Cheryl Barton is director of PharmaVision, 

Cheryl Barton

 diagnostic regulation (IVDR) introduces substantial changes in the regulatory framework for 

 diagnostic medical devices (1), replacing the current 

 diagnostic medical devices directive (IVDD) (2). For most diagnostic manufacturers, procedures for conformity assessment will become more complicated as companies transition away from self-certification and towards independent conformity assessment by Notified Bodies (NBs). Under the EU IVDR, companion diagnostics will fall under Class C and will therefore undergo a high level of scrutiny from NBs as well as tighter clinical requirements, particularly for pharmaceutical companies developing their own companion diagnostics.

One of the main changes in the IVDR is to increase the involvement of NBs. Under the current IVDD, less than 10% of high-risk devices are subject scrutiny by to NBs whereas under the new IVDR around 80% will be under their control (3). In addition, the IVDR introduces a new set of rules for ‘in-house’ devices including justification for the use of a device and requires diagnostic manufacturers to implement appropriate quality management systems to ensure their safety and performance of their devices (3).

On 24 Jan. 2022, the European NBs published a position paper identifying the key challenges in terms of ensuring adequate certification support IVDR and the new medical devices regulation (MDR) (4). The shortage of NBs with appropriate designation to the new IVDR (and MDR) has been a cause for concern; only six NBs had been designated to the IVDR, as of December 2021 (4). European NBs called for the regulators to extend the transition period for IVDR beyond May 2024 and for closer alignment between NBs and competent authorities regarding authorizing remote audits (3).

In December 2021, the European Parliament and the Council sanctioned the progressive roll out of IVDR from 26 May 2022 (5). This action will change the dates of application of some medical devices. For instance, the new requirements will apply from May 2025 for class D higher risk devices; whereas for devices of the lower risk class C (which include companion diagnostics), the date of application will be extended until May 2026, and applications for lower risk class devices (class B and A sterile) will start in May 2027 (5).

The European database on medical devices (EUDAMED) has been created to increase transparency and integrate different electronic systems to collate and process information about medical devices and related companies (manufacturers) (6). EUDAMED will be populated by the data owners, who are responsible for the quality of data, and part of EUDAMED will be accessible to the public (7).

EUDAMED is composed of six modules related to: actor registration, unique device identification (UDI) and device registration, NBs and certificates, clinical investigations and performance studies, vigilance and post-market surveillance, and market surveillance. The actor registration module became active 1 Dec. 2020 and enables economic operators to submit, by means of an actor registration request, the information necessary to obtain a single registration number (SRN) (8). The SRN allows economic actors to be clearly identified throughout the EU and is required by a NB when submitting an application for conformity assessment. Each actor needs to appoint at least one Local User Administrator (LUA) to verify, manage mandates, link (depending on actor role), and manage users and user access requests.

Modules two and three, the UDI/device registration and NBs and certificates, became active in October 2021. The second module introduces an EU device identification system based on a UDI linking the device to the applicable certificates to help improve traceability (9). The third module enables NBs to register information in EUDAMED regarding Conformitè Europëenne (CE) Mark certificates issued (including amendments and supplements), suspended, reinstated, withdrawn, or refused, and other restrictions imposed on these certificates; all information will be accessible to the public and help to improve transparency of the process (10).

Critical documents for the three remaining modules—clinical investigations and performance studies; vigilance and post-market surveillance; and market surveillance—will launch when the EUDAMED database becomes fully operational in May 2022. Industry experts anticipate that analytical and clinical performance data will come under greater scrutiny under the new IVDR and the performance evaluation report (PER) will require continuing updates. In addition, manufacturers are likely to face more stringent post-market surveillance requirements and may need to conduct post-market performance follow-up (PMPF) and provide period safety update reports (PSUR) for Class C and D devices (11).

The three remaining modules will provide clinical investigations or performance studies with a single identification number (SIN) and incident reports will automatically be assigned a reference number (the responsible competent authority will add its own additional case number). In addition, a field safety corrective action (FSCA) will automatically be assigned a reference number (the responsible competent authority will add its own case number). All these identifiers will help in the unequivocal identification of key case information, and the EUDAMED database will facilitate coordination and cooperation between member states (7).

Get ready … what is your regulatory compliance strategy?

The lack of official documentation for all six modules has made it challenging for companies to prepare for EUDAMED compliance. Therefore, it is essential for medical device manufacturers to establish a regulatory compliance strategy (

) (12) and put in place a leadership team to ensure the smooth transition to the new IVDR—failure to do so is likely to be met with lengthy product delays (13).

 Company checklist for regulatory compliance strategy for the new 

To this end, IVD manufacturers should have assigned budgets and staff to ensure their organization is fully prepared once EURAMED goes live at the end of May 2022. Staff will need to be trained to make sure data for all devices are entered into the EU database in a way that allows for extraction of EUDAMED-specific data, and procedures should be in place to ensure that data uploads or downloads are performed correctly and consistently (5). Manufacturers should also be ready to approach the competent authority to request an SRN, and at least one LUA should be appointed and other users authorized to enable staff to execute specific activities such as entering, reviewing, and uploading information in a timely manner (5).

Failure to adjust to these regulatory changes may result in penalties and loss of market access; however, the implementation of a good regulatory compliance strategy can help to mitigate these risks. While it may take time for manufacturers to navigate the new IVD regulations, it is hoped that the framework that has been put in place will provide them with a more efficient, transparent, and consistent pathway for the regulatory approval of IVDs.

Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on 

 Diagnostic Medical Devices and Repealing Directive 98/79/EC and Commission Decision 2010/227/EU (Text with EEA relevance

Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on 

Public health: Commission Proposes a Progressive Roll-out of the New In Vitro Diagnostic Medical Devices Regulation

,” Press Release, 14 Oct. 2021.
4. Emergo, “European Notified Bodies Issue Updates on MDR, IVDR Implementation Challenges,” Blog, 24 Jan. 2022.
5. EU, 

Proposal for a Regulation of the European Parliament and of the Councill amending Regulation (EU) 2017/746 as Regards Transitional Provisions for Certain 

 Diagnostic Medical Devices and Deferred Application of Requirements for In-House Devices COM/2021/627 Final

 [Accessed 20 April 2022].
7. R. Boumans, “Understanding the New Eudamed: The Role of Eudamed in MDR and IVDR Compliance,” 

, White Paper (August 2018).
8. S. Broussard, “EUDAMED3 Update: Two More Eudamed Modules Will Be Available Later This Year & Guidance on Alternatives Until the Remaining Three Modules are Released and the Database is Fully Functional,” 

 [Accessed 20 April 2022].
11. E. Loh and R. Boumans, “Understanding Europe’s New Medical Device Regulation—MDR 2017/745,” 

 [Accessed 20 April 2022].
13. Operon Strategist, “Is Regulatory Compliance Strategy for Medical Devices Effective?” 

When referring to this article, please cite it as C. Barton, “

Articles

On 26 May 2022, the European Commission will roll-out the new in-vitro diagnostic regulation.  

In-Vitro Diagnostic Regulation

On 31 Jan. 2022, the European Union (EU) initiated the three-year transition for member states to submit clinical trials under a new legal framework Clinical Trial Regulation 536/2014 (EU‑CTR) which replaces Clinical Trial Directive 2001/20/EC (EU-CTD) while increasing transparency and harmonizes the submission, assessment, and supervision processes for clinical trials in the EU (1,2). Between now and 31 Jan. 2023, sponsors can submit clinical trials under EU-CTD or EU-CTR; thereafter, all trial applications will be subject to EU-CTR (3).

Key differences between EU-CTR and EU-CTD

The EU-CTR aims to provide a more transparent and streamlined process whereby each multinational application will be required to submit a single National Competent Authority (NCA) or Ethics Committee (EC) per member state to run a clinical trial in several EU countries (

). This means that the sponsors’ regulatory team needs to collaborate with contract research organization (CRO) early to determine the roles and responsibilities of each party and carefully select the most appropriate reporting state as they will be responsible for coordinating the assessment throughout the trials’ lifecycle. The success of a clinical trial application is highly dependent on the quality of the submission and if a reporting member state refuses the Part I scientific/technical application, it is refused for all member states.

The Clinical Trial Information System (CTIS) replaces EudraCT enabling sponsors to centralize their electronic submission and allows for greater transparency and sharing of data throughout the development process. All communication is via the CTIS and all requests for information must be answered within 12 calendar days or the application lapses. Therefore, sponsor regulatory teams will need to monitor and coordinate responses to CTIS communications and synchronize activities for lifecycle planning because ongoing assessment in one member state prevents further substantial modifications to part I and/or II for all member states (4).

As with the implementation of any new information management system, sponsors may need to upgrade their IT infrastructure to make sure they are fully operational and to train and support staff, to ensure they are familiar with the CTIS interface and have assigned roles for application submissions and safety reporting (3).

Like the EU-CTD, the new EU-CTR are limited to interventional clinical trials; nevertheless, several new definitions have been included such as “low intervention clinical trials” to differentiate studies that pose minimal patient risk. Thus, sponsors of low interventional clinical trials can adopt a risk-based approach and may be required to submit Summary of Product Characteristics (SmPC) (5) rather than an Investigational Medical Product (IMP) Dossier (6) and face less stringent rules on monitoring, the release of the IMP (7,8), and content included within the Trial Master File (TMP) (9).

The EU-CTR has updated the definition of a legally designated representative (LDR) to include “a natural or legal person, authority, or body which according to member state law is empowered to give informed consent on behalf of the subject who is incapacitated or a minor.” In addition, substantial changes have been made to provisions for informed consent and detailed guidance is provided for:

consent for minors or incapacitated people

consent for pregnant or breastfeeding women

consent during trials in emergency settings (3).

EU-CTR do not apply to the United Kingdom (UK) since Brexit. Prior to their implementation in January 2022 the UK launched a public consultation. The UK Government has presented a series of proposals that provide a more modern and flexible approach than the EU-CTR (10). The UK consultation closed on 14 March 2022. Proposed legislative changes aim to update and strengthen the current clinical trial legislation to:

Promote public health and ensure protection of participants remains at the heart of legislation

Remove obstacles to innovation, whilst maintaining robust oversight of the safety of trials

Streamline the regulation of clinical trials and reduce unnecessary burden to those running trials by embedding risk proportionality into the framework

Facilitate the evaluation and development of new or better medicines to reduce the burden of disease on patients and society

Ensure the legislation builds international interoperability so that the UK remains a preferred site to conduct multi-national trials (10).

The new EU-CTR aims to address many of the limitations incurred with the EU-CTD, helping to streamline clinical trial applications, processing while improving transparency and securing the EUs competitiveness within the clinical trial arena. As the EU-CTR will be phased in over the next three-years, sponsors will need to determine the best route of adoption and ensure their regulatory teams have put in place operational procedures, IT management systems, and training and support, to enable them to conduct clinical trials and provide request for information (RFI) via CTIS in a timely manner.

Whilst the UK lags the EU in terms of its clinical trial regulations, it will have the opportunity to watch and learn from the roll out of EU-CDT and ensure that the new UK legislation provides a flexible, streamlined approach to clinical trial applications. Increased transparency, participant protection and broadening opportunities for greater risk stratification and diversity should enable the UK to compete within the global clinical trial arena and enable them to remain a leading global centre in research design, and delivery across all types and phases of clinical trials alongside their EU counterparts.

Regulatory Harmonization of Clinical Trials in the EU: Clinical Trials Regulation to Enter into Application and New Clinical Trials Information System to be Launched

,” Press Release, 25 Jan. 2022.
2. EC, 

 [Accessed 28 March 2022].
3. K. Bonnarens, “

Clinical Trial Regulation 536/2014 Objectives, Key Changes, and Transitional Arrangements

 (January 2022).
4. A. Khera and S. Bly, “Understanding the new EU Clinical Trial Regulation,” Article, 

, 28 Jan. 2022.
5. R. Pankow, et al., “EU Clinical Trial Regulation: Get Ready, Set, Go!” Article, 

 [Accessed 28 March 2022].
7. European Investigational Medicinal Product Dossiers, 

Investigational Medicinal Product Dossier—IMPD Guidance

Guideline on the Requirements for Quality Documentation Concerning Biological Investigational Medicinal Products in Clinical Trials

Guideline on the Content, Management, and Archiving of the Clinical Trial Master File (Paper and/or Electronic)

Consultation on Proposals for Legislative Changes for Clinical Trials,

When referring to this article, please cite it as C. Barton, “Regulating Clinical Trials,” 

In January 2022, Europe started to implement EU-CTR, a new regulatory framework for clinical trials, but what does this mean for pharma clinical research?

Regulating Clinical Trials

Pharma’s interest in decentralized clinical trials (DCTs) has increased during the past 10 years, and uptake has been catalyzed by the COVID-19 pandemic. In 2021, more than 1000 worldwide drug trials contained a virtual or decentralized element, and this is projected to increase to 1300 in 2022 (

 Uptake of decentralized clinical trials worldwide, 2010–2022. 

Source: adapted from Clinical Trials Arena, 2022 (1)

Since early 2010, telemedicine approaches including eDiaries, continuous glucose monitoring (CGM), blood glucose monitoring (BGMs), and activity trackers have all gained traction in clinical studies helping to reduce the number of onsite visits and allowing real-time direct-from-patient collection of data. In addition, mobile apps, smartphones and wearables, and the use of electronic Clinical outcome assessment (eCOA), eConsent, electronic patient reported outcomes (ePRO), and web-based questionnaires have been integrated into trial designs, easing patient participation, and enhancing patient engagement throughout the course of a trial. Furthermore, digitally enabled workflow and engagement platforms have simplified the trial process, reducing variations in data collection, resulting in fewer errors and shorter trial timelines and costs.

The adoption of DCTs or hybrid models has the added benefit of expanding the geographical reach of clinical trials into a variety of care settings including nursing homes and home health, as well as providing access to wider and more racially diverse patient populations, particularly in rare diseases (2). These are areas that continue to be scrutinized by the European Medicines Agency (EMA) and are discussed at length in the International Council for Harmonisation (ICH) guidelines, particularly in ICH guidelines E8 on general considerations for clinical trials (3) and E5 (4) on ethnic factors in the acceptability of foreign clinical data. Additionally, the implementation of the new European Clinical Trial Regulation 536/2014 (EU-CTR) also aims to improve transparency and patient awareness of clinical trials throughout the European Union (5)

What are the challenges of performing DCTs?

Despite the above benefits, DCTs present numerous challenges particularly relating to data privacy and regulatory compliance and change in standard operating procedures (SOPs) (6). The EU General Data Protection Regulation (GDPR) has been in place for several years and many argue that more stringent regulations need to be put in place. To this end, companies such as IQVIA (7) and Medable (8) have established DCT platforms that adhere to GDPR rules in each EU nation and include data protection impact assessments (DPIAs) to ensure compliance. DCT technology providers are also entering this space and attracting significant investment form private investors and special purpose acquisition companies (SPACs) as they provide digital solutions for sponsors to decentralize trials (9).

As digital technologies become more widely incorporated into clinical trials, the EU’s regulatory framework for DCTs/hybrid trials will need to evolve to incorporate digital data and emerging digital endpoints and Good Clinical Practice (GCP) protocols modernized (10). Moreover, wider adoption of digital tools and DCTs will enable sponsors to focus more on race and socioeconomic disparities and overcome some of the common barriers of conducting clinical trials helping to build trust, raise patient awareness, and improve communication (11). New EU guidelines on DCTs are due to be released later this year and should provide sponsors and clinical trialists with greater clarity and allow DCTs to become more mainstream over the coming years (12).

1. K. Parkins and A. Hillman, “2022 Forecast: DecentralizedTrials to Reach New Heights with 28% Jump,” 

, Analysis (Dec. 14, 2021).
2. A. Kalloo and J. Venticinque, “

5 Ways DCTs Can Positively Impact Trial Diversity

ICH Guideline E8 (R1) on General Considerations for Clinical Studies

, Guidance Document (Oct. 14, 2021).
4. EMA, 

ICH Topic E5 (R1) Ethnic Factors in the Acceptability of Foreign Clinical Data(Step 5)

, Guidance Document (September 1998).
5. EMA, “Regulatory Harmonization of Clinical Trials in the EU: Clinical Trials Regulation to Enter into Application and New Clinical Trials Information System to be Launched,” 

, Press Release, Jan. 25, 2022.
6. Z.I. Maharaj, et al., “

How Does GDPR Apply to Clinical Trial Sponsors Outside EEA? Views of EEA DPAs,” 

GDPR and DCTs: Don't be Complacent about Compliance

,” Product Information [Accessed Mar. 18, 2022].
9. B. Comer, “Science 37 Blockbuster SPAC Valuation Points To Growth In Decentralized Trials,” 

EMA Regulatory Science to 2025 Strategic Reflection

, Regulatory Procedural Guideline (2020).
11. O. Momoh, et al., 

“Inclusion and Diversity in Clinical Trials

European Patient’s Academy on Therapeutics Innovation, EUPATI

 (April 2020).
12. V. Sharma, “EU Decentralized Trials Guide Due Early In 2022,” 

Pharma’s interest in decentralized clinical trials (DCTs) increases as it helps to expand their geographical reach and racial diversity

Will Decentralized Clinical Trials Become Mainstream?

The Digital Therapeutics Alliance (DTA) defines digital therapeutics (DTx) as products that deliver: “evidence-based therapeutic interventions that are driven by high quality software programs to prevent, manage, or treat a medical disorder or disease. They are used independently or in concert with medications, devices, or other therapies to optimise patient care and health outcomes” (1).

Acceptance of DTx has grown rapidly over the past couple of years, particularly during the COVID-19 pandemic, as they can support patients in the remote management and treatment of a range of medical conditions including anxiety and depression. Importantly, they can be used as a standalone therapy or in conjunction with more pharmacological interventions or in-person therapy, and enable data to be collected, processed, and analysed, and then tailored to an individual’s medical needs.

In Europe, DTx regulations are fragmented and disparate (

). For instance, in the United Kingdom, DTx are classified by the National Institute for Health and Care Excellence (NICE) based on their functions and then stratified into evidence tiers based on the potential risk to the user (2). Conversely, in Italy DTx are classed as medical devices and must pass International Organization for Standardization (ISO) standards to ensure they are compliant with safety requirements. They are categorized according to their risk from level 1 being low risk for health and level 4 high-risk, which can have irreversible effects and impacts on health and/or mortality; the risk category defines the clinical data requirements and approval process (3).

 Regulatory framework for digital therapeutics (DTx) in Europe and the United Kingdom.

DTx are covered by European Union (EU) regulation 2017/745 on medical devices, which came into force on 26 May 2021 (4). The EU Medical Device Regulation (MDR) resulted in a more stringent pre-market security mechanism, provides greater regulatory oversite from notified bodies, and provides additional rules on clinical evidence and post-market surveillance. It established new risk classification for in-vitro diagnostic (IVD) medical devices as well as improving transparency and traceability of devices.

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 Conformité Europëenne (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 scrutinise all Class III and some Class IIB high-risk devices to ensure the safety and efficacy is supported by robust clinical data. 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.

In the United States, the Food and Drug Administration (FDA) has published draft guidance regarding changes to premarket submission of digital health technologies. This guidance includes software as a medical device (SaMD) and focuses on basic and enhanced risk devices and provides greater clarity on Software Requirement Specification (SRS) and Software Design Specification (SDS) regarding their intended use, functionality, safety, and effectiveness (5).

The non-profit organization, DTA was established in 2017 and has played a critical role in raising the profile of DTx. The organization engages with stakeholders and has helped to define and categorize DTx (

) (6) and to facilitate the establishment of standards, code of ethics, and best practices as well as advocating on regulatory and reimbursement. Investment in DTx continues to grow, and a plethora of solutions are now under development within a broad range of conditions to help target unmet medical needs (7).

 Digital therapeutics (DTx) product categories. 

[Source: modified from DTx Alliance, 2021 (6)]

While these regulatory changes are encouraging, the development of a reimbursement framework is also essential if DTx are to become universally adopted. To date, DTx manufacturers have implemented a variety of reimbursement models including business to business (B2B), business to consumer (B2C), and business to payer (B2P) with differing degrees of success. In Germany, Ireland, and the Netherlands, DTx manufacturers have directly targeted self-insured employer health plans, whereas in France, Belgium, and the United Kingdom, a B2P reimbursement model has proven successful.

Germany is embracing digital health, and other European countries are closely watching this space (8). In December 2019, Germany implemented the Digital Healthcare Act (DGV), to enable the reimbursement of prescribed DTx on a national level (9). To gain reimbursement, manufacturers must demonstrate evidence on safety, functionality, quality, data security and data protection, and an overall effect on improving patients’ care (10). On 9 April 2020, the (Digitale Gesundheitsanwendungen-Verordnung (DiGAV) or Digital Health Applications Ordinance was enforced to regulate the procedure and reimbursement eligibility requirements of digital health applications by statutory insurers (11). As of January 2022, 28 digital solutions are available for reimbursement and are now listed on the Federal Institute for Drugs and Medical Devices (BfArM) (12) (

 Digital solutions listed on the Federal Institute for Drugs and Medical Devices. 

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.

1. DTA, “Digital Therapeutics: Definitions and Core Principles,” 

Evidence Standards Framework for Digital Health Technologies

, Framework Document (March 2019).
3. G. Gussoni, “Digital Therapeutics: An Opportunity for Italy, and Beyond,” 

Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on Medical Devices, Amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and Repealing Council Directives 90/385/EEC and 93/42/EEC

Content of Premarket Submissions for Device Software Functions

, Draft Guidance (November 2021).
6. DTA, “DTx Product Categories,” 

, Fact Sheet (January 2021).
7. DTA, “Therapeutic Area for Which Digital Therapeutic Products are Available or Currently Being Developed,” 

, Fact Sheet (March 2020).
8. S. Gerke, A.D. Stern, and T. Minssen, 

, 3, 94 (2020).
9. Bundesanzeiger Verlag, 

Gesetz für eine bessere Versorgung durch Digitalisierung und Innovation

 (Bonn, Germany, 9 Dec. 2019).
10. Noerr, “Digital Healthcare Act,” News Story, 5 April 5 2020.
11. Bundesanzeiger Verlag, 

Verordnung über das Verfahren und die Anforderungen der Prüfung der Erstattungsfähigkeit digitaler Gesundheitsanwendungen in der gesetzlichen Krankenversicherung (Digitale Gesundheitsanwendungen-Verordnung—DiGAV)

 (Bonn, Germany, 8 April 2020).
12. Bundesinstitut für Arzneimittel und Medizinprodukte, “DiGA Directory,” 


Vol. 34, No. 1
January 2022
Pages: 8–9

When referring to this article, please cite it as C. Barton, “Regulating Digital Therapeutics,” 

DTx manufacturers are taking advantage of the new regulatory flexibility, afforded by the COVID-19 pandemic, to pilot new products and generate real-world evidence to support regulatory filing and reimbursement.