses devices in all three risk classes, from a WiFi-enabled digital pulse oximeter (Class I) to remotely controlled continuous glucose monitoring systems (Class III). In some instances, FDA considers software to constitute a medical device (FDA, 2017).

Affordability and reimbursement: See the previous discussion of reimbursement. Various national efforts to expand internet access have been key to the expansion of telehealth access, and will continue to be critical moving forward, as advanced technologies demand higher bandwidth.

Social and ethical considerations: Ethical issues raised by telehealth in the government sector include disparities in telehealth (and broadband) access, fiduciary duties of health care providers, privacy, equity, and workforce concerns.

Volunteer/Consumer

For the purposes of this case study, the primary actors within the volunteer/consumer sector are patients and consumers accessing telehealth, including mHealth. It is important to keep in mind that many members of “the public” nationally and internationally never have the opportunity to be patients or consumers of emerging technologies, and so do not show up in the following analysis. These members of the public may nonetheless be affected by the development, deployment, and use of such technologies, and those impacts should be taken into account.

Science and technology: Prior to the COVID-19 pandemic, mHealth apps may have been most people’s primary experience with telehealth, as many of these apps are free or low-cost to download for iOS and Android phones (Friedman et al., 2022). There is little data available on the safety and efficacy of many of these apps.

Governance and enforcement: Currently, there is little regulatory enforcement of many mHealth apps, though a number of mHealth devices have received FDA clearance.

Affordability and reimbursement: As noted previously, insurance coverage for telehealth has expanded dramatically in recent years, and particularly since the start of the COVID-19 pandemic. mHealth apps are free or low-cost to download, though they require that the consumer have a smartphone and internet access.

Private companies: These include mHealth app developers and companies like Apple and FitBit, offering direct-to-consumer health and wellness applications outside health care institutions and employee-sponsored wellness programs.

Social and ethical considerations: Potential drivers include adult children caring for aging parents at a distance, seeking the capacity to both monitor their parents’ health and safety and communicate with their parents’ health care providers; concerns about equity regarding access if Apple continues to expand in the mHealth space and Android continues to lag (more than half of U.S. smartphone owners have Androids, and Android users have a lower average income than iPhone users); and concerns about the use of mHealth devices/toys with children in regard to safety, efficacy, and privacy/data security (Comscore, 2014).

Ethical and Societal Implications

What is morally at stake what are the sources of ethical controversy does this technology/application raise different and unique equity concerns.

In outlining the concerns of the authors in terms of the use of this technology, we considered the following ethical dimensions, as outlined in the recent National Academies of Sciences, Engineering, and Medicine report A Framework for Addressing Ethical Dimensions of Emerging and Innovative Biomedical Technologies: A Synthesis of Relevant National Academies Reports (NASEM, 2019).

• Promote societal value
• Minimize negative societal impact
• Protect the interests of research participants
• Advance the interests of patients
• Maximize scientific rigor and data quality
• Engage relevant communities
• Ensure oversight and accountability
• Recognize appropriate government and policy roles

It is important to keep in mind that different uses of this technology in different populations and contexts will raise different constellations of issues. For example, telephone-based telehealth can be very different than video- or app-based telehealth, with different implications when used to serve urban, high-income adults versus rural, low-income children. Some of the specific concerns might include the following (Nittari et al., 2020):

• Is the quality of care delivered via any given telehealth platform of comparable quality to in-person care? What is gained? What is lost?
• How does a focus on efficiency or cost savings affect compassion/patient welfare? (Jacobs, 2019)
• How is continuity of care affected by communication gaps or barriers between providers at a distance, the patient, a physically present clinical care team, mHealth applications, and documentation in the medical record?
• Are there risks to safety associated with virtual physical exams and treatment?
• What is the effect on the physician–patient relationship and the establishment of trust in the absence of any physical interaction?
• What are the risks to patient privacy and confidentiality, particularly in mHealth, and how can they be mitigated?
• What kind of access to and control over data produced by mHealth devices do patients/consumers have?
• What are the proprietary interests over domains of fragmented patient data and how do they affect care?
• How can governance address the blurring boundary between personal medical data, public health data, and monetized consumer data?
• What ought the requirements be for content and documentation of informed consent for telehealth as a mode of care, and within telehealth, for example, for the transmission and processing of health data?
• How should countries regulate telemedicine when telemedicine services and patients are split across jurisdictions? When the operation of devices is split across jurisdictions?
• How will the changing global political climate likely affect the regulation of telemedicine?
• What are the issues raised by telemedicine across state and national borders, including both ethical (e.g., lack of cultural awareness or familiarity) and legal (e.g., cross-jurisdictional credentialing, regulation, liability)?
• What is the level of reliability and fidelity of data transmitted from mHealth devices?
• Who, how, and with what permissions can various actors access, store, and use the vast amounts of data generated by various telehealth interactions?
• How transparent and accountable are the algorithms used by commercial telehealth devices/apps, as well as the data collection, storage, and use by telehealth companies?
• Which entities involved in telehealth are outside the “covered entity” for the purposes of HIPAA, and how do they collect, store, and use patient data?
• Will a shift to telehealth increase or decrease the isolation and quality of life of historically underserved and marginalized populations, including the elderly, and others with visual, hearing, or cognitive impairments? What about caregivers managing a dependent’s telehealth participation?

Beyond Telehealth

mHealth “is at the swirling confluence of remote sensing, consumer-facing personal technologies, and artificial intelligence (AI)” (Sim, 2019). Currently, AI, wearable and ambient sensors, and other emerging technologies are being used in research and are able to suggest future possibilities, but these have not yet been realized in the market. AI, of course, brings with it a whole host of additional concerns related not only to the technical challenges, including reliability and explainability of autonomous systems but also significant ethical concerns, including those related to bias in training data leading to structural racism being replicated at scale with AI, trust, trustworthiness of systems, and so on. Smart homes, also in ascendance, hold potential in the telehealth space, but the potential health benefits (and risks) remain largely in the future.

As alluded to previously, it is possible to foresee numerous future scenarios regarding the evolution of telehealth. In an effort to probe the kinds of worries the authors have about the trajectories of emerging technologies, to expand the range of lessons learned from each case, and ultimately to “pressure test” the governance framework, the authors have developed a brief “visioning” narrative that pushes the technology presented in the core case 10–15 years into the future, playing out one plausible (but imagined) trajectory. The narrative was developed iteratively in collaboration with a case-specific working group, with additional feedback from members of CESTI. All reviewers are acknowledged in the back matter of this paper. Each narrative is told from a particular perspective and is designed to highlight a small set of social shifts that shape and are shaped by the evolving technology.

Telehealth Case Visioning Narrative

Perspective: A remote caregiver and digital health navigator dyad

It is 2035, and the home has become the preferred site for the receipt of most acute and non-acute medical services (labs, imaging, nursing visits, retail pharmacy) in the United States. Termed hospital-at-home (HaH), it is also the dominant model for non-ICU-level in-person care in much of the world. Although this care paradigm has been around for decades, the COVID-19 pandemic catalyzed this shift due to physical distancing requirements and fears among patients about contracting the virus within the hospital setting. Massive investments from the private sector into telemedicine platforms, coupled with technology advancements in AI-enabled remote monitoring, voice-activated medical devices, augmented reality, and sensors were also pivotal in this care transformation. Results from randomized controlled trials showed that the HaH was just as effective as the traditional hospital setting for a wide range of medical conditions, and with lower cost. However, the data on patient safety has been mixed thus far, with certain kinds of care episodes demonstrating clear reductions in adverse events while others result in poorer outcomes, often due to poor recognition of the need for escalation to emergency care (e.g., malignant bowel obstruction being mistaken for constipation). Hospital visits are increasingly limited to serious conditions that mandate an in-person work-up (e.g., biopsy for a cancer diagnosis) or procedural intervention (e.g., surgical procedure or cardiac catheterization).

Chronic Disease Management

Beyond increasing access to specialty providers (physicians, nurses, pharmacists, physical therapists), this new care paradigm revolutionized chronic disease management. Through “digital touchpoints,” providers were able to durably increase patients’ engagement with their own self-care and remotely manage the trajectory of chronic diseases at increasingly earlier time points. By leveraging ambient clinical intelligence tools (i.e., Internet of Medical Things [IoMT]), all data became re-imagined as health care data, including music preferences, voice pitch, communication logs, gait, step counts, and sleep patterns—a process known as digital phenotyping. In this new personalized care paradigm, conditions such as hypertension, diabetes, heart failure, and renal insufficiency were now managed prospectively and continuously as opposed to in a reactive and episodic fashion. Patients could now be managed within the context of their lives, and for many, this meant the ability to safely “age in place.” However, over time questions arose as to how the governance of emerging technologies intersects with the provision of care in the home. Specifically, issues regarding data standards, quality assurance, interoperability, oversight, bias, and transparency were yet to be definitively addressed in the context of care delivery. Whom should be held legally responsible in instances of harm due to erroneous automated diagnosis? How can the authenticity, accuracy, and integrity of such a wide variety of devices be reliably established?

Impact on Equity

Unfortunately, HaH in some cases led to a widening of existing equity gaps. This is because many of the infrastructural technologies were not developed through the lens of equity or cultural competency (e.g., to account for language barriers, vision/hearing/physical impairments, digital and health literacy, or other impacts of the social determinants of health). Non-English-speaking patients who were more than 80 years of age had tremendous difficulty engaging with this care model, as their communication preferences were more consistent with an in-person encounter. Although HaH uptake was relatively low in areas of high economic deprivation due to poor infrastructure and add-on device costs (smartphones and sensing equipment), great strides were made in improving access to rural communities, in step with investments in broadband and satellite internet service. For the first time, specialty care became available in many areas previously described as “medical deserts.” There was also growing recognition that HaH models implicitly exclude individuals experiencing unstable housing or homelessness.

Impact on the Health Care Workforce

The often ad hoc implementation of these virtual workflows sent prevailing levels of physician burnout soaring even higher due to the lack of clear practice guidelines, time to engage with the data and patient communication that these systems generate, and concerns for liability exposure. Lengthy wait times were reported in many urban areas, as physicians now had to manage two distinct clinic schedules (in-person and virtual). There was also considerable displacement of many health care provider roles due to automation and the transition to HaH. Custodial staff, nursing assistants, clerical workers, and some administrative staff roles were transitioned out of the traditional medical infrastructure and into caretaker or home health worker roles. For those “essential health care workers” such as nurses and physicians, retraining was set in motion by credentialing bodies to ensure that fluency in statistics, data science, and information systems became core competencies, allowing these workers to remain relevant and effective in the new digital age. Rote memorization of medical facts was no longer the norm in medical schools. A stronger emphasis was also placed on the human skills that cannot be displaced with automation such as empathy, physical examination, and implicit bias awareness. New health care roles also emerged in this data-rich delivery paradigm, such as digital health navigators, telenurses, and health data specialists. However, many of these new positions and several traditional ones (e.g., physicians, nurses, care coordinators) were increasingly outsourced to global vendors in an attempt to reduce the administrative costs of health care. In this distributed staffing model, international hubs of excellence also began to emerge for certain conditions or treatments (e.g., Sweden for the best interpretation of radiology images). With this in mind, the broader question of how to appropriately regulate remote second opinions across international borders arose. What licensure requirements should be enforced for the practice of international telemedicine? In an increasingly networked world, do state-based licensures still make sense? Calls for the nationalization of medical licensure, or at a minimum the harmonization of requirements across states, were proposed by a variety of stakeholders.

Data Privacy, Trust, and the Wisdom of Crowds

Mr. Jeff Jackson is a 63-year-old Black male with hard-to-control type 2 diabetes, early-onset Alzheimer’s disease, and stable chronic heart failure (CHF). He has chosen to live alone in Youngstown, Ohio, since his wife died 5 years ago. An implanted microchip is able to sample, interpret, and transmit biometric (heart rate, temperature, oxygen saturation) and biochemical data (blood glucose, sodium levels, creatinine levels) about Mr. Jackson at high frequency. AI algorithms embedded within wall-mounted camera-based sensors are also able to detect the progression of his Alzheimer’s or warning signs of acute exacerbations of his CHF. All of this information is relayed 24/7 to a “digital health navigator” assigned by his health plan who serves as a health coach and care coordinator. As outlined in the consent agreement, monthly summaries of routine care are sent to his 23-year-old daughter, Jean, who resides in Miami, Florida. Potentially concerning events sensed in Ohio automatically trigger real-time “red alerts” to both the digital navigator and Jean. Arrangements like this raised many questions during their rollout, including but not limited to the potential vulnerability of these technologies to data breaches and cyberattacks, particularly since the identifiable medical record of every U.S. patient was transitioned to the cloud to facilitate interoperability and timely access. Should HIPAA include the home digital infrastructure in its scope? Under what circumstance should employers or insurance companies have access to personal data? What should be the recourse for care episodes involving harm due to egregious digital navigator negligence? Lastly, instances wherein elder or child abuse or domestic violence were detected using camera-based sensors (“bycatching”) raised ethical concerns as to whether the gravity of these offenses justified circumventing the confidentiality, privacy, and anonymity of involved patients and family members. These events also give rise to the broader question of who owns or is able to repossess these data. Will commercial entities be able to contract and monetize passively captured (audio or video) personal information (e.g., targeted advertising on social media based on fridge contents)?

About 6 months ago, based on his personality traits, risk preferences, and at the strong suggestion of his daughter, Jeff joined a health platform called “All2Gether” that linked individuals across the globe based on more than 200 phenotypes. The goal was to provide phenotype-specific social support to reduce loneliness. The platform offered crowd-sourced medical advice based on lived experiences, behavioral change interventions, and in some instances, mental health therapies based on biofeedback techniques. The much-heralded age of “democratizing medical knowledge” had finally arrived, with these platforms now able to serve millions of people worldwide and drive robust engagement. Over time, Jean had grown much more comfortable entrusting her father’s health data to these cloud-based platforms, rather than a primary care physician or the digital health navigation company. For Jean, this mistrust in her father’s primary care physician and the digital health navigation company was undergirded by the fact that neither she nor Jeff had direct access to the raw data or proprietary algorithms that informed his care. Conspiracy theories and science denial began to rapidly proliferate on these platforms, casting doubt on the value of long-established medical treatments and entrenching health care mistrust. This accelerated in some quarters, a rejection of digital therapeutics and data-driven medicine all together, in favor of more relationship-based approaches to health care.

The international reach of these companies also made regulatory oversight difficult because the practice of medicine is usually controlled through state-specific licensure. Legal experts pointed out that these international platform companies are often predatory and in violation of the existing corporate practice of medicine. Proponents argue that these companies are not “health services establishments” and their business model does not constitute a “provider–patient relationship,” in fact, they claim it is no different from a patient-initiated search engine query. Furthermore, for many patients in rural areas and parts of the developing world, these platforms are the only portal to timely and affordable medical advice. All of these issues are illustrative of the fact that many of the normative behaviors and standards around the practice of medicine evolved well before the information boom associated with the internet and digital care transformation catalyzed by the COVID-19 pandemic.

Telehealth Case Study: Lessons Learned

Some lessons drawn from the above core case and visioning exercise that can inform the development of a cross-sectoral governance framework for emerging technologies focused on societal benefit are given below.

• The coexistence of health and non-health (e.g., wellness) applications can complicate governance.
• It is important to keep in mind the dual roles of state and federal regulation, as well, potentially, of regional (e.g., European Union) regulation.
• There are opportunities for shared or distributed governance in the gaps between regulatory authorities.
• There is a potential role for cross-sectoral governance groups at multiple levels and stages of governance.
• It is important to keep in mind the role of key enabling technologies (e.g., internet access and speed) in the development of the primary technology of interest.
• Key stakeholders to a technology will need to be adequately prepared for large shifts (e.g., dramatic ramping up of telehealth).
• Opportunities for regulatory nimbleness have been revealed by the federal response to the COVID-19 pandemic (e.g., steps skipped).
• Attention must be paid to the equity implications of access (or lack thereof) to enabling technologies.
• Attention should be paid to identifying and assessing the impact of intangible losses (e.g., healing touch, patient–provider relationships).
• Despite an explicit focus and justification for telehealth based on concerns about equity and access, success has been mixed—improving access in some cases and recapitulating existing inequities in others.
• Special attention must be paid to technologies requiring collection, storage, and use of human data.
• As the degree to which our lives are lived online versus in-person, we can become increasingly alienated from our normal markers of trust.
• We lack appropriate governance tools for a health care delivery landscape that is becoming increasingly digital and international.
• We may need to reconsider the traditional risk/benefit analysis of health care treatments when the opportunity for “immediate rescue” in situations of acute decompensation, no longer exists due to physical distance.
• One person’s valued benefit is another person’s harm (and vice versa) (e.g., home monitoring for safety versus surveillance).
• In order to adequately assess the risk/benefit balance, we need to make the trade-offs explicit (e.g., gains in convenience versus loss of privacy).
• We need both ethics and governance frameworks for addressing instances of “bycatching” (e.g., elder abuse captured via camera-based sensors).
• Technology (beyond traditional social media) can drive or erode trust in medical expertise (e.g., dissemination of false information about available treatment options on online platforms).
• There is flexibility/lack of oversight in the grey area that exists following the development of promising data regarding a new technology, but before proven efficacy and regulated products; this lack of oversight can drive innovation and investment in emerging technologies or delivery models, but also comes with risks.
• In the digital home, there are no silos around work/personal or public/private. What happens when the same living environment has to pivot from a place of rest to a place of work (remote work) to a place to get care (hospital-at-home)?

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https://doi.org/10.31478/202311e

Suggested Citation

Mathews, D., A. Abernethy, A. J. Butte, P. Ginsburg, B. Kocher, C. Novelli, L. Sandy, J. Smee, R. Fabi, A. C. Offodile II, J. S. Sherkow, R. D. Sullenger, E. Freiling, and C. Balatbat. 2023. Telehealth and Mobile Health: Case Study for Understanding and Anticipating Emerging Science and Technology. NAM Perspectives. Discussion Paper, National Academy of Medicine, Washington, DC. https://doi.org/10.31478/202311e .

Author Information

Debra Mathews, PhD, MA, is Associate Director for Research and Programs at the Johns Hopkins Berman Institute of Bioethics and Professor, Department of Genetic Medicine at the Johns Hopkins University School of Medicine. Amy Abernethy, MD, PhD, is President of Product Development and Chief Medical Officer at Verily. Atul J. Butte, MD, PhD, is Priscilla Chan and Mark Zuckerberg Distinguished Professor at the University of California, San Francisco. Paul Ginsburg, PhD, is Professor of the Practice of Health Policy and Management at the University of Southern California and Senior Fellow at the USC Schaeffer Center. Bob Kocher, MD, is Partner at Venrock. Catherine Novelli, JD, LLM, is President of Listening for America. Lewis Sandy, MD, is Principal and Co-founder, Sulu Coaching. John Smee, PhD, is Senior VP Engineering at Qualcomm Technologies, Inc. Rachel Fabi, PhD, is Associate Professor, Center for Bioethics and Humanities at SUNY Upstate Medical University. Anaeze C. Offodile II, MD, MPH, is Chief Strategy Officer at Memorial Sloan Kettering Cancer Center. Jacob S. Sherkow, JD, MA, is Professor of Law at the Illinois College of Law, Professor of Medicine at the Carle Illinois College of Medicine, Professor at the European Union Center, and Affiliate of the Carl R. Woese Institute for Genomic Biology at the University of Illinois. Rebecca D. Sullenger, BSPH, is a medical student at the Duke University School of Medicine. Emma Freiling, BA, is a Research Associate at the National Academy of Medicine. Celynne Balatbat, BA, was the Special Assistant to the NAM President at the National Academy of Medicine while this paper was authored.

Acknowledgments

This paper benefitted from the thoughtful input of Bernard Lo , University of California San Francisco; and George Demiris , University of Pennsylvania.

Conflict-of-Interest Disclosures

Amy Abernethy reports personal fees from Verily/Alphabet, relationships with Georgiamune and EQRx, and personal investments in Iterative Health and One Health, outside the submitted work. Atul J. Butte reports support for the present manuscript from National Institutes of Health; grants or contracts from Merck, Genentech, Peraton (as a prime for an NIH contract), Priscilla Chan and Mark Zuckerberg, the Bakar Family Foundation; royalties or licenses from NuMedii, Personalis, and Progenity; consulting fees from Samsung, Gerson Lehman Group, Dartmouth, Gladstone Institute, Boston Children’s Hospital, and the Mango Tree Corporation; payment of honoraria from Boston Children’s Hospital, Johns Hopkins University, Endocrine Society, Alliance for Academic Internal Medicine, Roche, Children’s Hospital of Philadelphia, University of Pittsburgh Medical Center, Cleveland Clinic, University of Utah, Society of Toxicology, Mayo Clinic, Pfizer, Cerner, Johnson and Johnson, and the Transplantation Society; payment for expert testimony from Foresight, support for attending meetings and/or travel from Alliance for Academic Internal Medicine, Cleveland Clinic, University of Utah, Society of Toxicology, Mayo Clinic, Children’s Hospital of Philadelphia, American Association of Clinical Chemistry, Analytical, and Life Science & Diagnostics Association; patents planned, issued, or pending from Personalis, NuMedii, Carmenta, Progenity, Stanford, and University of California, San Francisco; participation on a Data Safety Monitoring Board or Advisory Board from Washington University in Saint Louis, Regenstrief Institute, Geisinger, and University of Michigan; leadership or fiduciary role in other board, society, committee or advocacy group, from National Institutes of Health, National Academy of Medicine, and JAMA; and stock or stock options from Sophia Genetics, Allbirds, Coursera, Digital Ocean, Rivian, Invitae, Editas Medicine, Pacific Biosciences, Snowflake, Meta, Alphabet, 10x Genomics, Snap, Regeneron, Doximity, Netflix, Illumina, Royalty Pharma, Starbucks, Sutro Biopharma, Pfizer, Biontech, Advanced Micro Devices, Amazon, Microsoft, Moderna, Tesla, Apple, Personalis, and Lilly. Paul Ginsburg reports personal fees from the American Academy of Ophthalmology outside the submitted work. Bob Kocher reports being a Partner at the venture capital firm Venrock which invests in technology and healthcare businesses. Dr. Kocher is on the Boards of several healthcare services businesses that utilize telehealth technology including Lyra Health, Aledade, Devoted Health, Virta Health, Accompany Health, Sitka, Need, and Candid. Jacob S. Sherkow reports employment with the University of Illinois, grants from National Institutes of Health, personal fees from Expert Consulting services, outside the submitted work.

Correspondence

Questions or comments should be directed to Debra Mathews at [email protected].

The views expressed in this paper are those of the authors and not necessarily of the authors’ organizations, the National Academy of Medicine (NAM), or the National Academies of Sciences, Engineering, and Medicine (the National Academies). The paper is intended to help inform and stimulate discussion. It is not a report of the NAM or the National Academies. Copyright by the National Academy of Sciences. All rights reserved.

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PERSPECTIVE article

This article is part of the research topic.

Reducing Animal Use in Carcinogenicity Testing

ICH S1 Prospective Evaluation Study and Weight of Evidence Assessments: Commentary from Industry Representatives Provisionally Accepted

• 1 Lilly Research Laboratories, Eli Lilly (United States), United States
• 2 Alnylam Pharmaceuticals (United States), United States
• 3 Organon, United States
• 4 ASKA Pharmaceutical Co., Ltd., Japan
• 5 Merck (United States), United States
• 6 Boehringer Ingelheim (Germany), Germany
• 7 Takeda Development Centers Americas, United States
• 8 Astellas Pharma (Japan), Japan

The final, formatted version of the article will be published soon.

Industry representatives on the ICH S1B(R1) Expert Working Group (EWG) worked closely with colleagues from the Drug Regulatory Authorities to develop an addendum to the ICH S1B guideline on carcinogenicity studies that allows for a weight-of-evidence (WoE) carcinogenicity assessment in some cases, rather than conducting a 2-year rat carcinogenicity study. A subgroup of the EWG composed of regulators have published in this issue a detailed analysis of the Prospective Evaluation Study (PES) conducted under the auspices of the ICH S1B(R1) EWG. Based on the experience gained through the Prospective Evaluation Study (PES) process, industry members of the EWG have prepared the following commentary to aid sponsors in assessing the standard WoE factors, considering how novel investigative approaches may be used to support a WoE assessment, and preparing appropriate documentation of the WoE assessment for presentation to regulatory authorities. The commentary also reviews some of the implementation challenges sponsors must consider in developing a carcinogenicity assessment strategy. Finally, case examples drawn from previously marketed products are provided as a supplement to this commentary to provide additional examples of how WoE criteria may be applied. The information and opinions expressed in this commentary are aimed at increasing the quality of WoE assessments to ensure the successful implementation of this approach.  

Keywords: carcinogenicity testing1, rat carcinogenicity2, rasH2-Tg mouse dose selection3, regulatory toxicology4, carcinogenicity weight-of-evidence criteria5, best practice6

Received: 28 Jan 2024; Accepted: 03 May 2024.

Copyright: © 2024 Vahle, Dybowski, Graziano, Hisada, Lebron, Nolte, Steigerwalt, Tsubota and Sistare. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. John Vahle, Lilly Research Laboratories, Eli Lilly (United States), Indianapolis, United States Mx. Frank Sistare, Merck (United States), Kenilworth, 07033, New Jersey, United States

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