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EDITED BY
Janet Sultana,
Mater Dei Hospital, Malta
REVIEWED BY
Andrea Aiello,
Intexo Società Benefit, Italy
Patricia Vella Bonanno,
University of Malta, Malta
John Borg,
Malta Medicines Authority, Malta
*CORRESPONDENCE
Cassandra M. Nighswander
cassandra.nighswander@alirahealth.com
Claudia Leopaldi
claudia.leopaldi@alirahealth.com
†
These authors have contributed equally to this
work and share first authorship
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This article was submitted to Regulatory Affairs,
a section of the journal Frontiers in Medical
Technology
RECEIVED 17 November 2022
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PUBLISHED 20 February 2023
CITATION
Mantovani A, Leopaldi C, Nighswander CM and
Di Bidino R (2023) Access and reimbursement
pathways for digital health solutions and in vitro
diagnostic devices: Current scenario and
challenges.
Front. Med. Technol. 5:1101476.
doi: 10.3389/fmedt.2023.1101476
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terms.
Access and reimbursement
pathways for digital health
solutions and in vitro diagnostic
devices: Current scenario and
challenges
Andrea Mantovani1,2†, Claudia Leopaldi1,2*†,
Cassandra Maria Nighswander1,2*†and Rossella Di Bidino3
1
Alira Health, Milan, Italy,
2
Alira Health, Basel, Switzerland,
3
Fondazione Policlinico Universitario Agostino
Gemelli IRCCS, Graduate School of Health Economics and Management (ALTEMS), Rome, Italy
Objectives: Digital therapeutics (DTx) are innovative solutions that use meaningful
data to provide evidence-based decisions for the prevention, treatment, and
management of diseases. Particular attention is paid to software-based in vitro
diagnostics (IVDs). With this point of view, a strong connection between DTx
and IVDs is observed.
Methods: We investigated the current regulatory scenarios and reimbursement
approaches adopted for DTx and IVDs. The initial assumption was that countries
apply different regulations for the access to the market and adopt different
reimbursement systems for both DTx and IVDs. The analysis was limited to the
US, European countries (Germany, France, and UK), and Australia due to
maturity in digital health product adoption and regulatory processes, and recent
regulations related to IVDs. The final aim was to provide a general comparative
overview and identify those aspects that should be better addressed to support
the adoption and commercialization of DTx and IVDs.
Results: Many countries regulate DTx as medical devices or software integrated
with a medical device, and some have a more specific pathway than others.
Australia has more specific regulations classifying software used in IVD. Some
EU countries are adopting similar processes to the Digital Health Applications
Abbreviations
AI, artificial intelligence; ARTG, Australian register of therapeutic goods; BfArM, Bundesinstitut für
Arzneimittel und Medizinprodukte; ASA, American society of anesthesiologists; CAGR, compound annual
growth rate; CDx, companion diagnostics; CE, Conformitè Europëenne; CLFS, clinical laboratory fee
schedule; CMS, centers for medicare and medicaid services; CNEDIMT, Commission nationale d’évaluation
des dispositifs médicaux et des technologies de santé; CPT, current procedural terminology; CTTI, clinical
trials transformation initiative; DHT, digital health technology; DiGA, digital health applications; DiGAV,
Digitale-Gesundheitsanwendungen-Verordnung; DTAC, digital technology assessment criteria; DTC, direct-
to-consumer; DTx, digital therapeutics; DVG, Digitale-Versorgung-Gesetz; EC, European commission; EDL,
essential in vitro diagnostics; EFTA, European free trade association; EMA, European medicines agency;
ESF, evidence standards framework; EU, European union; FDA, food and drug administration; FTC, federal
trade commission; G-BA, Gemeinsame Bundesausschuss; GSP, genome sequencing procedure; HAS, Haute
Autorité de Santé; HIPPA, health insurance portability and accountability act; HR-pQCT, high-resolution
peripheral quantitative computed tomography; HTA, health technology assessment; ICER, incremental cost-
effectiveness ratio; InEK, Institut für das Entgeltsystem im Krankenhaus; IT, information technology; IVD,
in vitro diagnostics; IVDR, in vitro diagnostic regulation; MAC, medicare administrative contractor; MBS,
medical benefits schedule; MDR, medical device regulation; MTEP, medical technologies evaluation
program; MTG, medical technology guidance; NHS, national health service; NICE, national institute for
health and care excellence; P&R, pricing and reimbursement; PAMA, protecting access to medicare act;
PBAC, pharmaceutical benefits advisory committee; PLA, proprietary laboratory analyses; PMA, pre-market
approval; SA, service attendu; SaMD, software as a medical device; SiMD, software in a medical device; SFS,
structural fragility score; SHI, statutory health insurance; TGA, therapeutic goods administration; WP, work
packages
TYPE Review
PUBLISHED 20 February 2023
|
DOI 10.3389/fmedt.2023.1101476
Frontiers in Medical Technology 01 frontiersin.org
(DiGA) under Germany’s Digitale-Versorgung Gesetz (DVG) law, which deems DTx eligible
for reimbursement during the fast access pathway. France is working on a fast-track system
to make DTx available to patients and reimbursable by the public system. The US retains
some coverage through private insurance, federal and state programs like Medicaid and
Veterans Affairs, and out-of-pocket spending. The updated Medical Devices Regulation
(MDR) and In Vitro Diagnostic Regulation (IVDR) in the EU includes a classification system
specifying how software integrated with medical devices, and IVDs specifically must be
regulated.
Conclusion: The outlook for DTx and IVDs is changing as they are becoming more
technologically advanced, and some countries are adapting their device classifications
depending on specific features. Our analysis showed the complexity of the issue
demonstrating how fragmented are regulatory systems for DTx and IVDs. Differences
emerged in terms of definitions, terminology, requested evidence, payment approaches
and the overall reimbursement landscape. The complexity is expected to have a direct
impact on the commercialization of and access to DTx and IVDs. In this scenario,
willingness to pay of different stakeholders is a key theme.
KEYWORDS
digital therapeutics, in vitro diagnostics, reimbursement, regulatory, access, software, device, digital
health
1. Introduction
The World Health Organization (WHO) recently released the
global strategy on digital health as a visionary document that
provides a framework for countries to implement and expand
digital health services. The vision of the strategy is to improve
for everyone and everywhere the access to appropriate, accessible,
affordable, scalable, and sustainable person-centric digital health
solutions to prevent, detect and respond to epidemics and
pandemics. The strategy is to support the development of
infrastructures and applications that enable countries to use
health data to promote health and well-being. The aim of the
WHO’s Global Strategy on Digital Health 2020–2025 is to
develop partnerships at the national, regional and global levels to
align resources and investments to focus on sustainability and
growth of digital health (1).
To reach these goals the regulation related to the access to the
market and criteria adopted for reimbursement play a crucial role.
As recognized by the WHO, digital health solutions could help in
disease detection. Key technologies for disease detection are In Vitro
Diagnostic Devices (IVDs). They are used in clinical, laboratory or
outpatient settings with the aim specifically to help in the detection
of diseases and, as a consequence, in the selection of appropriate
treatment protocols. Nowadays, the use of digital technology in
healthcare is a way to increase access to diagnostic and triage
services and may improve the quality of this process (2). Emerging
solutions including the use of artificial intelligence, health bots,
online triage systems may present opportunities for patient care
and address issues of high costs and time consumption (2).
Therefore, more attention must be paid to software. Under that
point of view a strong connection among Digital Therapeutics
(DTx) and IVDs emerged.
For those reasons our analysis focused on a specific subset of
health technologies, (DTx and IVD) and on a specific phase of
their cycle of life (access to the market and reimbursement).
2. Background
2.1. Digital therapeutics (DTx)
Digital health is an umbrella term that encompasses a variety of
terms, including e-health, m-health and telehealth and captures
everything from electronic patient records, remote monitoring,
connected devices, digital therapeutics and more.
Despite disagreement in the definition of digital health (3), it is
clearly how the digitalization of health is associated with a long list
of aspects from appropriate management of big data to reliability of
Artificial Intelligence (AI)/Machine Learning (ML) algorithms. Not
secondary, it is the need to guarantee information security and
allow to patient real control over their own health data.
The global digital health market was expected to reach US$
881 Billion in 2021, with a CAGR (Compound Annual Growth
Rate) of 20.14% in 2027 (4). Growing smartphone adoption,
better Internet connectivity, improved healthcare information
technology (IT) infrastructure, an increase in the prevalence of
chronic diseases, a rising demand for remote patient monitoring
services, and easier access to virtual healthcare, will all contribute
to the market growth.
Not all digital health technologies have the same clinical value.
We decided to focus our attention on Digital Therapeutics (DTx),
which are evidence-based therapeutic interventions driven by
software to prevent, manage, or treat a medical disorder or
disease (5). DTx are patient-facing software applications that
have a proven clinical benefit. For example, DTx can support
patients in self-managing symptoms and thereby improve their
quality of life and other clinical endpoints. Digital Therapeutics
use digital implements, such as mobile devices, apps, sensors,
virtual reality, the internet of things, and other tools to spur
behavioral changes in patients. So far, about 250 different
products have been identified with about 150 of these being
commercially available (6). Digital therapeutic development can
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Frontiers in Medical Technology 02 frontiersin.org
have a positive impact on providing well customized health services
as their design is tailored to fit patients’needs.
Digital Therapeutics are either as a standalone therapy or in
conjunction with more conventional treatments, such as
pharmacological or in-person therapy or with certain hardware or
other sensory or mechanical devices. The treatment depends on the
collection and processing of digital measurements. Because of the
digital nature of the methodology, data is collected and analyzed as
both a progress report and a preventative measure. Currently,
treatments are developed for the prevention and management of a
wide variety of diseases and conditions, such as type II diabetes (7),
congestive heart failure (8), Alzheimer’s disease (9), anxiety,
depression (10), and several others.
Taken together, this patient-centered disruption is rapidly
changing how the industry operates and how services are
developed and delivered, rebuilding relationships between key
stakeholders such as the research-based industry, patients,
healthcare professionals, health institutions, and regulators. The
tools and technologies that will reshape healthcare are rapidly
becoming available in hospitals and homes across Europe. The
transition to a more digital hospital infrastructure requires
investments from people, technological platforms, and processes. If
working together properly, the integration of digital technologies
can result in higher quality care, improved operational efficiencies,
and increased patient satisfaction (11).
2.1.1. DTx regulations and reimbursement
pathways
Given their potential role in the delivery of care, the use of DTx
should be proven through clinical trial studies to demonstrate their
clinical efficacy and should be evaluated by Health Technology
Assessment (HTA) bodies in order to be reimbursed and
prescribed by physicians, as it happens with medicinal products.
Our study moved from a double assumption: countries differ in
their regulatory systems for digital health solutions and therefore
for DTx, in addition these systems are not yet fully prepared to
regulate DTx, and all other health technologies associated with
them, as IVDs.
Indeed, currently, countries have an applicable framework
for digital solutions, they are included under the regulatory
framework for medical devices, software as a medical device
(SaMD), or software in a medical device (SiMD). Products within
these frameworks are categorized into classes based on their risk
classification. Occasionally, in DTx products are included in these
classifications depending on a countries’regulations. Countries
differ in their guidelines to allow the product to be recognized for
approval by regulatory bodies. Some countries may not have any
established guidelines that fit DTx products and reimbursement
may be unlikely due to a lack of incentive.
For each country in scope (US, Germany, France, UK, and
Australia), the regulatory status is outlined and preceded by a
brief description of the institutions involved. Relevant
reimbursement opportunities in terms of public coverage, private
coverage, employer-sponsored, and consumer-funded healthcare
are identified. This provides a setting for the challenges and
opportunities that will be mentioned later in this manuscript.
2.2. In vitro diagnostic devices (IVDS)
In vitro diagnostics are recognizedas a diagnostic test that is done
on blood or tissue samples extracted from the human body to detect
diseases or give an overall view of a patient’s health condition. They
are typically used in laboratories, but some forms can be used in
one’s home. For instance, direct-to-consumer (DTC) IVDs are
diagnostic tests that require the consumer to collect a specimen to
send to a laboratory for analysis to assess one’s risk for developing
a disease.
Regardless of the setting of use, there are different types of IVDs
that can be used depending on the patient’s condition or what type
of treatment they are likely to benefit from. Next-generation
sequencing tests are useful tools to utilize precision medicine in
treating patients for diseases, while Companion Diagnostics (CDx)
are IVDs that are used in combination with a therapeutic drug and
are strictly link to the identification of biomarkers. For instance,
CDx could help to identify the appropriate patient group most likely
to benefit from a therapeutic product, to predict serious adverse
reactions, or to monitor the response to treatment in order to
improve the dosage scheme (12).
Disruptive diagnostics is a term used to describe innovative
technologies able to make diagnostic products more effective,
efficient, and accurate (13). It describes many forms of diagnostic
tests, such as genome sequencing and imaging techniques, but more
recently has included Artificial Intelligence or Machine Learning
based diagnostic tools. These specific diagnostics use Al algorithms
known as deep learning to completely interpret information from
large amounts of data. New technologies utilizing AI are being
developed for many indications to increase efficiency, reduce time to
treatment, lower costs, and allow for more precise and effective
therapies. In genomic testing diagnostics, deep learning is be used to
identify cancer cells, determine their type, and predict what
mutations may occur in a tumor from images of a specificcancer(14).
2.2.1. In vitro diagnostic regulations and
reimbursement pathways
The WHO uses three strategic priorities to emphasize the
importance of having IVDs available to those who need them.
These priorities include access to quality, affordable, and
appropriate healthcare products to advance universal health
coverage, address health emergencies, and promote healthier
populations. The WHO prequalification team evaluates the safety
and performance of tests according to international standards so
they can be eligible for procurement. This can give countries the
opportunity to determine if they should purchase certain
diagnostics. In addition, the WHO maintains a list of IVD
recommended at the point of care that should be used in every
country, the WHO Model List of Essential In Vitro Diagnostics
(EDL). The IVDs on this list are endorsed by the latest clinical
evidence to support their use everywhere. Developments of IVD
regulations depend significantly on how medical devices are
classified. These regulations, as well as those of digital health
solutions are subject to adaptation, because of the advancements
within the world of medical technology (15).
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3. Aim of the analysis
We investigated the current regulatory scenarios and
reimbursement approaches adopted for DTx and IVDs. The starting
assumption was that countries apply different regulations for the
access to the market and adopt different reimbursement systems for
both DTx and IVDs.
Our specific focus was on the international context where digital
approaches (software) to disease detection are becoming quite
common. The analysis was limited to the US, European countries
(Germany, France, and UK), and Australia due to maturity in
digital health product adoption and regulatory processes, and recent
regulations related to IVDs. Nonetheless their market relevance was
taken into account.
Our attention, as stated, was concentrated on the regulatory
and reimbursement processes. With the term regulatory we
referred to the process that must be followed to access to the
market, while with reimbursement processes, we meant steps and
criteria followed to define the price reimbursed by a public or
private institution.
The final aim was to provide a general comparative overview
and identify those aspects that should be better addressed to
support the adoption and commercialization of DTx and IVDs.
4. Methods
A scoping review of publications and grey literature was
conducted to understand the current regulatory scenarios and
reimbursement approaches adopted for DTx and IVDs.
First, grey literature review was conducted for DTx to understand
the current level of usage, acceptability, reimbursement, and
assessment. The review included the U.S. Food and Drug
Administration (FDA), the European Medicines Agency (EMA)
and main Health Technology Assessment (HTA) agencies public
reports. Included HTA agencies were: National Institute for Health
and Care Excellence (NICE) for United Kingdom, Haute Autorité
de Santé (HAS) for France, Gemeinsame Bundesausschuss (G-BA)
for Germany, and the Pharmaceutical Benefits Advisory Committee
(PBAC) based in Australia.
For the scoping review on IVDs, an analysis was done of the
regulatory guidelines for IVDs in each country. Updated laws and
pathways were covered to assess the present and future landscape of
usage of IVDs in healthcare practices. In appropriate situations,
the regulation of Software in IVDs was assessed to show the
acceptability of digital maturity in certain countries.
In addition, one important source was the DTx Alliance
(DTA), a non-profit trade association of industry leaders
and stakeholders dedicated to providing information on the
background, current access status, and value of DTx products in
select countries. It is the leading international organization on
digital therapeutic thought leadership and education.
In-depth information was uncovered and helped facilitate a
comparison across the countries in scope considering the pathways
for DTx, gaps in access, and future prospects for DTx integration.
The specific categories of information assessed from Digital
Therapeutics Alliance (DTA) were product category, regulatory
agency involved, product risk classifications, regulatory review,
pre-submission opportunities, regulatory guidelines, and product
recognition. The same process was performed for reimbursement
opportunities, which included information on public and private
insurance coverage, employer-sponsored healthcare, and consumer
funding status. The most relevant types of coverage were reported.
5. Results
In this section, we provide a brief description of the agencies
and national bodies involved in regulatory and reimbursement
decisions that are relevant for DTx and IVDs. The purpose is to
give a general overview of the bodies involved in the entire
adoption and commercialization process of a product.
Data reported in Tables 1,2is the base of our analysis.
In Table 1 the main regulatory and reimbursement agencies for
medical technology for each country are specified to introduce the
bodies involved in these processes.
Table 2 lists the relevant documents that contains existing
guidelines DTx and IVDs must follow to be regulated in given
countries.
In the following, more details are reported for each selected
country. In addition, when investigating the specific national
scenario, reimbursement options are specified given that both
digital therapeutic and in vitro diagnostic devices may be
reimbursed through public or private insurance options or other
TABLE 1 Agencies involved in the regulation and reimbursement of
medical technology.
Country Main regulatory
agency
Reimbursement/HTA
agency
USA The FDA is responsible for
approving new DTx within
the software-as-a-medical-
device category.
Depends on the classification of
the device and the level of
coverage requested (Medicare,
Medicare Advantage, Medicaid,
the Department of Defense)
Germany The Federal Institute for
Drugs and Medical Devices
(BfArM) and The German
Institute of Medical
Documentation and
Information (DIMDI)
Institute for the Hospital
Remuneration System (InEK)
France National Agency for the
safety of Medicines and
Health Products (ANSM)
National Commission for
Evaluation of Medical Devices
and Health Technologies
(CNEDiMTS)
United
Kingdom
Medicines and Healthcare
products Regulatory Agency
(MHRA)
National Institute for Health and
Care Excellence (NICE); local
commissioning groups (CCGs)
Australia Therapeutic Goods
Administration (TGA) for
medical devices
The Medical Services Advisory
Committee makes
recommendations on inclusions
in Medical Benefits Schedule
(MBS)
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Frontiers in Medical Technology 04 frontiersin.org
solutions (as out-of-pocket payments or employee sponsored
healthcare (20).
5.1. DTx regulatory status
5.1.1. US
The FDA is responsible for approving new DTx within the
software-as-a-medical-device (SaMD) category. It is explicitly
recognized that they are developed and validated differently than
traditional medical devices (defined as hardware-based MD).
FDA supports various plans to advance digital health technology
approvals, including the Software Precertification (Pre-Cert) Pilot
Program launched in July 2017 and concluded in September 2022
(21). This program is expected to inform the development of a
future regulatory model that provides more streamlined and efficient
oversight of software-based medical devices. One of the most
relevant conclusions of the pilot is the emerged need of an
“appropriate new legislative authority…to support the development
and implementation of a new regulatory paradigm”, while FDA will
continue to develop policies and tools within the current authorities.
That the main reason of the creation of the Digital Health Center of
Excellence, whose mission is meanwhile to provide advice and
support for the regulatory review of digital health technology.
Strictly related are the regulations and guidelines defined by:
•The Health Insurance Portability and Accountability Act
(HIPAA), which protects the privacy and security of certain
health information.
•The Federal Trade Commission (FTC) Act, which prohibits
deceptive or unfair acts, including false or misleading claims
about safety and performance of apps.
•The FTC’s Health Breach Notification Rule which requires
certain businesses to provide notifications following breaches
of personal health record information (22). These guidelines
are applicable under all circumstances.
For medical devices, including SaMD, the US has a specific process
in which the product is classified by risk, either as:
•Class I (general controls)
•Class II (special controls in addition to general controls)
•Class III (premarket approval in addition to general controls)
Some Class I and II products are exempt from marketing
submission but must still register and list with the FDA.
Some following pathways for regulatory review are the 510(k)
pathway, which is a pre-market submission for medical devices to
be approved by the FDA, the De Novo pathway, which requires a
market authorization to demonstrate assurance of safety and
efficacy, and the Pre-market Approval (PMA) pathway, which is a
stringent market submission to demonstrate safety and effectiveness.
A clinical trial is generally required for the PMA pathway. As
product recognition, Class I and II exempt are FDA coded only
if a product code exists and enforcement discretion products are
not FDA listed. Class II products are FDA cleared under the 510
(k) pathway, and FDA granted under the De Novo pathway.
Class III products are FDA approved under the PMA pathway (22).
Another pathway that is voluntary for some medical devices
and device-led combination products the Breakthrough Devices
Program. This has replaced the Expedited Access Pathway and
Priority Review for medical devices and helps accelerate the
market approval of products that can be effective for life-
threatening or debilitating conditions.
5.1.2. EU member states
At the European level, the regulation, (EU) 2017/745, is a
regulation of the European Union on the clinical investigation
and sale of medical devices for human use. No specific legal
regulation exists on DTx while the EMA and the European
Commission (EC) are beginning to explore these solutions.
Compared with the US, Europe appears as a fragmented with no
single harmonized process for national body approval and
reimbursement. It is a hard-to-crack market for DTx innovators,
even with new regulations such as MDR (EU Regulation 2017/
745). Some European countries have their own unique way of
assessing digital health, meaning that they have a lower reward
than the bigger markets (i.e., the USA).
However, the European Commission (EC) is proposing the
European Health Data Space, for digital transformation in all EU
member states, including regulations for data privacy, EU
General Data Protection Regulation, medical devices, AI, and
HTA (23). This is an ecosystem comprised of health-related rules
and regulations, standards, and a common framework to support
the emergence of digital health practices. This has the goal of
empowering individuals through the use of digital health and the
control of personal data. This action will aim to increase trust in
systems handling personal data, and foster innovation in policy
making and regulatory activities.
At a national level, some European countries, such as Germany
and France use a consistent framework for classifying products for
regulatory review. The DTx manufacturer must first complete a
self-assessment risk clarification in accordance with the standards
defined by the Medical Device Coordination Group (MDCG) to
determine the level of CE mark necessary for the product. The
framework comprises Class IIa, which includes most DTx
TABLE 2 Documents containing guidelines for the regulation of digital
therapeutics and in vitro diagnostics.
Country Guidelines to be met
for digital
therapeutics
Guidelines to be met for
in vitro diagnostics
US Title 21 of the Code of Federal Regulations (21 CFR)
Germany Medical Device Regulation
(MDR) (16)
In Vitro Diagnostic Regulation
(IVDR) (16)
France
UK The Medical Technologies
Evaluation Program
(MTEP)
The Medical Device Regulations
2002 (17)
Australia How the TGA regulates
software-based medical
devices (18)
Australian regulatory guidelines
for medical devices (ARGMD)
(19); Principles of In Vitro
Diagnostic (IVD) Medical Devices
Classification
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Frontiers in Medical Technology 05 frontiersin.org
software, and Class IIb, which includes DTx products with higher
risks or consequences. Class I DTx do not qualify for regulatory
review and remain under MDR. For product recognition,
countries in the EU require a CE mark (20).
5.1.3. UK
According to the DTA, UK still regulates DTx products under
the MDR to determines the necessary CE mark. The types of
products that qualify for regulatory review remain the same as
those in France and Germany. UKCA mark requirements will be
updated soon, however they are still derived from the EU CE
Mark regulations. Product recognition with a CE Mark will
remain this way until July 2023 (20).
For software and AI-based medical devices, the MHRA has
announced a new program, the Software and AI as Medical
Device Change Programme to emphasize the inclusion of these
types of devices in regulatory processes. The Change Programme
will identify the necessary steps for a regulatory framework to
protect these DTx and other software-based medical devices. The
UK government has highlighted some key points to describe
their approach in the implementation of this program. With the
expansion of AI and software in medical devices, a priority of
this program is to cover possible regulations to ensure these
devices are used safely and responsibly. A deeper focus on
patient engagement and communities will also be a key priority
as the purpose is for these devices to follow the proper regulation
and reach users successfully (24).
Work packages (WP) were established to understand the
problems that needed to be addressed in order to move forward
with a successful regulatory framework including software and
AI-based medical devices WP1 covers the qualification of SaMD
and software in medical devices to establish a clear definition of
these types of products according to these updated regulations.
Specific guidance will be published to understand certain
scenarios that bring uncertainties when regulating medical
devices with a software component:
•SaMD versus wellbeing and lifestyle software products
•Medical device software versus IVD software
•Research use only “exemption”For SaMD
•Custom made devices
•Requirements for software in a kit/software system/software in
procedure pack/software as a service
•Accessories to a medical device or IVD
Other WPs cover topics including Classification, Premarket
requirements, Post market surveillance, Cyber Secure Medical
Devices, AI Rigor, AI interpretability, and AI Adaptivity. The overall
purpose of these WPs is to ensure safe adoption and use and protect
patients while simultaneously accelerating innovation (24).
5.1.4. Australia
The Therapeutic Goods Administration is responsible for
regulating DTx in Australia. There is a specific framework for
regulating software-based medical devices. Any regulated product
that meets the definition of a medical device, and is not excluded
or exempt, is required to be listed in the Australian Register of
Therapeutic Goods (ARTG). If a device is excluded or exempt, it
means the TGA lacks some authority over the regulation of this
device, and therefore does not have to be listed. There are three
steps for a device to be placed on the ARTG:
1. The manufacturer must obtain a certification from the TGA or
a comparable oversees regulator. This is only required for
manufacturers of class II and above medical devices.
2. The sponsor of the medical device must submit the
manufacturer’s certificate to the TGA before submitting and
ARTG application
3. The sponsor must then submit the ARTG inclusion application
A pre-submission process is available for any TGA submission and
can be requested at any stage of the submission process, with the
proper documentation present (marketing documents, data,
instruction manuals).
All DTx products must comply with the Essential Principles,
with various relating to SaMD. All other Essential Principles that
apply to the product must be considered. Clinical evidence is not
necessarily required, however, many innovative, class II, and class
III products may require an RCT (20).
5.2. DTx reimbursement pathways
5.2.1. Summary
Reimbursement options for DTx varyamong countries discussed.
Coverage may be available situationally (e.g., therapeutic area) or due
to the type of insurance scheme. Table 3 summaries the implications
of the current scenario in terms of coverage of DTx to highlight the
possibilities and limitations present in each country. Coverage
possibilities analyzed include public and private insurance schemes,
employer sponsored coverage, and consumer funded coverage.
5.2.2. US
Regarding reimbursement in the US, there are different
possibilities depending on the classification of the device and the
level of coverage requested.
With public coverage, there are different subsets of government
funded insurances that apply to digital health solutions. These
include Medicare, Medicare Advantage, Medicaid, and coverage
by the Department of Defense. Medicaid care plans may consider
fee-for-service coverage or benefit-program coverage on a state-
by-state basis. The Department of Defense covers some DTx
products that have a hardware component.
With private insurance, some products are covered through
a fee-for-service basis. Exempt DTx medical devices and
enforcement discretion classified medical devices are reimbursed
through a set of unique device identifier codes. Regulated Class II
and III medical devices may or may not require a prescription (20).
5.2.3. Germany
On 19 December 2019, the Digital Supply Act (DVG) came
into force in Germany. This meant that since 2020, clinicians
have been able to prescribe, and Statutory Health Insurance
(SHI) funds reimburse medical apps and digital health
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treatments (DiGA—BfArM). To ensure such treatments are
available to patients as quickly as possible, the regulatory agency,
Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM),
has developed a new process to speed up reimbursement: the
DiGA Fast-Track. Germany has established pathways for the
reimbursement of DTx through the DiGA pathway and selective
contracts with SHIs. Products listed on the DiGA directory are
fully reimbursed by SHIs. The BfArM is responsible for decisions
regarding DiGA listings.
The BfArM assesses these DiGA treatments in terms of patient
benefit, data protection and information security and quality. After
an application is received, the BfArM has 3 months to check
whether the products meet the requirements set out in the DiGA
Ordinance. However, the manufacturers must also prove that the
app has a positive effect on patient care. If the assessment is
successful, the product can then be included in the DiGA list.
The products on this list can then be prescribed and are covered
by SHI funds (25).
To be included in the DiGA directory, products must meet the
following specific requirements:
•be a Class I or IIa medical device, compliant with Annex I and II
of DiGAV on data protection, IT security, interoperability,
robustness, consumer protection, ease of use, support of
healthcare providers, quality of medical content and patient
safety
•proveatleastonehealthcarebenefit positive Versorgungseffekte)
which could be a medical benefit or patientenrelevante Struktur-
und Verfahrensverbesserungen
•demonstrate clinical relevance in a retrospective study,
preferably a randomized control trial. It is possible to have
a permanent listing where all requirements are filled or a
preliminary listing where there are 12 months for clinical
evidence to be submitted. Selective contracts allow for full or
partial reimbursement from negotiating with individual SHIs
to deciding on reimbursement of individual SHIs (25).
5.2.4. France
When the value of the DTx has been assessed, the second step
is the negotiation of the price. Currently, the actors involved are the
company and the CEPS (26).
While for DTx which are not eligible to the standard procedure
or in the absence of robust demonstration of their clinical benefit/
risk profile, other pathways are possible, as in the case of
telemonitoring experimentation.
In 2023 a new regulation for reimbursement of DTx is
expected. Agence du Numérique en Santé, the HAS (Haute
autorité de santé) and the ANSM (Agence nationale de sécurité
du medicament et des produits de santé), are developing
guidelines taking as reference the German experience (27).
To be eligible for reimbursement in France and funded through
the standard P&R procedure regarding medical devices, DTx will
need to provide:
•A CE marking as a medical device and privacy
•Compliance with EU General Data Protection Regulation
•A General Health Technology Assessment carried out by the
Commission nationale d’evaluation des dispostifs médicaux et
des technologies de (CNEDIMT) and HAS
•An actual medical benefit assessment
•A Clinical Evidence Evaluation
•A demonstration of clinical and socio-economic added value
•However, up to now, there are no current reimbursement
pathways for DTx products, but it is possible to make
individual funding decisions (28).
Firstly, the CNEDIMTs gives an opinion on the actual medical
benefit, a Service attendu (“SA”). The opinion about SA
determines whether the connected medical device is reimbursed
(SA sufficient) and the rate of its reimbursement by the French
national health insurance (important SA: 65% reimbursement,
moderate: 30%; low: 15%) or not (insufficient medical benefit).
The SA must take into consideration: severity of the disease,
efficacy/adverse effects ratio, intended role in the therapeutic
strategy in comparison with other available interventions, public
health benefits. To be eligible for reimbursement, the DTx must
demonstrate a sufficient efficacy/safety ratio in a robust clinical
study. The HAS published guidelines to explain how to develop a
digital therapeutic which complies with the French HTA
requirements and which elements are needed to be favorably
assessed by the CNEDIMTs (28).
If the SA is evaluated sufficient, the CNEDIMTs gives its
opinion as well on the “Added Medical benefit assessment”
TABLE 3 Reimbursement landscape in given countries.
Country Public health insurance Private health insurance Employer sponsored Consumer funded
US Products covered depending on insurance scheme Most products covered, with some
limitations
Coverage available through
direct negotiation
Out-of-pocket
payments possible
Germany Statutory health insurance coverage; Digital health
product directory (DiGA); selective contracts
Not obliged to cover products but
possible through direct negotiation
Not common Low willingness to pay
out-of-pocket
France Individual funding decisions; Some experimental
coverage options
Some coverage of specific items Not common Low willingness to pay
out-of-pocket
UK No national reimbursement, local organizations for
funding and reimbursement
Some products partially covered, but
not a common route
Not common Low willingness to pay
out-of-pocket
Australia Some schemes available depending on therapeutic
area
Some products covered depending on
benefit and efficiency gains
Protection insurance providers
may fund digital health
Difficult; co-pays
common
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[America Society of Anesthesiologist (ASA)]. The added medical
benefit measures the digital therapeutic added clinical value
compared with existing interventions already reimbursed and is
used to determine the price. The digital therapeutic is innovative
when the assessment is from ASA I to III. If the new digital
healthcare product brings a minor improvement compared to the
current strategy, the assessment is an ASA IV. In case of no
improvements of the clinical value compared with other
alternatives, the assessment is an ASA V (28).
5.2.5. UK
Funding and reimbursement of DTx in the UK is done on a
local level by NHS organizations. There are 43 integrated care
systems (ICSs) responsible for DTx funding. Digital Therapeutics
and other digital health products are included in the national
NHS library if they fulfill the necessary criteria in the Digital
Technology Assessment Criteria (DTAC) framework. However,
this does not imply reimbursement (29). Evidence demonstrating
the safety and efficacy of the device will be necessary to prove it
is worth being funded. There is an alternative approach through
a separate ring-fenced budget, however, this route may hinder
the ability of HCPs to provide the best treatment pathways
for patients and discourage the integration of DHTs into
treatment pathways.
The NHS has identified three key criteria that DHTs must meet
in order to receive funding:
1. Be appropriately CE/UKCA marked to be placed on the
market in the UK, ensuring that the device is safe, and works
as described by the manufacturer
2. Pass the DTAC to ensure that they meet core standards for
clinical safety, data protection, security, interoperability,
accessibility, and usability; and
3. Be recommended by NICE, to ensure they are plausibly
cost-effective and therefore represent value for the NHS (30)
The purpose of having these criteria in place is to create a high
standard and set an example for other countries to follow.
Having standards to follow can also promote innovation by
having clear access and reimbursement mechanisms in place to
follow.
5.2.6. Australia
Reimbursement for DTx through public health insurance may
be possible in certain circumstances depending on the therapeutic
area, if the digital product is in companion to a device, prosthetic,
therapeutic, or service. Schemes include:
•Pharmaceutical Benefits Scheme (PBS)
•Medical Benefits Schedule (MBS)
•National Diabetes Services Scheme (NDSS)
•National Disability Insurance (NDIS)
Although there is no direct pathway for coverage of DTx through
private insurance, some insurers may decide to engage if the
product reduces cost of care, creates efficiency gains for the
health insurer, or increases engagement (31).
5.3. IVD regulatory status
5.3.1. US
The FDA classifies IVDs as medical devices into Class I, II, or
III according to its risk to assure safety and effectiveness in practice.
It is possible for an IVD to be classified as a biological product,
which would be subject to section 351 of the Public Health
Service Act. An early classification of the IVD will determine
which regulatory path to take (32). The classification of existing
IVDs can be found in the Code of Federal Regulations list,
specifically in 21 CFR 862, 21 CFR 864, 21 CFR 866.
Like other medical devices, IVDs are subject to premarket and
post-market controls. There are a few relevant processes conducted
by the FDA to assess the quality of the product and the relevance of
any related issues.
A pre-submission process is encouraged by the FDA in some
circumstances in order for the submitter to receive feedback.
Some circumstances include:
•If the device involves a new technology, intended use, or analyte,
so the FDA can be informed on the use of this novel feature
•If there is assistance needed in defining regulatory pathways
•If the study involves complex data
•If the predicate or reference method is unclear or uncertain
•If the new device is a multiplex device capable of simultaneously
testing a large number of analytes (33)
A 510(k) pathway review process for IVDs evaluates the analytical
performance of the device compared to the predicate including
measures like bias or inaccuracy of the new device, the imprecision
of the new device, and the analytical specificity and sensitivity.
A premarket approval (PMA) is a process where the FDA
evaluates the safety and effectiveness of Class III. For IVDs
specifically, the safety is linked the impact of the device
performance on the patients’health, specifically the what the
impact would be from a false negative or false positive.
New guidelines have been developed to re-assess the inclusion of
Laboratory Developed Tests (LDTs) as IVDs. The FDA issued a draft
guidance and a discussion paper that outlines regulatory requirements
and limitations surrounding certain types of LDTs (34).
5.3.2. EU member states
The In Vitro Diagnostic Regulation (IVDR) is the new regulatory
basis for placing on the market, making available, and putting into
service in vitro diagnostic medical devices on the European market
and the EU’s current directive on in vitro diagnostic medical devices
which will be replaced (98/79/EC). As a European regulation, it will
be effective in all EU member states and European Free Trade
Commission (EFTA) states immediately without need to be
transferred into the law of the respective states; however, national
laws may be adapted to support some requirements in more detail.
The IVDR became effective on May 25, 2017. The EC are
implementing several guidance documents to satisfy the
requirements to be met.
Patient safety is central in the new regulation. Various
requirements for manufacturers are imposed to demonstrate that
the medical device is safe and performs consistently as intended
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when it is used as intended by the manufacturer. The current
directive dates from 1998. It is now quite old and no longer fit
for purpose. The introduction of the new directives brings a
more robust set of requirements, which are much more adaptable
to the change over time.
With the start of application, some in-vitro diagnostic devices
fall into higher levels and must be declared compliant for the
first time with the involvement of a Notified Body. Due to the
now phased introduction [Regulation (EU) 2022/112], the
transition periods for all IVD apply as follows:
•For products that already required the involvement of a Notified
Body under the IVDR, 26 May 2025 is the key deadline. For
devices that are newly classified by the IVDR and now require
the involvement of a Notified Body for the first time, the
following deadlines apply regarding the transition periods:
○05.2025—Class D
○05.2026—Class C
○05.2027—Class B
○05.2027—Sterile Class A
Until the above-mentioned deadlines, products can be placed on the
market with a declaration of conformity according to 98/79/EC.
However, the declaration of conformity must be issued before 26
May 2022 and there may not be any significant changes to the
design and purpose of the medical devices before the end of the
transition period. The phased introduction of the IVDR means no
change compared to the previous requirements of the IVDR for in
vitro diagnostic medical devices that do not require the
involvement of a Notified Body. For them, the IVDR will be fully
applicable from 26 May 2022. This concerns the following:
Class A non-sterile devices
•“new”in vitro diagnostic medical devices for which no
certificate or declaration of conformity has yet been issued in
accordance with Directive 98/79/EC (IVDD).
Manufacturers of IVD may still have well-filled warehouses. Therefore,
the question may arise on how to proceed with the remaining goods.
All products can be placed on the market in accordance with the
cut-off date rules mentioned at the beginning of this chapter;
However, placing the remaining goods on the market under
Directive 98/79/EC (IVDD) is no longer possible. Manufacturers
need to implement different strategies to handle IVD stocks (23).
Medical Device Software (MDSW), as intended by the
manufacturer to be used with an IVD, is treated specifically as a
IVD MDSW (23). Specific classifications of this subset of medical
devices are highlighted in Table 4.
In addition to the change in classification rules, there is an
increased harmony between the IVDR and the MDR the equivalent
for medical devices, including a focus on clinical evaluation and
increased transparency through the wider supply chain.
5.3.3. UK
Regulations for IVDs are established in the UK MDR 2002.
This document gives general guidance on different products
considered for approval, the classification of different IVDs, and
the following steps to take once the item is classified.
There are four existing categories which define the risk that the
IVD may pose in a healthcare setting. These categories include:
•General IVDS
•IVDs for self-testing
•IVDs in the classifications stated in Part IV of the UK MDR
2002, Annex II List B
•IVDs in the classifications stated in Part IV of the UK MDR
2002, Annex II List A
A conformity assessment must be followed according to the
category the IVD falls under. Certain requirements must be met
to ensure compliance with designated standards (17).
5.3.4. Australia
IVDs are regulated based on the risk they pose in a therapeutic
setting. The framework that applies to all medical devices applies to
IVDS as well and includes:
•Pre-market assessment—conformity assessment
•Market authorization—inclusion in the ARTG
•And post-market monitoring—continuing compliance with all
regulatory, safety and performance requirements and standards.
IVDs have a separate risk-classification including:
•Class 1—No public health risk or low personal risk
•Class 2—Low public health risk or moderate personal risk
•Class 3—Moderate public health risk or high personal risk
•Class 4—High public health risk
There is a framework available that lists the types of IVD software
that is regulated (31). The five circumstances where IVD software is
regulated are outlined in Table 5.
5.4. IVD reimbursement pathways
5.4.1. US
Considering the reimbursement of IVDs and LDTs in the US,
Medicare has specific processes for billing, coding, and pricing that
are administered by the Centers for Medicare and Medicaid
TABLE 4 MDSW classification under the IVDR.
Type of software/intended purposed Regulation
Software intended to be installed on a fully automated enzyme-
linked immunosorbent assay (ELISA) analyzer, and intended to
determine the Human HbA1c concentration in serum from the
results obtained with a Human HbA1c ELISA, intended to
screen for and diagnose diabetes and monitor diabetic patients
Class C per
Rule 3 (k)
Software within a PAP stain automated cervical cytology
screening system, intended to classify the PAP cervical smear as
either normal or suspicious
Class C per
Rule 3 (h)
Software for the interpretation of automated readings of line
immunoassay for the confirmation and determination of
antibodies to HIV-1, HIV-1 group O and HIV-2 in human
serum and plasma
Class D per
Rule 1
Software that uses maternal parameters such as age,
concentration of serum markers and information obtained
through fetal ultrasound examination for evaluating the risk of
trisomy 21
Class C per
Rule 3 (1)
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Services (CMS). These decisions also act as a baseline for private
insurance companies.
The CMS relies on a network of Medicare administrative
contractors to serve as contact points for healthcare providers
and the Medicare Fee for Service program. Laboratory tests are
reimbursed by the CMS under the Clinical Laboratory Fee
Schedule (CLFS) which defines reimbursement rates for each
type of test. To ensure that reimbursement codes are issued,
updated, and maintained as they should be, Current Procedural
Terminology (CPT) codes are used. The CPT codes are five-
character codes that indicate what type of care has been provided.
For LDTs specifically, Category I CPT codes should be reviewed
to describe the specific diagnostic test. A Medicare Administrative
Contractor (MAC) and private payers are asked to provide
reimbursement. In addition, proprietary laboratory analyses (PLA)
codes are assigned to specific tests defined in the Protecting
Access to Medicare Act (PAMA). These include advanced
diagnostic laboratory tests (ADLTs), clinical diagnostic laboratory
tests (CDLTs), multianalyte assays with algorithmic analyses
(MAAA) and genomic sequencing procedures (GSPs) (35).
5.4.2. European countries
In most of the European countries, IVD tests that are
performed at the hospital, are included in drug related group
(DRG) tariff and laboratories are funded using a global budget
principle. However, in out-patient settings, many countries have
specific reimbursement frameworks for IVD tests, most
commonly using a fee-for-service payment model. Table 6 lists
existing situations for obtaining reimbursement in Germany,
France, and the UK.
5.4.3. Australia
Private insurance is fairly common for patients in Australia to
utilize, with about 44% of the population using private hospital
cover in 2018 (36). Patients can have private insurance for
hospital or general cover. While private insurance can cover a
portion of the associated costs, the remainder is covered by the
Medicare Benefits Schedule or MBS.
The Medicare Benefits Schedule is a list of services which
includes diagnostic tests that the Australian government subsidizes.
6. Discussion
Digital therapeutics are likely to become a critical player in
healthcare in coming years. Self-regulating alone is no longer the
only available option. Government and regulatory agencies are
working on the definition of ad hoc regulatory pathways able to
respond to the specific features of DTx and to their pace of
technological change.
Our analysis showed the complexity of the issue demonstrating
the fragmentation of regulatory systems for DTx and IVDs at
international level. Despite limiting our attention to few
countries, differences emerged in terms of definitions,
terminology, requested evidence, payment approaches and the
overall reimbursement landscape. In the majority of the selected
countries, regulatory pathways for DTx are aligned to those
already adopted for medical devices even in terms in requested
evidence to submit to regulatory agencies. Even if the definition
of DTx is not included in the definition of a medical device, they
are considered a specific kind of medical device as in the case of
FDA, which defines them as SaMD.
The scenario is evolving, however, as demonstrated by the
creation in US of a specific unit inside FDA dedicated to DTx
and the conclusions of the Pre-Cert Pilot Program. It clearly
concluded that a new legislative authority could be necessary in
the near future. The German DiGA is very specific in terms of
the evidence that needs to be submitted for accessing the market.
Some countries have shown interest in working to develop a
similar Framework (37). France has a conditional reimbursement
pathway, PECA (38). This supports a product for reimbursement
while the evidence generation gap is being filled. This pathway
covers remote monitoring solutions where there is no “generic
line”for the specific indication, as well as DTx. To be covered,
there needs to be some promise that an evidence gap will be
closed, and a clinical benefit will be meaningful (38).
TABLE 5 IVD software regulations in Australia.
Type of software/intended
purposed
Regulation
1. Software that is built into an IVD
medical device
The instrument with the installed/
embedded software is a single IVD. The
IVD classification rule 1.6 in Schedule
2A specifies that all instruments that
are IVDs are Class I IVDs
2. Software that is supplied separately
to and IVD medical device but is
intended to operate or influence the
IVD
A distinct IVD that is separate to the
IVD instrument or analyzer. According
to Regulation 3.3 (5) under Principles
for applying the classification rules in
the Regulations, software that drives or
influences a medical device has the
same classification as the medical
device
3. Software that is intended to be used
to provide diagnostic or therapeutic
information and is not intended to
drive or influence an IVD medical
device
An IVD. IVD software that is not
intended to drive or influence an IVD
instrument (or medical device that is
not an IVD) is classified according to
its intended purpose. This applies to
Class II, III, and IV IVDs
4. Software that is intended for
handling patient-related information.
Including results from IVD devices,
which may be used in combination
with an IVD instrument
Does not meet the definition of a
therapeutic good. Software that handles
clinical information and has a
diagnostic and therapeutic function is
considered an IVD. Software that
performs a manipulation on the data
that affects the interpretation of results,
or generates new diagnostic data, makes
the software a medical device
5. Corrections to software errors A correction to the IVD (not a distinct
IVD). Correction to software may be a
product correction under the Uniform
Recall Procedure for Therapeutic
Goods. If the functionality that changes
the intended purpose of the software is
added, the software may be considered
a distinct IVD to the original
Adapted from software as in vitro medical devices (IVDs), therapeutic goods
administration (TGA), 2013. Copyright 2013 by TGA.
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These conclusions could be extended to IVD. With this,
countries are recognizing these technological developments, and
fitting them into national regulations. It is important to note that
the new regulation distinguishes among a software that is
intended to be used, alone or in combination with a medical
device or IVDR. Australia, as noted earlier, also has a specific
guidance on how to classify types of IVDs that involve a type of
software. The US has established some acceptance of software
use in a proposal from 2019, to establish the foundation for pre-
market review for AI and machine learning software
modifications. This, however, does not specify how to handle the
integration of this with IVDs (39).
The complexity is expected to have a direct impact on the
commercialization of and access to DTx and IVDs. In this scenario,
willingness to pay of different stakeholders is a key theme as well as
willingness to consider as part of reimbursement packages.
6.1. Accessibility to DTx
In European countries, approval and reimbursement are
decided separately, slowing down the accessibility of DTx
products. In the US, public and private providers have different
approaches to reimbursement. Private payers are much more
ahead in their willingness to pay for DTx products. Medicare, as
one of the public healthcare providers, has no mechanism for
reimbursing DTx. Since there is no broad system and DTx
products may be categorized at different levels due to differing
mechanisms and benefits, they are evaluated by payers on an ad-
hoc basis. In the US, since each DTx product is not reimbursed
based on specific criteria, it could be reimbursed using a few
different approaches. These include out-of-pocket payments by
patients, as a medical device where the app is sold to a hospital
based on its medical benefit, or via a health savings account (20).
Europe has quite advanced public reimbursement systems in
comparison to the US, with more established reimbursement
methods; however, inconsistencies among countries makes it
difficult to accommodate all DTx products, IVD-related included.
Some European countries may be ahead in terms of
reimbursement. For example, Germany is setting the stage for
advanced, fast-tracked methods for reimbursement through the
DiGA pathway for digital health apps, and some countries, such
as France are trying to adopt similar methods. However, there are
still challenges regarding reimbursement opportunities that limit
scalability, given that regulatory frameworks differ among
countries and that the regulatory framework is being standardized
in the EU Member States, with the UK no longer in the EU.
There are some issues that are inhibiting the process of
adopting a more common system for reimbursement within and
among countries. It is slow-growing, and payment models vary
greatly. Specific barriers to adopting this broader system include
differing requirements, approaches, and frameworks at local and
regional levels. Some issues with costs and low profitability for
providers or unclear reimbursement of services associated with
adopting DTx products do not give enough incentives for payers
to support these instead of in-person medical visits. Some
providers may also be hesitant in adopting some DTx solutions
if data inputs are not coming from a standardized system. Health
records may be disconnected from the hospital setting to DTx
apps; thus, it can be difficult to measure efficacy over time.
While reimbursement pathways are starting to look more
promising in some ways, for example the US is developing digital
formularies for broader claims reimbursement, challenges within
the market remain (40).
There has been a step in the right direction with different bodies
and organizations providing some detailed guidelines that use a
common language on the navigation of DTx opportunities. The
Digital Therapeutics Alliance lays out all necessary assessments
DTx developers would need to follow to secure an optimal
reimbursement pathway. This framework can be built on with any
continuing developments. A similar scheme, IMPACT virtual care
first (V1C) initiative, co-developed by the Digital Medicine Society
(DiMe) offers various resources, contract guidelines, payment
models, and a library of reimbursable codes (40).
Marketing tactics are a solution in promoting the use of DTx. If
patients experience high satisfaction rates, this could potentially
steer healthcare professionals in the direction of supporting them
and getting the attention of policy makers and payers.
6.2. A look ahead
DTx developers still have a long way to go in navigating the
feasible options regarding reimbursement for DTx products. To
TABLE 6 Reimbursement solutions for IVDs in selected European countries.
Country Health
system
Benefit basket Catalog characteristics Elements of tariff calculation
Germany Social Health
Insurance
Uniform value scale Positive list, generic
description of medical act
Non-medical acts involved/time spent based on
expert opinion, material costs, investment costs
France Etatist Social
Health
Insurance
Nomenclature of the medical biological acts Positive list, generic
description of medical act
Time spent on medical act, stress level during
medical act, mental effort, technical competence
UK National Health
Service
Benefit basket as defined by the National
Institute for Health and Care Excellence
guidance on technologies
Commercial tests are specified
within NICE guidance
Cost parameters in relation to efficiency,
appropriateness, and quality; standard costs of
related medical acts in the regions
Adapted from shedding light on reimbursement policies of companion diagnostics in European countries p. 608. Copyright 2020 by ScienceDirect.
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manage the risks with this and heighten opportunities, it is
important to focus on the most promising therapeutic areas.
Communicating with payers and regulators early in the process
can eliminate unnecessary steps in setting prices as well as provide
a more realistic outlook by studying the most practical DTx
solutions. Understanding where the DTx product is better suited
geographically can also lead to its success, by focusing on the US
for profitability and Europe for feasibility.
The new EU MDR should help to simplify the exchange of data
on medical devices and improve data collection and post-market
surveillance to reinforce end-user confidence in DTx solutions.
However, Class I products have been upgraded and now require
notified bodies designated by EU member states to assess them
before a CE mark is granted; previously manufacturers provided
self-declaration for these products. The requirements for pre-
and post-market clinical data have increased and expert panels
will now scrutinize all Class III and some Class IIb high-risk
devices to ensure the safety and efficacy is supported by robust
clinical data. This is envisaged to be a major hurdle for the
access of these products as the number of notified bodies in
Europe is limited. This may increase the data burden for DTx
developers and potentially increase the approval time to market.
A key objective of these regulatory changes is to ensure a high
standard of safety and quality of digital health products while
providing patients with quicker access and reimbursement to
these innovative solutions. However, the EU MDR contains no
specific provisions for DTx and further clarity on the subdivision
into risk classes. The approach to be taken by notified bodies
concerning regulations applicable to DTx would be useful and
enable companies to determine the most appropriate route to
market based on the risk–benefit each product brings.
With the MHRA introducing the Software and AI as a Medical
Device Change Programme, regulation of DTx will hopefully become
a more streamlined process that can promote similar activities in
other countries. An emphasis on clinical evidence for DHT
products that are on the way to approval and reimbursement will
highly support their use and promote innovation in the world of
medical devices. The specifics of this are available in the Evidence
standards framework for digital health technologies. With this, the
UK hopes to be a leading example in the regulatory environment
for DHTs and be in line with the increasing adoption of software
and AI solutions in healthcare settings. Involvement in the Digital
Therapeutics Summit was an important opportunity to receive
advice on how to tackle any challenges that remain for the outlook
of DHTs in the UK (30).
6.3. The future for IVDs
The diagnostic landscape is ever changing, making healthcare
practices cheaper, more effective, and more efficient. Disruptive
diagnostics is a term to define using innovative technology to
allow for more improved practices when detecting diseases.
Many forms of disruptive diagnostics are using AI-supported
technologies to improve the functionalities of diagnostic tests.
These developments foster many positive changes in the
healthcare landscape. More effective diagnostic tools allow for
earlier detections and more efficient treatment plans.
Personalized medicine will play a larger role as well, and
hopefully lessen the burden on healthcare providers (13).
The US framework for regulating IVDs can be compared to the
new IVDR in the EU. There are some notable differences in the
type of regulatory oversight, classification method, and
importance of clinical evidence. In the FDA framework, the
recent development of reassessing how LDTs should be regulated
has posed some uncertainties for manufacturers and laboratories.
It is possible that a certain LDT is not considered and IVD
anymore, so this leaves a need for updated regulations to include
these LDTs as well (34).
Australia’s framework for assessing software in combination
with IVDs provides a benchmark for other countries to
understand if this would be an effective element to implement.
As it may be more common to see IVDs with a software
component in the future, this could impact healthcare practices
in terms of cost and efficiency.
7. Conclusion
In Europe, there are encouraging signs that countries are
adopting more centralized pathways to regulate DTx, but further
clarification is needed to drive future innovation and enhance
patient access to a broader array of life-changing digital health
solutions. Given that Germany has taken the lead on introducing
a legal framework for certification of digital apps to achieve DTx
status and reimbursement, it will be interesting to see what
approaches other European countries implement over the coming
months.
With regards to IVD, the IVDR is assisting in clearly classifying
certain devices to assess whether they fit the criteria and can be
regulated in certain countries. With some types of IVD adopting
AI-supporting features, they must fit into these frameworks to be
utilized in practice. If regulations are adapting to support these
types of devices, there could be a promising outlook on disease
detection being more efficient and effective. It is important that
the technology-supported features are well regulated so they can
work properly in the healthcare conditions they are addressing.
Author contributions
All authors listed have made a substantial, direct, and
intellectual contribution to the work and approved it for
publication.
Conflict of interest
AM, CL, and CN are employed by Alira Health. The remaining
author declares that the research was conducted in the absence of
any commercial or financial relationships that could be construed
as a potential conflict of interest.
Mantovani et al. 10.3389/fmedt.2023.1101476
Frontiers in Medical Technology 12 frontiersin.org
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.
References
1. WHO. Digital health (2019). Available at: https://www.who.int/health-topics/
digital-health#tab=tab_1 (Accessed January, 2023).
2. STL Partners. Digital health diagnostics and triage (2022). Available at: https://
stlpartners.com/articles/digital-health/digital-health-diagnostics-and-triage/
(Accessed January, 2023).
3. Burrell A, Zrubka Z, Champion A, Zah V, Vinuesa L, Holtorf AP, et al.
How useful are digital health terms for outcomes research? An ISPOR
special interest group report. Value Health. (2022) 25:1469–79. doi: 10.1016/j.jval.
2022.04.1730
4. Research and Markets. Global digital health market (2022 to 2027) - industry trends,
share, size, growth, opportunity and forecasts. GlobeNewswire newsroom, research and
markets (2022). Available at: https://www.globenewswire.com/news-release/2022/02/17/
2387239/28124/en/Global-Digital-Health-Market-2022-to-2027-Industry-Trends-Share-
Size-Growth-Opportunity-and-Forecasts.html (Accessed January, 2023).
5. Dang A, Arora D, Rane P. Role of digital therapeutics and the changing future of
healthcare. J Family Med Prim Care. (2020) 9(5):2207–13. doi: 10.4103/jfmpc.jfmpc_
105_20
6. Digital health trends 2021. IQVIA. Available at: https://www.iqvia.com/insights/
the-iqvia-institute/reports/digital-health-trends-2021 (Accessed January, 2023).
7. Shan R, Sarkar S, Martin SS. Digital health technology and mobile devices for the
management of diabetes mellitus: state of the art. Diabetologia. (2019) 62:877–87.
doi: 10.1007/s00125-019-4864-7
8. MacKinnon GE, Brittain EL. Mobile health technologies in cardiopulmonary
disease. Chest. (2020) 157:654–64. doi: 10.1016/j.chest.2019.10.015
9. Öhman F, Hassenstab J, Berron D, Schöll M, Papp KV. Current advances in
digital cognitive assessment for preclinical Alzheimer’s disease. Alzheimers Dement.
(2021) 13:e12217. doi: 10.1002/dad2.12217
10. Fleming T, Bavin L, Lucassen M, Stasiak K, Hopkins S, Merry S. Beyond the trial:
systematic review of real-world uptake and engagement with digital self-help
interventions for depression, low mood, or anxiety. J Med Internet Res. (2018) 6:
e199. doi: 10.2196/jmir.9275
11. Deloitte Italia. The digital hospital of the future: deloitte (2017). Available at:
https://www2.deloitte.com/it/it/pages/life-sciences-and-healthcare/articles/global-
digital-hospital-of-the-future.html (Accessed January, 2023).
12. Valla V, Alzabin S, Koukoura A, Lewis A, Nielsen AA, Vassiliadis E. Companion
diagnostics: state of the art and new regulations. Biomark Insights. (2021)
16:11772719211047763. doi: 10.1177/11772719211047763
13. Fitzpatrick S. What is ‘disruptive diagnostics’and how is it changing health care?
(2018). Available at: https://edgy.app/what-is-disruptive-diagnostics-and-how-is-it-
changing-health-care (Accessed January, 2023).
14. Dias R, Torkamani A. Artificial intelligence in clinical and genomic diagnostics.
Genome Med. (2019) 11(1):70. doi: 10.1186/s13073-019-0689-8
15. WHO. In vitro diagnostics, global (2020). Available at: https://www.who.int/
health-topics/in-vitro-diagnostics#tab=tab_1 (Accessed January, 2023).
16. Medical Devices Coordination Group. MDCG 2021-24 guidance on
classification of medical devices (2021). Available at: https://health.ec.europa.eu/
system/files/2021-12/mdcg_2021-27_en.pdf.
17. The medical devices regulations 2002. Legislation.gov.uk, Queen’s printer of acts
of parliament. Available at: https://www.legislation.gov.uk/uksi/2002/618/contents/
made (Accessed January, 2023).
18. Therapeutic Goods Association. How the TGA regulates software-based medical
devices. Australian government: department of health (2021). Available at: https://www.
tga.gov.au/sites/default/files/how-tga-regulates-software-based-medical-devices.pdf.
19. Therapeutic Goods Administration. Australian regulatory guidelines for medical
devices. Australian government: department of health and ageing (2011). Available at:
https://www.tga.gov.au/sites/default/files/devices-argmd-01.pdf.
20. DTA. Understanding DTX by country. DTX by country - digital therapeutics
alliance. Available at: https://dtxalliance.org/ (Accessed January, 2023).
21. US Food & Drug Association. The software precertification ( pre-cert) pilot
program: tailored total product lifecycle approaches and key findings (2022).
Available at: https://www.fda.gov/media/161815/download (Accessed January, 2023).
22. FDA: U.S. Food and Drug Adminstration. Medical devices. Available at: https://
www.fda.gov/medical-devices.
23. Public Health. European health data space. Available at: https://health.ec.europa.
eu/ehealth-digital-health-and-care/european-health-data-space_en (Accessed January,
2023).
24. Medicines and healthcare products regulatory agency. Software and AI as a
medical device change programme. GOV.UK (2022). Available at: https://www.gov.
uk/government/publications/software-and-ai-as-a-medical-device-change-
programme.
25. BfArM. The fast-track process for digital health applications (DiGA) according
to section 139e SGB V. A guide for manufacturers, service providers and users (2020).
Available at: https://www.bfarm.de/SharedDocs/Downloads/EN/MedicalDevices/
DiGA_Guide.html (Accessed January, 2023).
26. HAS Press Release. Assessing medical devices embedding artificial intelligence
(2019). Available at: https://www.has-sante.fr/jcms/p_3119829/en/assessing-medical-
devices-embedding-artificial-intelligence (Accessed January, 2023).
27. Akbari S. Digital therapeutics: how French DTX regulations will follow Germany’s
lead. Smartpatient Gmbh, smart patient (2021). Available at: https://www.smartpatient.
eu/blog/digital-therapeutics-dtx-regulation-france-following-germanys-diga-model.
28. Vollmer L, Walzer S, Foxon G, Danev V, Berard I, Benazet F. Comparison of
market access routes of digital health applications in France, Germany and the UK.
PMD17 - MEDVANCE. medvance (2020). Available at: https://medvance.eu/wp-
content/uploads/2021/01/ISPOR-2020_Medvance_Digital-health-appliations.pdf
(Accessed January, 2023).
29. NICE. Evidence standards framework (ESF) for digital health technologies.
Available at: https://www.nice.org.uk/about/what-we-do/our-programmes/evidence-
standards-framework-for-digital-health-technologies (Accessed January, 2023).
30. Pollard C, Johnson W, Revell Ward D. Improving access to digital health
technology: approvals, reimbursement and uptake. NHS choices, NHS. Available at:
https://www.england.nhs.uk/aac/publication/summary-of-national-guidance-for-
lipid-management/.
31. TGA. Australian government: department of health and aged care, therapeutic goods
administration (2022). Available at: https://www.tga.gov.au/ (Accessed January, 2023).
32. Center for Devices and Radiological Health. In vitro diagnostics. U.S. food and
drug administration (FDA). Available at: https://www.fda.gov/medical-devices/
products-and-medical-procedures/in-vitro-diagnostics (Accessed January, 2023).
33. Martinez S. A comparison of IVDR to FDA IVD regulatory submission
requirements. RQM+ I MedTech CRO –regulatory, trials, lab services,
reimbursement (2021). Available at: https://www.rqmplus.com/blog/a-comparison-
of-ivdr-to-fda-ivd-regulatory-submission-requirements (Accessed January, 2023).
34. Center for Devices and Radiological Health. Laboratory developed tests. U.S.
food and drug administration (FDA). Available at: https://www.fda.gov/medical-
devices/in-vitro-diagnostics/laboratory-developed-tests.
35. Gandhi M. LDT and IVD reimbursement in the U.S. explained. Clinical
conversations, ThermoFisher (2022). Available at: https://www.thermofisher.com/
blog/clinical-conversations/ldt-ivd-reimbursement-explained/.
36. Australian Government Department of Health and Aged Care. Medicare benefits
schedule (MBS) review (2022). Available at: https://www.health.gov.au/initiatives-and-
programs/mbs-review (Accessed January, 2023).
37. Stevovic J. Digital therapeutics (DTX): how to get reimbursed in the EU, UK and the
US (2022). Available at: https://blog.chino.io/dtx-how-to-get-reimbursed-in-the-eu-uk-
and-the-us-an-overview-of-the-existing-regulatory-frameworks/ (Accessed January, 2023).
38. Synergus. France launches fast-track process for reimbursement of digital
solutions (2022). Available at: https://synergusrwe.com/blog/france-launches-fast-
track-process-reimbursement-digital-solutions (Accessed January, 2023).
39. Center for Devices and Radiological Health. Artificial intelligence and machine
learning in software (2021) U.S. food and drug administration (FDA). Available at:
https://www.fda.gov/medical-devices/software-medical-device-samd/artificial-
intelligence-and-machine-learning-software-medical-device (Accessed January, 2023).
40. Stone A. Paving the payment path for DTx (2022). Available at: https://www.
reutersevents.com/pharma/commercial/paving-payment-path-dtx (Accessed January,
2023).
Mantovani et al. 10.3389/fmedt.2023.1101476
Frontiers in Medical Technology 13 frontiersin.org
