Expert Review of Medical Devices

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Recommendations for the design and

implementation of an Early Feasibility Studies
program for medical devices in the European
Union

Giuditta Callea, Carlo Federici, Rachele Freddi & Rosanna Tarricone

To cite this article: Giuditta Callea, Carlo Federici, Rachele Freddi & Rosanna Tarricone (2022)
Recommendations for the design and implementation of an Early Feasibility Studies program for
medical devices in the European Union, Expert Review of Medical Devices, 19:4, 315-325, DOI:
10.1080/17434440.2022.2075729

To link to this article: https://doi.org/10.1080/17434440.2022.2075729

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EXPERT REVIEW OF MEDICAL DEVICES
2022, VOL. 19, NO. 4, 315–325
https://doi.org/10.1080/17434440.2022.2075729

PERSPECTIVE

Recommendations for the design and implementation of an Early Feasibility Studies

program for medical devices in the European Union
Giuditta Calleaa, Carlo Federicia, Rachele Freddia and Rosanna Tarricone a,b

a
Centre for Research on Health and Social Care, SDA Bocconi School of Management, Italy; bDepartment of Social and Political Science, Bocconi
University, Milan, Italy

ABSTRACT ARTICLE HISTORY

Introduction: Early Feasibility Studies (EFS) are among the pre-market clinical investigations allowed by Received 2 January 2022
the International Standard for Clinical investigation of medical devices (MD) for human subjects. The Accepted 6 May 2022
Food and Drug Administration (FDA) introduced an EFS program in the US in 2013. The European Union KEYWORDS
(EU) MD Regulation, that entered into force in May 2021, opened the possibility of EFS in the EU. Clinical evidence; early
However, European countries at present have no standardized procedural framework for EFS. In this feasibility study; European
paper, we address the desirability of a European EFS program. Union; Health Technology
Areas covered: Characteristics of EFS conducted so far are reviewed, and perceptions of an expert, Assessment regulation;
multidisciplinary panel of key stakeholders are explored regarding desirability and feasibility of medical devices regulation;
a European EFS program and critical factors favoring or hampering its implementation. medical devices; pre-market
Expert opinion: Implementing an EFS program in the EU would contribute to creating a favorable clinical investigation
environment for early-stage clinical investigations, with positive effects on the quality and timeliness of
clinical evidence for novel MDs, and attractiveness of the European system for pre- and post-market
clinical research. Based on discussion with experts, also leveraging on the US experience, three
dimensions should be considered for effective design and implementation: process, resources, and
ethical issues.

1. Introduction improved collaboration between the FDA and MD innovators;

in October 2011, the FDA began to pilot a Network of Experts
European regulation of medical devices (MDs) has always Program to overcome the internal lack of experience and
been considered less stringent than that applied in the expertise needed to review emerging, innovative medical
United States (US) [1]. However, recent years have witnessed technologies by engaging with top scientific experts, mem­
a marked turnaround. The new European Union (EU) Medical bers of professional health-care societies, when deemed
Device Regulation (MDR) [2], in force since May 2021, is necessary; finally, in November 2011, with the double intent
expected to make the regulatory framework in Europe more to recoup the US leading role in pre-market research for MDs
restrictive as it strengthens clinical evidence requirements, and accelerate access to medical technologies, the FDA soli­
while the American Food and Drug Administration (FDA), cited sponsors of innovative device technologies to apply to
from 2010, has undertaken a broad review process of its pre- a pilot program for early feasibility study (EFS) investigational
market device program, following complaints that regulation device exemption (IDE) [6]. In 2013, guidance on
provided disincentives to manufacturers to conduct research Investigational Device Exemptions (IDEs) for Early Feasibility
and seek market approval, thus potentially delaying access to Medical Device Clinical Studies was finally issued [7].
novel MDs for American patients [3]. Indeed, between 2004 As described in the guidance document, EFS are limited
and 2009 clinical studies for MDs conducted in the US listed exploratory clinical investigations which take place early in the
on ClinicalTrials.gov were reported to have dropped from 87% development phase of a device, typically before the device
to 45% [4], prompting the FDA to seek measures to alleviate design has been finalized, in a small number of patients.
barriers to clinical studies for innovative MD producers [5]. Differently from traditional feasibility studies, which aim to
Among the initiatives put in place by the FDA to improve capture preliminary safety and effectiveness results and sup­
the balance between necessary regulatory oversight and port the planning of larger pivotal studies, the purpose of EFS
unnecessary regulatory burden, was the establishment of is more related to demonstrating proof of concept and opti­
new and modified policies to create a collaborative environ­ mizing device design and procedure through iterative feed­
ment for early clinical investigation of MDs in the US. In back loops during early clinical experience, when further
February 2011, the FDA’s Center for Devices and Radiological information cannot be obtained through additional preclinical
Health (CDRH) proposed the Innovation Pathway, a priority testing or when appropriate nonclinical tests are unavailable.
review program for pioneering MDs characterized by Notably, the FDA EFS program is not aimed to create an

CONTACT Giuditta Callea [email protected] Centre for Research on Health and Social Care, SDA Bocconi School of Management, Via Sarfatti 10,
20136 Milan, Italy
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
316 G. CALLEA ET AL.

discussions with FDA during the 30-day IDE supplement

Article highlights review cycle, may be used to address deficiencies or where
● Early Feasibility Studies (EFS) are limited clinical investigations of
changes to the clinical protocol do not meet the criteria for
medical devices (MD) conducted in a small number of subjects a 5-day notice (interactive review process). The program’s
early in development to evaluate the device design concept with main characteristics and timelines are summarized in Figure 1.
respect to initial clinical safety and functionality and to guide device
modifications through iterative feedback loops during early clinical
Part of the 2014–2015 CDRH Strategic Priorities [8], the EFS
experience. program has been successful in attracting early-stage clinical
● EFS are among the pre-market clinical investigations allowed by the investigations to the US: since its implementation, the number
International Standard ISO 14155:2020 for Clinical investigation of
MDs for human subjects.
of EFS IDEs received by the FDA increased from 26 in 2014 to
● The American Food and Drug Administration (FDA) launched an EFS 73 in 2018, and the number approved annually increased from
program in 2013. European countries at present have no standar­ 24 to 53 [9]. The CDRH 2018–2020 Strategic Priorities report
dized procedural framework specific for EFS. The new European
Union (EU) MD Regulation, that entered into force in May 2021,
cited reduced time and cost as advantages of the EFS program
opened the possibility of EFS programs in the EU. and predicted for the near future increased initiation of first
● A European EFS program would contribute to create a favorable regulatory approval processes by manufacturers in the US –
environment for early-stage clinical investigations, with positive
effects on both the quality and timeliness of clinical evidence for
and thus faster access for patients [10]. During the COVID-19
novel MDs, and the attractiveness of the European system for pre- pandemic, the interest in EFS remained high, with 61 studies
and post-market clinical research. submitted and 49 approved [11].
● Recommendations are proposed for the design and implementation
of a European EFS program based on discussion with officers of the
In the 2020 edition of the International Standard ISO 14155
Italian Ministry of Health and a panel of experts, also leveraging on Clinical investigation of medical devices for human subjects –
the US EFS experience. Good clinical practice, EFS have been included among the
● Three dimensions are of key importance: process, resources, and
ethical issues.
possible types of pre-market clinical investigations to assess
initial clinical safety, performance, or effectiveness of MDs [12].
This opens the possibility of implementing EFS programs in
Europe. More recently, the Medical Devices Coordination
Group (MDCG) – an expert group composed of representatives
accelerated pathway to market approval, but rather it seeks to of all Member States supporting the Commission in ensuring
create a favorable environment for the conduction of EFS, a harmonized implementation of MD and in-vitro diagnostics
therefore leading to higher quality and timely evidence gen­ Regulations – released guidance that explains the appropriate
eration. Successful EFS can be extended and subsequently regulatory pathways for clinical investigations under the MDR.
transitioned into pivotal trials. Since the devices investigated The guidance clarified that pilot stage clinical investigations
in EFS are at such early stages of development, one of the such as EFS conducted to support conformity assessment (i.e.
main characteristics of the EFS program is that the FDA may gather preliminary safety and/or performance data), are
accept a higher degree of uncertainty and require less pre­ directly regulated by the MDR ex article 62 and do not fall
clinical data to support study initiation [3]. A greater emphasis under the Member State national regulatory pathways ex
is placed on monitoring and patient protection measures as article 82 [13].
compared to studies at later stages of device development. In Despite the possibility to implement EFS programs,
addition, following the recognition of the specific nature of European countries at present have no standardized proce­
the studies, the FDA EFS program has been shaped according dural framework for this type of study. Consequently, EFS
to key principles, including interactive dialogue between FDA, are either put forward as individual requests for compassio­
sponsors, and innovators prior to and during the EFS IDE nate use or submitted as traditional feasibility studies. This
submission; predefined phases and times for the submission in turn may act as an incentive for applicants to overstate
review process; and flexible, risk-based management of device the potential benefits (or understate the potential risks) of
and/or clinical protocol modifications during the study. The the technology and forces bodies in charge of assessing the
latter envisages different procedures depending on the nature request for the study to apply evaluation criteria that are
of the change, and whether these changes had been pre­ different from those which would be appropriate for EFS. In
viously identified and foreseen during the interactive review addition, in countries like Italy, the conventional process to
process between the sponsor and the FDA. Briefly, there are pre-market study authorization is relatively ‘static’ in that it
three main procedures to manage modifications. First, is based on the one-off submission of the study documen­
changes that do not imply significant design variation and tation by the sponsor, without any previous interactions and
do not affect the interpretation of the results can be made with only one subsequent round of revisions and requests
through 5-day notification, without requiring FDA approval. for integrations by the competent authority [14]. Similarly,
Second, approval of anticipated or proposed device, or proto­ after study initiation, current procedures to implement
col changes can be obtained contingent on the completion of changes to either the protocol or the device are likely to
an agreed-upon test plan and acceptance criteria so that, after be inappropriate for these types of studies, where such
successful completion of testing, the sponsor can begin to modifications are more common compared to more mature
study the modified device without additional FDA action (con­ clinical studies. In fact, in many cases, changes to the study
tingent approval). Third, interactive review of IDE supplements protocol or device may indeed be one of the expected
and amendments, involving the continuation of informal outcomes of an EFS (for instance, if the purpose of the
 EXPERT REVIEW OF MEDICAL DEVICES 317

Figure 1. Main features (panel a) and timeline (panel b) of the FDA Early Feasibility Studies.

study is to establish the optimal coating material for of a European EFS program and the critical factors that would
a device between two previously identified alternatives). favor or hamper its implementation.
So, it is not uncommon that clinical investigations not
approved in European countries as feasibility studies are
resubmitted and approved by the FDA as EFS.
In the long run, the absence of an ad hoc, standardized
2. Materials and methods
framework for early evidence generation might reduce The research was conducted through several consecutive
European countries’ attractiveness for clinical studies and steps presented in Figure 2 and described in detail below.
first approvals, and therefore it is crucial to stimulate debate A mix of methodologies was used, both qualitative (i.e. one-
and create awareness among European policymakers. to-one interviews, focus groups, surveys) and quantitative (i.e.
The aim of this study was to investigate the characteristics data collection and design/implementation/elaboration of EFS
of the EFS program implemented by the FDA and explore databases). Both in preparing the questions (open-ended,
perceptions of key stakeholders involved in the regulatory neutral) and in conducting the interviews/group discussion
approval of novel MDs regarding the desirability and feasibility (in a neutral, open, and non-judgmental way, without sharing
research team personal opinions and views) we referred to the

Figure 2. Steps of the methodology.

318 G. CALLEA ET AL.

standards and best practices for qualitative research proposed from public officers regarding the opportunity to implement
by Cresswell and Poth [15]. a similar program in Italy. The meetings also sought to identify
First, to gain insight into the characteristics of EFS, in key aspects to address when designing and implementing an
March 2019 we conducted a search of the studies registered EFS program to explore with a broader set of stakeholders.
on ClinicalTrials.gov by using the keywords ‘early feasibility’ The interviews were conducted by two of the authors (GC,
with no restrictions on status, condition, disease, or country. PhD, female; and CF, PhD, male), health economists, experi­
We selected EFS involving the use of MDs – alone or in enced in conducting qualitative interviews and group discus­
combination with drugs – and excluded those involving sions. A junior health economist (RF, female) served as
drugs only. The main goal of this preliminary search was to observer and note taker. The moderators conducted the inter­
identify the prevalent clinical areas where EFS are conducted views in a neutral, open, and non-judgmental way, and did
to inform the subsequent research phases. The search was not share their personal opinions and views in order not to
updated in April 2022 to include all EFS registered through influence participant answers. From these meetings, four
December 2021 and complemented by a search on the World open-ended, neutral questions were drafted covering (1) the
Health Organization International Clinical Trials Registry desirability and main advantages of an EFS program in Europe,
Platform (ICTRP), a literature search on PubMed, Google, and and specifically in Italy; (2) potential challenges related to the
American Heart Association/American Stroke Association implementation of an EFS program and main ethical consid­
(AHA/ASA) journals, and with searches on main news websites erations; (3) elements requiring special consideration during
(i.e. Cardiac Interventions Today citoday.com, Cardiovascular the application process for an EFS; and (4) the types of devices
Business cardiovascularbusiness.com, Cardiovascular News that would be suited for an early feasibility study and mini­
cardiovascularnews.com, Endovascular Today evtoday.com, mum eligibility criteria (Table 1).
and PRNewswire www.prnewswire.com) using the same key­ Subsequently, in February 2020 a purposive sample of 10
words. For all identified EFS, we analyzed study details pro­ experts was selected among clinical investigators, biomedical
vided by ClinicalTrials.gov and searched all available engineers, academics, members of scientific and professional
documentation. In cases of major doubt, we requested infor­ associations, members of ethics committees, developers of new
mation from device manufacturers. We designed an ad hoc technologies, including representatives of the industry. To
database that was fed with the following information involve the most fitting stakeholders, we selected experts from
extracted from the retrieved documents: clinical trial number, the main therapeutic areas identified in the EFS database (i.e.
study title, status at the time of the search (e.g. recruiting, sectors where such studies were most frequent): cardiovascular,
completed, suspended, terminated), results, conditions, inter­ diabetes, and neurology. All the identified members agreed to
ventions (i.e. device, drug, radiation, biological, behavioral, participate in a panel meeting. Due to travel limitations imposed
procedure, other), primary and secondary outcomes, spon­ by COVID-19, the original full day, in-person workshop in
sor/collaborators, number of patients enrolled, sex, age, March 2020 was re-organized as a two-hour web conference
study phase, study type (i.e. observational or interventional), postponed to July 2020. To maximize efficiency for the reduced
allocation (i.e. randomized or non-randomized), intervention time available for the panel discussion, preliminary materials,
model (i.e. single group, sequential, parallel, crossover assign­ validated by the MoH, were sent to all participants in advance
ment), masking (i.e. open, double, triple), primary purpose (e.g. in June 2020. These materials included a briefing document and
prevention, treatment, supportive care), observational model three video lessons recorded by GC, CF, and RT, summarizing the
(i.e. case-only, case-control, cohort), time perspective (i.e. pro­ goals of the initiative, the main features of the FDA EFS program
spective or retrospective), registration date, start date, and and the four questions to be addressed by the panel, without
completion date, and location. Moreover, we grouped the unveiling the authors’ views and opinions. Before the web panel
conditions and diseases according to the chapters of the meeting, one of the authors (GC) conducted individual online
International Classification of Diseases, 9th revision – Clinical interviews with each of the experts with the aim to have feed­
Modification (ICD-9-CM). back in advance on the four questions and to identify the main
As a second step, we conducted qualitative interviews with aspects to discuss during the panel. Consent to video-record the
Italian Ministry of Health (MoH) officials and an expert panel interviews was obtained, and the recordings were professionally
(Figure 2) to collect and synthetize opinions on the appropri­ transcribed. Transcript data were then analyzed using qualitative
ateness and feasibility of an EFS program, and to identify
recommendations for its implementation. We focused on
Italy as a case-study as it is second in number of medical Table 1. Questions regarding the possible implementation of an EFS program in
Europe discussed with the panel.
technology companies and the fourth largest MD market in
Q1 – In your opinion, can a procedural innovation like the EFS program
Europe [16], which makes it an optimal testing ground for promoted by the FDA be useful in the Italian context and what critical
implementation of an EFS program at the European level. aspects can be overcome thanks to it?
Between March 2019 and February 2020, meetings were Q2 – What challenges are posed by the implementation of an EFS program?
In particular, what ethical aspects need to be carefully considered due to
held with the director and members of the Office for Clinical the higher risk profile linked to the early development phase of the
Investigations at the Italian MoH, Directorate General for investigated devices?
Medical Devices and Pharmaceutical Services, which is the Q3 – Which parts of the application form require more attention compared to
traditional feasibility or pivotal studies?
competent authority for MDs in Italy. These meetings had Q4 – What types of devices might benefit most from the implementation of
the objective of familiarizing participants with the main char­ an EFS program? Is it possible to define a set of minimum admissibility
acteristics of the EFS program in the US, and eliciting opinions criteria?
 EXPERT REVIEW OF MEDICAL DEVICES 319

content analysis by identifying recurring themes and sorting preparing to meet the MDR requirements and whether they
them into categories. The July 2020 plenary meeting with had started designing or implementing national EFS programs.
panel members and the MoH was moderated by GC, where key In December 2020, we invited all 27 competent authorities,
points derived from individual interview analysis were presented including the UK, to complete the survey, which remained active
and discussed to work toward consensus on the main aspects until January 2021. In the absence of replies, we searched rele­
involved in evaluation of the feasibility, design and implementa­ vant websites for mention of national EFS programs.
tion of an EFS program. During both individual interviews and
the board meeting, the moderator asked neutral questions and
did not share her own nor research team opinions so as not to 3. Results
influence opinions and answers. The remarks emerging from the
first phase of the interviews and panel discussion were then 3.1. Characteristics of EFS
synthesized and shared with the MoH and panel members for Overall, we identified 198 EFS registered by December 2021,
comments and integrations. with 152 on ClinicalTrials.gov and the remaining found
As a last step, we designed an ad hoc survey to investigate through other sources. The number of studies, by start
how other European competent authorities for MDs were date, increased over time and peaked in 2021 (Figure 3).

Figure 3. Time trend of EFS.

Figure 4. Main characteristics of EFS.

320 G. CALLEA ET AL.

Approximately 58% of the studies were ongoing or about to 3.3.1. Desirability and main advantages of a European EFS
be initiated at the time of the search, 25% were completed program
and 8% abandoned (Figure 4 panel a). Roughly 92% of the Overall, all the members of the panel agreed that an EFS program
EFS are interventional (Figure 4 panel b) and 83% are single would be highly desirable in Europe and unanimously supported
group assignment (i.e. studies in which all participants the implementation in Italy of a pioneering framework for EFS to
receive the same intervention/treatment) (Figure 4 panel be used as a pilot experience for Europe. Indeed, both during the
c). More than half of the studies focused on diseases of individual interviews and the panel discussion, several potential
the circulatory system (59%), followed by diseases of the contributions for a European EFS program were identified, sub­
nervous system (10%) and endocrine, nutritional, and meta­ sequently grouped into two broad themes. The first relates to the
bolic diseases – in particular diabetes – (9%) (Figure 4 panel definition of a dedicated administrative procedure and an ad
d). On average, completed studies enrolled 17.7 patients hoc, standardized framework for the successful initiation and
and had a duration of 13 months; terminated EFS were conduction of EFS in Europe, to maximize the efficiency of
stopped after 14.2 months after enrolling 9.6 patients evidence generation processes. The introduction of clearer
(Figure 4 panel e). More than three-fourths (73.7%) of the rules for the submission and management of EFS was considered
studies were conducted in the US and 6.2% joint with other favorable as it would allow greater certainty for the sponsors
countries (Figure 4 panel f). European countries seem to regarding the requirements to initiate a study, documentation to
have limited experience with EFS, with only 27 studies be produced, procedures in place, and especially the timing of
conducted. Germany is the most experienced, with nine each step in the process from first contact with the competent
studies conducted, followed by France and Poland (six) authority through definitive study evaluation and decision. Such
and Italy (five). For studies starting in 2021 and 2022, that a program would also help overcome the limits of the traditional
are currently recruiting patients, the location is often not pathway characterized by poor interaction between the compe­
available. tent authority and sponsors during the application process for
a study. The possibility of instituting continuous, dynamic dialo­
gue within an established procedural framework was perceived
3.2. Presence of European EFS programs as better suited to promote real exchange on and mutual under­
standing of the characteristics of the innovation and the pro­
Our survey received five complete responses from European
posed evidence generation plan. Such dialogue was seen to
competent authorities for MDs: Italy and Sweden, the only two
foster reciprocal knowledge and trust between manufacturers,
countries with previous EFS experience, Bulgaria, Finland, and
investigators, and regulatory authorities. In addition, mirroring
Slovenia. All declared that they have not implemented EFS
the FDA EFS program, the possibility to introduce specific pro­
programs or produced national regulations/laws/rules for
cedures for managing changes to the study protocol or modifi­
these types of studies. Searches conducted on the websites
cations to investigational devices was also perceived to increase
of non-replying competent authorities highlighted the exis­
flexibility, in keeping with the early stage of development of the
tence of rules for the conduction of pre-market clinical inves­
technology and the ultimate purpose of EFS.
tigations (e.g. traditional feasibility studies, first-in-human,
The second theme relates to the ability of an EFS program in
pivotal studies) in all European countries. Nevertheless, none
Europe to attract R&D investment and strengthen the biomedical
of them have implemented formal EFS programs or collabora­
sector’s competitiveness, especially for micro, small, and midsize
tive pre-submission frameworks with EFS-like iterative interac­
enterprises. The board members also highlighted that early
tions with study sponsors.
experience with new technologies on the part of clinicians and
Concerning the actions taken in preparation for full
sites facilitates the subsequent undertaking of pivotal studies,
application of MDR, complementary national regulations
generating a multiplier effect for personnel skills and competen­
have been adopted in Bulgaria, Finland, Slovenia, and
cies and attracting capital investment.
Sweden, and new administrative procedures and reorgani­
zation activities have been implemented by the Slovenian Importantly, among the panel there was consensus that these
and Swedish competent authorities. The Italian Ministry of types of studies should not supplant informative nonclinical
Health has not taken any action among those proposed testing or in any way reduce the acceptability level of clinical
(i.e. complementary national regulations, new administra­ studies, i.e. in terms of the amount of successfully conducted
tive procedures, reorganization, national regulations for preclinical tests needed to initiate a clinical study, the required
some types of clinical investigations for human subjects level of evidence on device safety, or the expected risk–benefit
not mentioned in the MDR) because the national regula­ ratio for the patient. Rather, EFS should enhance the efficiency of
tions transposing the European Directives are currently evidence generation processes by limiting non-informative
under review based on MDR requirements. investigations and maximizing returns of studies in terms of
information gathered to reduce uncertainties regarding the
devices investigated.
3.3. Suggestions for the implementation of an EFS
program by the expert panel members
3.3.2. Potential challenges related to the implementation
In this section, we present the results of the discussion with of an EFS program in Italy and main ethical considerations
the expert panel members and their suggestions for the Several potential challenges, ranging from administrative and
implementation of a European EFS program. bureaucratic issues to cultural and ethical considerations, were
 EXPERT REVIEW OF MEDICAL DEVICES 321

identified which would need addressing to ensure successful criteria for experimenting centers and patients. First, as an
implementation of an Italian EFS program. First, a clear legal essential precondition, applicants should clearly justify the
and procedural framework delineating the role and nature of suitability of the EFS to answer the planned research questions
EFS from the Italian Government was considered of vital and why further preclinical testing would not be appropriate
importance to provide required flexibility and facilitate the or informative for the development of the product.
initiation and execution of these types of studies. Second, Assessment of the adequacy and comprehensiveness of pre­
the Italian EFS program would necessarily need to accommo­ clinical evidence should also include any possible in-silico
date and function within the system of Internal Ethics application (i.e. computer simulation used to form patient
Committees (IECs) in Italy. According to most members of virtual cohorts for testing the safety and/or efficacy of new
the panel, important aspects to address regarding IECs include drugs and of new medical devices [17]) which may contribute
their heterogeneous nature in terms of risk aversion, quality, to further reduce uncertainty regarding device performance
and timing of the approval processes, as well as the availability prior to its use in human subjects. Second, it was argued that
of resources and technical expertise, especially concerning all patient protection measures should be enhanced. Analysis
clinical investigations of MDs. More in general, panelists raised of the risks and potential device failures should consider the
a cultural issue regarding the poor propensity of IECs to early development stage of the technology and provide
positively assess requests for EFS. Possible explanations given a thorough analysis of the whole spectrum of potential device
were again the lack of technical skills to correctly understand failures and their consequences on patients. For each of the
and assess an EFS, and the lack of a clear definition of the identified risks, particular attention should be devoted to
medical-legal responsibilities for these early-stage studies, defining an appropriate risk-mitigation strategy to minimize
which may lead to a general conservative approach to avoid the additional risk incurred by the patient during the study.
excessive risk-taking. A similar issue concerns the need for Given the likely complexity and novelty of the device under
a proper insurance system, able to address the nature of investigation, risk analysis should also include evaluation by
these studies and correctly evaluate the risks associated with highly specialized non-clinical experts (e.g. biomedical engi­
their implementation. Third, an FDA-like EFS program would neers) to verify the technical characteristics of the devices, the
require dedicated, highly skilled staff who follow the applicant appropriateness of the construction materials and production
from the initial dialogue phase, several weeks before the sub­ processes, and the congruity between the description of the
mission of the study application, and throughout its imple­ device and its mechanism of action with the expected
mentation. Indeed, this type of ‘follow-up’ is far more complex performance.
and time consuming compared to the procedures currently in While the safety and risk analysis would require more
place and therefore would require appropriate resizing of any emphasis due to the intrinsic nature of EFS and the device
administrative structure dedicated to the program. In addition, under investigation, minor importance was given to statistical
since EFS studies usually involve highly innovative devices considerations such as calculation of the required sample size
with novel mechanisms of actions, evaluation of ethical and the power of the study, given the fact that the general
aspects is likely to be more complex and uncertain, requiring aim of EFS is not to obtain statistically significant estimates of
a high level of expertise from both applicants and assessors. In the device safety or performance. Naturally, for the study to
fact, EFS inherently carry a higher risk profile, which all actors meet the required ethical standards, the applicants should
involved in the authorization process (i.e. IECs, competent also clearly show that the identified risks are offset by greater
authority) should be competent to assess and correctly bal­ expected benefit for the patient.
ance against the potential benefits of the technology. Building Another relevant part of the application that may need
the necessary technical competency would require significant more consideration in EFS is the informed consent form
investment, to expand dedicated staff for the competent given to patients. This should clearly detail the potential risks
authority, IECs and study applicants. However, the design of to patients from the experimental device compared to their
a network of external collaborators such as independent current condition or any other alternative procedures, the
research centers or universities or members of professional additional risks related to the non-definitive design of the
scientific associations to be involved by competent authorities device and any other aspects that may be relevant for the
as external assessors could provide a suitable and indepen­ patient to make an informed decision.
dent structure to support the program. The nature of EFS also requires careful consideration of the
criteria for selecting the investigating centers participating in
3.3.3. Elements requiring consideration during the the study and the patients to be enrolled. Regarding the
application for an EFS selection of the sites, it was noted that the way these studies
It was generally agreed that no further documentation should are managed may be different as opposed to more mature
be required of applicants when applying for an EFS compared studies and requires both greater clinical and management
to other pre-CE mark studies (e.g. traditional feasibility stu­ expertise and the right ‘cultural’ approach. For example, EFS
dies), as the standard documentation already satisfies all infor­ may require closer follow-up of patients and higher capacity
mation (e.g. related to patient safety and study ethics) needs to promptly respond to any adverse events, but they also
to assess the application for a study. However, some parts of require the capacity to culturally manage a high rate of fail­
the documentation may require more attention, such as ures (e.g. higher mortality or adverse events) compared to
patient protection measures, informed consent, or selection studies with more defined device designs and patients often
322 G. CALLEA ET AL.

in better condition. In general, high volume, teaching and clinical evidence in cases where the criteria for allowing indi­
research hospitals were deemed the most appropriate setting vidual compassionate use are met.
for the conduction of EFS. Regarding the characteristics and the stage of development
Selection criteria for patients to enroll in an EFS may also of the devices, it was argued that devices with a high degree
require specific considerations in the application. On one of novelty (i.e. disruptive innovations) and high potential to
hand, severely ill patients with no available alternative treat­ improve existing clinical standards were generally regarded as
ments would likely ensure a positive risk–benefit ratio in EFS better candidates for EFS. However, discussion also centered
applications. On the other hand, patients’ conditions should on whether it would be ethical to consider the potential
not be too compromised, to allow data collection, which is benefits accrued to future patients as one of the criteria to
informative for the purposes of the study. Therefore, the evaluate the admissibility of a device for EFS.
enrollment of lower-risk patients was also discussed, although Beyond their use to assess innovative devices in the early
whether ethical standards would be met in this case should be phases of development, the admissibility of other types of
verified on a case-by-case basis, after considering the existing devices was also discussed. For example, other potential can­
risk profile of the device under investigation and available didates for EFS applications might include more mature tech­
alternatives. nologies used for a novel indication, or even devices
introducing incremental innovations compared to previous
3.3.4. Types of devices that would be suited to an early generations. In all cases, however, compliance with the two
feasibility study and minimum eligibility criteria broad principles mentioned above, i.e. the inappropriateness
One general aspect that emerged from the panel discussion is of further non-clinical testing and an (expected) favorable
that it would be difficult to pre-specify a minimum set of risk–benefit ratio would still need to be met.
criteria to decide which candidate devices are admissible for
EFS. In addition, the definition of a list of devices eligible for 3.4. Key recommendations for the implementation of
EFS, to be periodically updated by the MoH, was not consid­ a European EFS program
ered advisable given the high pace of innovation that would
require continuous updating of the list. However, two broad Based on the discussion with the Italian MoH and the panel of
principles achieved agreement, which basically reiterate that experts, also leveraging on the US experience, we formulated
mentioned above. First, the use of the device on human several key recommendations for the design and implementa­
subjects should be regarded as the only way to further pro­ tion of a European EFS program and grouped them into three
duct development, and all available types of preclinical tests, dimensions: process, resources, and ethical issues (Figure 5).
including bench, animal, and in-silico models, should be pro­
ven to be inappropriate to collect the required evidence.
4. Discussion
Second, the potential benefits to patients should offset the
potential risks related to their condition or any other available This paper provided a broad overview of the characteristics of
therapeutic option. This means that devices that are designed the Early Feasibility Studies program implemented by the FDA
to treat severe conditions and unmet needs would be more and the views and perceptions of key stakeholders on the
likely to be approved for EFS. Related to this latter aspect, EFS desirability, feasibility, and challenges of implementing an
were considered an efficient and structured way to collect FDA-like EFS program in Europe, and specifically in Italy.

Figure 5. Recommendations for the successful implementation of a European EFS program.

 EXPERT REVIEW OF MEDICAL DEVICES 323

Europe is the second largest market for medical technolo­ Given the low quantity of evidence normally available for MDs,
gies after the US [16] and exhibits an excellent level of innova­ combining all efforts would be beneficial for manufacturers, reg­
tiveness: in 2021, nearly 15,320 patent applications for medical ulatory agencies, and ultimately patient safety. The spontaneous
technologies were filed with the European Patent Office (EPO), birth of the International Medical Device Regulatory Forum
41% of which were from European countries [18]. Nonetheless, (IMDRF), a voluntary group of MD regulatory agencies of the US,
full application of MDR will inevitably have consequences for the EU, Australia, Brazil, Canada, China, and Japan, to accelerate
the European industrial sector, for example in terms of higher international MD regulatory harmonization and convergence is
development costs [1]. This in turn may affect the competi­ a good omen. To further enhance collaboration, homogenization,
tiveness of the European MD sector, and the expected uptick and harmonization of EFS, a permanent working group could be
in regulatory requirements in Europe may push manufacturers established within the IMDRF.
to relocate their global clinical development strategies in The formal recognition of EFS among the pre-market
countries with a more favorable environment, and then use clinical investigations allowed in Europe would add
the evidence generated to support their CE Mark application a missing piece in the evidence generation plan that the
in Europe. This may reduce the attractiveness and role of MDR requires over the whole technology life cycle [20],
European investigation centers and ultimately affect the pos­ from preclinical pre-market (e.g. toxicology and biocom­
sibility for European patients to obtain timely access to inno­ patibility tests, in silico trials, early HTA) to clinical pre-
vative medical technologies. In a similar fashion to the market (e.g. first-in-human exploratory studies, EFS, com­
developments that led the US to review their pre-market parative effectiveness studies) to post-market phases (e.g.
device program, a European-wide EFS program may contri­ long-term registries, observational studies). EFS may be
bute to counterbalance such trends. particularly informative in the pre-market phase studies,
Because of the early stage of device development at the time as information obtained during their execution can guide
of EFS, and the distinctive features of these studies as opposed to device modifications and eventually condition the conti­
more mature studies, great emphasis needs to be put on pro­ nuation or suspension of the product’s development. The
moting transparent and honest dialogue between the parties – concept of generating evidence across the various stages
innovators, competent authorities, clinical investigators, IEC, and of medical technologies’ life cycle is quite common and
assessors – involved before and after study authorization. several approaches have been proposed, the two most
Eventually, such dialogue would also facilitate deeper knowl­ prominent being the Total-Product-Life-Cycle [21],
edge and reciprocal trust between manufacturers, competent endorsed by the FDA, and the IDEAL (Idea, Development,
authorities and IECs that was deemed key to successful imple­ Exploration, Assessment, and Long-term study) framework
mentation of the program. The promotion of dialogue among [22], originally developed for surgical interventions and
parties is in line with the overall approach adopted at the EU several years after adapted for MDs through the IDEAL-D
level to improve evidence generation processes and avoid unne­ framework [23].
cessary delays in providing market access to innovative health The establishment of an EFS program would require
technologies. The MDR explicitly envisages the possibility for considerable organizational and financial effort as compared
manufacturers of class III and certain class IIb devices to consult to the procedures currently in place for pre-market author­
an expert panel on questions of clinical development and inves­ izations. Therefore, adequate mechanisms to monitor the
tigation [2]. Similarly, the new European Union Regulation on performance of the EFS program, and whether it achieves
Health Technology Assessment (HTA) (Regulation (EU) 2021/ planned objectives should also be established. In the US,
2282) [19], approved in January 2022 with full application by a public–private partnership between the FDA and industry
January 2025, provides for health technology developers to called Medical Device Innovation Consortium (MDIC) was
engage in early dialogue with European HTA bodies as one of created with the objective of further enhancing the effi­
the four pillars of cooperation among EU Member States on this ciency of EFS conducted in the US [24]. To that end, several
matter. performance metrics were defined, specifically time to FDA
Recent European health policies have been characterized IDE approval, time to site IEC approval, time to contract
by a tendency toward centralization and harmonization. For approval, and time to first subject enrolled by site.
instance, the EU Regulation on MDs [2] and HTA [19] estab­ Performance metrics baselines were computed thanks to
lished coordination groups. A similar harmonized approach the 2017 MDIC Metrics Program, that collected data from
would be desirable for the implementation and management 13 EFS sponsors on study and site performance from studies
of a European EFS program. To overcome the fragmentation in performed in 2015–17 and the so-called ‘60/60/60’ goal (i.e.
the regulatory process that has historically characterized the the time to execute the EFS Clinical Trial Agreement,
EU, by harmonizing and sharing processes, procedures, achieve IEC approval, and enroll the first patient) was
approaches, and methods, we envisage the creation of defined [25]. The analyses showed good performance on
a European EFS Coordination Group. This would also help to the time to EFS IDE protocol approval and site internal
capitalize on competencies and knowledge. Because EFS are review panel approval, but cited several administrative bar­
not widely understood, even less so in the EU where they are riers, for example regarding the times required for site
not formally recognized, bringing together the jurisdictions, contracting and patient enrollment [24,26]. To achieve the
institutions, and scholars who have worked on this issue performance goal, MDIC created a network of sites and
would be a great advantage for Member States. sponsors to favor a learning environment and share best
324 G. CALLEA ET AL.

practices, and developed an EFS tool kit comprised a Master that clinical investigations not approved in Europe as tradi­
Clinical Trial Agreement template, contract language library tional feasibility studies are resubmitted and approved as
& negotiation tool, patient Informed Consent Form tem­ EFS in the US, under the FDA EFS program launched in
plate, and background information for IEC and research 2013, with the aims of increasing early patient access to
staff and for patients [27]. Registration of the EFS in potentially beneficial medical devices in the US; reestablish­
EUDAMED, the European database of MDs currently under ing or increasing US participation in the early clinical evalua­
implementation, will allow to establish ad hoc metrics and tion of innovative medical devices; enhancing collaboration
monitor the performance of these studies. among developers, industry, regulators, and investigators;
In this respect, our database on EFS has some limitations: first, and utilizing the Investigational Device Exemption regula­
since registration on databases such as ClinicalTrials.gov is not tions to protect study participants during the EFS.
mandatory for small clinical trials to determine feasibility and In December 2021, the European Parliament and the
certain trials to test prototype devices, we were not able to Council of the European Union approved a Regulation on
identify the actual number and characteristics of all EFS that Health Technology Assessment entering into force in
have been conducted over the years. This explains the reason January 2022 that will fully apply as of January 2025 [19].
why our data underestimate the number of approved studies The objective of the Regulation is to establish a common
reported by FDA officers Farb and Dreher [9], who rely on FDA framework for joint clinical assessments of health technolo­
CDRH data. Moreover, as EFS are not officially recognized by gies, improve the functioning of the EU internal market and
European Competent Authorities, eventual EFS approved as tra­ promote the health of EU patients.
ditional feasibility studies are unlikely to be labeled EFS in pub­ The approval of the EU Regulation on HTA, that will intro­
lications and might have not been identified by the searches. duce centralized assessments on clinical dimensions, poses to
Therefore, our database might lack some relevant articles. Member States the challenge of embracing a comprehensive
and shared vision of clinical evidence generation. EFS are the
missing element in the European clinical pre-market stage.
A discussion among Member States and the development of
5. Expert opinion
a shared framework for EFS, that employs agile procedures,
The European Union Regulation on Medical Devices entered enhances collaboration and trust among stakeholders, stan­
into force in May 2021. It embraces clinical evidence genera­ dardizes evaluation processes and criteria, and provides
tion across the entire lifecycle of MDs, from preclinical pre- patient protection measures, are strongly recommended. The
market to clinical pre-market to post-market stages. Each absence of a European structured framework for EFS will pre­
stage is prodromal to the next and characterized by an appro­ clude European countries from early-stage R&D investment,
priate level of clinical evidence [20]. Consistent with interna­ reduce the attractiveness of European investigation centers,
tional standards for MDs [28], the evidence generation process and ultimately affect the possibility for European patients to
normally starts with preclinical, toxicology, and biocompatibil­ obtain timely access to innovative medical technologies.
ity tests aimed to optimize design, prototype development, A European-wide EFS program may contribute to counterba­
and manufacturing engineering. This stage is followed by lance such trends.
a clinical, pre-market phase, typically starting with exploratory
studies intended to answer specific questions that may condi­
tion the continuation or suspension of the product’s develop­
ment program. Declaration of Interest
At this stage, a relevant option may be represented by early The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
feasibility clinical investigations. EFS are pre-market studies
the subject matter or materials discussed in the manuscript. This includes
recognized by the International Standards for clinical investi­ employment, consultancies, honoraria, stock ownership or options, expert
gation of MDs for human subjects, that can be used to eval­ testimony, grants or patents received or pending, or royalties.
uate the device design concept with respect to initial clinical
safety and device clinical performance or effectiveness (if
appropriate) as per intended use in asmall number of subjects
when this information cannot practically be provided through Acknowledgement
additional nonclinical assessments or appropriate nonclinical The Centre for Research on Health and Social Care Management (CERGAS),
tests are unavailable. [12] SDA Bocconi School of Management, received an unrestricted grant from
EFS may be particularly important as information obtained the Directorate-General of Medical Devices and Pharmaceutical Service,
during their execution can guide device modifications. Ministry of Health, Italy.
The authors would like to thank the Italian Ministry of Health Director-
European countries have no standardized procedural fra­ General of Medical Devices (Marcella Marletta), the Office for Clinical
mework for EFS. In the absence of a specific framework, in Investigations director (Pietro Calamea) and members (Paolo Colletti,
Europe EFS are submitted either as individual requests for Adele Misticoni Consorti, Luisa Mariani, and Marina Urpis), and the expert
compassionate use or as traditional feasibility studies, and panel members (Sergio Cerutti, Christian Cipriani, Claudio Cobelli,
the competent authorities in charge of assessing the Giovanni Esposito, Carlo Di Mario, Simona Frontoni, Luigi Mazzei,
Massimo Napodano, Alberto Priori, and Tiziana Marotta) for the time
requests apply evaluation criteria neither specifically they dedicated to participating in the meetings and focus groups.
designed nor appropriate for EFS. So, it is not uncommon We wish to thank Helen Banks for providing language assistance.
 EXPERT REVIEW OF MEDICAL DEVICES 325

Funding 11. Dreher ML, Rouabhi O, Farb A. Early feasibility study program during
the COVID-19 pandemic, edition 26, 2021 Mar 23. Available from:
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Directorate General for Medical Devices and Pharmaceutical Services 12. ISO 14155:2020 clinical investigation of medical devices for human
(Grant No. J46C18000670005). subjects – good clinical practice. Available at: https://www.iso.org/
standard/71690.html?browse=tc.
13. Medical Device Coordination Group (MDCG). 2021. Regulation (EU)
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medici non recanti la marcatura CE (pre market). Available from:
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