TYPE Review

PUBLISHED 15 December 2022

DOI 10.3389/fpubh.2022.1081150

Decentralized clinical trials

OPEN ACCESS (DCTs): A few ethical
considerations
EDITED BY
Tambone Vittoradolfo,
Campus Bio-Medico University, Italy

REVIEWED BY
Solomiia Fedushko, Carlo Petrini1*, Chiara Mannelli1 , Luciana Riva1 ,
Lviv Polytechnic, Ukraine
Armin D. Weinberg, Sabina Gainotti1 and Gualberto Gussoni2
Baylor College of Medicine,
1
United States Bioethics Unit, Istituto Superiore di Sanità, Rome, Italy, 2 Clinical Research Department, FADOI
Research Centre, Milan, Italy
*CORRESPONDENCE
Carlo Petrini
[email protected]
Decentralized clinical trials (DCTs) are studies in which the need for patients
SPECIALTY SECTION
This article was submitted to to physically access hospital-based trial sites is reduced or eliminated. The
Digital Public Health, CoViD-19 pandemic has caused a significant increase in DCT: a survey
a section of the journal
Frontiers in Public Health
shows that 76% of pharmaceutical companies, device manufacturers, and
Contract Research Organizations adopted decentralized techniques during
RECEIVED 26 October 2022
ACCEPTED 30 November 2022 the early phase of the pandemic. The implementation of DCTs relies on the
PUBLISHED 15 December 2022 use of digital tools such as e-consent, apps, wearable devices, Electronic
CITATION Patient-Reported Outcomes (ePRO), telemedicine, as well as on moving trial
Petrini C, Mannelli C, Riva L, Gainotti S
and Gussoni G (2022) Decentralized
activities to the patient’s home (e.g., drug delivery) or to local healthcare
clinical trials (DCTs): A few ethical settings (i.e., community-based diagnosis and care facilities). DCTs adapt
considerations. to patients’ routines, allow patients to participate regardless of where they
Front. Public Health 10:1081150.
doi: 10.3389/fpubh.2022.1081150 live by removing logistical barriers, offer better access to the study and the
COPYRIGHT
investigational product, and permit the inclusion of more diverse and more
© 2022 Petrini, Mannelli, Riva, Gainotti representative populations. The feasibility and quality of DCTs depends on
and Gussoni. This is an open-access several requirements including dedicated infrastructures and staff, an adequate
article distributed under the terms of
the Creative Commons Attribution regulatory framework, and partnerships between research sites, patients and
License (CC BY). The use, distribution sponsors. The evaluation of Ethics Committees (ECs) is crucial to the process
or reproduction in other forums is
of innovating and digitalizing clinical trials: adequate assessment tools and a
permitted, provided the original
author(s) and the copyright owner(s) suitable regulatory framework are needed for evaluation by ECs. DCTs also
are credited and that the original raise issues, many of which are of considerable ethical significance. These
publication in this journal is cited, in
accordance with accepted academic include the implications for the relationship between patients and healthcare
practice. No use, distribution or staff, for the social dimension of the patient, for data integrity (at the source,
reproduction is permitted which does
during transmission, in the analysis phase), for personal data protection, and for
not comply with these terms.
the possible risks to health and safety. Despite their considerable growth, DCTs
have only received little attention from bioethicists. This paper offers a review
on some ethical implications and requirements of DCTs in order to encourage
further ethical reflection on this rapidly emerging field.

KEYWORDS

DCTs, Research Ethics, Bioethics, healthcare, digitalization

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Petrini et al. 10.3389/fpubh.2022.1081150

Introduction In light of the above, it should be noted that currently, in

many cases, DCTs do not replace conventional trials. Rather,
Decentralized clinical trials1 (DCTs) make use of they are supplementary to them.
digital technologies and other methods to enable access The therapeutic areas for which DCTs are most readily
of patients to clinical research, remote data collection and applicable are those in which telemedicine is most advanced
monitoring, and communication between the investigators and like diabetes, neurorehabilitation, cardiovascular diseases,
participating subjects. pulmonary diseases and, more recently, COVID-19.
In a DCT, enrolled patients are no longer required to One of the main challenges in the implementation of DCTs
frequently travel to a healthcare facility in order to participate (in Europe and worldwide) at the current time regards the
in the trial, as they are able to take part from their normal living fact that the existing regulatory frameworks were devised with
environment. The center of gravity of the trial therefore shifts conventional clinical trials in mind. Besides, there are still very
from the study site (i.e., the hospital) to the patient’s home. few documents and guidelines on the planning, design and
Thus, DCTs can adapt to patients’ routines and allow them to evaluation of DCTs and decentralized methods (1), and this
participate regardless of their geographical position. is in some ways surprising since DCTs are not absolutely a
DCTs can include the direct delivery of investigational novel mode.
medicinal products (IMP) to participating subjects, laboratory Indeed, the earliest studies on the feasibility of “Internet
examinations and/or instrumental tests carried out in centers trials” date back to 2003. Since then, there has been a
other than the trial site and close to the patient’s home, and home continuous crescendo, for example the first “Trial over the
visits by healthcare professionals. This study model typically Internet” was patented in the USA in 2007. In 2011, Pfizer
involves use of Internet, smartphones and their applications, conducted the first fully-decentralized randomized study titled
telemedicine platforms, social media and similar technologies “Research on Electronic Monitoring of Overactive Bladder
at different stages of the trial (patients’ enrolment and consent, Treatment Experience, REMOTE” (2, 3), the results of which
clinical checks, remote data collection, monitoring and source were published in 2014. In this trial, the Internet was used
data verification). for subject enrolment, the administration of online screening
In DCTs, remote data collection can be active or passive. questionnaires and provision of electronic outcomes diaries,
When it is active, the patient is required to enter data using and the investigational medicinal product was delivered to the
one or more devices, whereas when it is passive the data are patients’ homes.
logged by the device/s used in the study (e.g., wearables or Over the last decade, all major pharmaceutical companies
sensors) without active intervention by the patient. In both have conducted DCTs. According to a survey carried out
cases, patient involvement in data collection may actually be by the consulting company McKinsey in December 2019,
more active than with conventional participation at a healthcare immediately before the pandemic, 38% of representatives of
facility. Furthermore, by means of electronic instruments, DCTs the pharmaceutical industry and contract research organizations
allow constant contact between the patient and research staff. (CROs) anticipated that the majority of their activities would be
DCTs are not an all-or-nothing method, as the comprised of “virtual” studies and 48% anticipated conducting
decentralization can be of varying degrees. The use of trials in which most of the activities would be carried out at
technology does not exclude personal interaction or the patients’ homes. When McKinsey asked the same questions 1
possibility of the patient traveling to a healthcare facility and year later, the answers were 100 and 89%, respectively (4).
participating in the trial under certain circumstances. More It should therefore be pointed out that the COVID-19
specifically, a DCT may include procedures that cannot be pandemic has stimulated a considerable increase in DCTs: a
carried out in a home environment. Many DCTs are therefore in survey conducted by Oracle (5) showed that, already in the
hybrid form, combining home-based, traditional on-site visits, 1st year of the pandemic, 76% of pharmaceutical companies,
and study procedures. device manufacturers and CROs had adopted decentralized
DCTs are especially useful in cases that make travel difficult techniques. Of these, 7% used fully decentralized methods.
for the patient, either for clinical conditions (e.g., neuromuscular Actually, COVID-19 has provided a significant proof of concept
diseases), or logistical barriers, when research sites are far (PoC) regarding clinical trials in a context of emergency and, in
from patient’s home (as often occurs in case of rare diseases). particular, on the integration of decentralized approaches.
Decentralized studies are particularly suitable for low- to In order to support the on-going process, in March 2020 the
medium-complexity conditions, and for studies that are not FDA issued in the United States specific operational guidelines
excessively long. covering many of the challenges posed by the decentralization
of activities in clinical studies, with its “Guidance for Industry,
Investigators, and Institutional Review Boards” (6).
On 4 February 2021, the European Commission published
1 This paper only refers to DCTs on medicinal products. the fourth version of its guidelines on the management of

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clinical studies during the COVID-19 pandemic, i.e. “Guidance important, especially in research on rare diseases, because
on the Management of Clinical Trials during the COVID-19 it favors inclusion, and improves the representativeness and
(Coronavirus) Pandemic.” Despite the temporary nature of generalisability of the results.
these guidelines, which were designed for the management of • More convenient conditions for subjects, with less
clinical trials during the health emergency, they contain key avoidable discomfort and suffering, in particular for frail
information for the implementation of DCTs. Moreover, they subjects. DCTs do away with waiting times, contact with the
include the authorization of procedures such as the delivery suffering of other patients, in some cases hospitalization,
of investigational products at patient’s home, home-based possible exposure to pathogens in hospital settings that can
visits, use of community-based diagnostic facilities, and remote cause complications.
monitoring of collected data / source data verification (7). • Greater autonomy for the participating subject, who can
Now the question is whether, which and how those methods remain at home at least for part of the study procedures.
authorized by the central European and local authorities • Greater convenience for families and caregivers.
during the emergency will pass from derogation to rule. In • The possibility of collecting “real-time” and “real-
certain European countries, in recent years, the competent world data,” in the subjects’ usual living environment
institutions have started to deal with the matter starting from and therefore avoiding potential bias resulting from
the local regulatory framework, in order to provide guidance to assessments performed in ad hoc facilities.
investigators and sponsors (8, 9). • The possibility of evaluating endpoints difficult to measure
It is crucial to carry out feasibility studies in order to with conventional studies, thanks to the ways in which the
identify the opportunities and the challenges from a regulatory data can be collected.
standpoint and to favor the authorization and implementation • Time-saving.
of DCTs (10). • Cost-saving.
The opportunities appear to be numerous. It has been
suggested that DCT approaches can be justified and particularly Although some studies show an increase in patient retention
suitable for trials with chronic diseases, rare diseases, immobile rates in DCTs and better compliance with procedures than in
participants, self-administrable IMP, lower safety risk profile, conventional trials (due to the home setting, use of electronic
and confirmatory clinical trials. Particularly in rare disease reminders, an overall less burdensome participation etc.), there
studies, the changes necessitated by the COVID-19 pandemic is no full consensus regarding these aspects in the literature
have provided an opportunity to become a standard approach. (17, 18).
Although some DCT projects were developed even earlier in this Nevertheless, despite considering the significant benefits
area, during COVID-19 they forcibly entered clinical practice decentralized trials can offer, it is also necessary to mention
offering advantages in terms of patient burden, practicality, disadvantages (some of them may occur in CTs as well).
inclusion and data quality (11). Potential barriers, limitations and risks associated with the
However, not all clinical trials are suitable for implementation of DCTs (19–24), include:
decentralization and hybrid solutions appear as the more
reasonable scenario in the very majority of cases. Future • Potential amplification of inequalities. Groups with
research will be needed to demonstrate, for example, whether reduced access to technologies could be penalized. This
studies on DCTs or hybrid DTCs are particularly suitable for aspect should be considered both in relation to the ability to
carrying out prevention or screening studies compared to use devices and the availability of the equipment required
treatment clinical studies. for connection, i.e., access to a stable connection (which
may depend on both economic and geographical factors)
and of supporting devices.
The risks and benefits of DCTs • Partial application (DCTs are not suitable for all
medical conditions).
The possibility of decentralizing studies affords a number • Remote data collection can favor quality, thanks to
of opportunities, with ethical and clinical implications (12–16). automation of the processes involved. However, the quality
The potential advantages of DCTs include: of collection can be jeopardized as it takes place in a less
“protected” setting than a research facility. This may lead to
• The possibility of enrolling subjects who are unlikely the risk of technical failures when digital devices are used.
to be able to take part in conventional trials, because Therefore, deterioration in data quality at the source and
their home is a long way from a healthcare facility, or during transmission are possible.
because of physical difficulties in reaching the facility. • Risks regarding the validity and reliability of the data
Facilitated access allows a higher number of patients to collected. One example is the “6-min walk test” used to
be eligible for participation. This aspect is particularly assess the effects of treatments aimed at improving walking

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capacity in patients with peripheral artery disease. In order are conducted remotely, personal contacts are infrequent (or
for the data to be reliable, the test must be performed by completely absent): it is therefore important to provide chances
making the patient walk on a rigid and flat surface, and of for direct exchange and communication during the initial stage
accurately documented length. However, when the test is and whenever the need arises. In this perspective, face-to-face
carried out by a patient at home, it may be troublesome to communication should take place between the investigator and
ensure that the surface meets the requirements, is obstacle- the potential trial participant. If this discussion takes place in a
free and precisely measured (25). This inconsistency could digital / virtual mode, this should be generally performed in real
have an impact on the reliability of the data. Although time where the parties are able to see and communicate with
mistakes and inaccuracy may occur in conventional trials each other via audio and video, and to ask questions.
as well, factors that may jeopardize validity and reliability
in DCTs should be properly identified and addressed.
• A methodological bias may arise from the combined
Access
use of clinical measurements performed in a hospital or
home setting. A typical example is that of arterial blood
DCTs can increase the number of individuals eligible for a
pressure measurement.
trial by removing the logistical and geographical barriers but, at
• Some clinical checks may be less accurate if conducted
the same time, they can increase inequalities in access, penalizing
remotely. This can lead to potential issues for the wellbeing
individuals who do not possess the technologies or the skills
and safety of patients.
required. The availability of technologies should not constitute
• Risks regarding the protection of personal data, also due to
an exclusion criterion and the necessary equipment should be
the increased number of actors involved (e.g., couriers for
provided by the sponsor.
delivery of the investigational product, providers for home
Participants and, if necessary, also their caregivers, should
assistance and digital services, etc).
be provided not only with initial training on using the
• Data breach risks.
devices, but also with on-going support throughout the
• Risk of weakening the physician-patient relationship.
progress/evolution/unrolling of the DCT.
• Potential isolation of the trial subject, who does not have
opportunities to meet and share experiences with other
patients taking part in the same study.
Data collected, transmitted, and analyzed

Some requirements In general, special care must be taken when applying the
basic criteria that pertain to all data processing:
Information and consent
• Lawfulness, fairness, and transparency. Data must be
Given their nature, DCTs often involve the use of e-consent processed lawfully, fairly, and in a transparent manner in
of various forms. relation to the data subject.
E-consent has advantages over the conventional paper form, • Restriction of the purpose: data must be processed for
for example it can be filed easily, retrieved rapidly, updated specified, explicit, and legitimate purposes. They must
readily and promptly shared amongst the staff involved. Among also be processed in a manner that is compatible with
relevant aspects, it is important to ensure that the systems used such purposes.
for e-consent have proportionate security levels, and safeguards • Minimization: personal data must be adequate, relevant
regarding confidentiality are in place. and restricted to the purposes for which they were collected.
Special care must be dedicated to the clarity and • Accuracy and updating: data must be accurate and up-
completeness of the information provided to the patient. to-date. There must be procedures in place for the timely
In the case of fully-digital consent, the validity of the signature correction or erasure of inaccurate data.
must be guaranteed from a legal perspective as well. It must • Restriction of storage: data must be stored in a form that
be borne in mind that electronic signatures, particularly permits the identification of the data subjects only for
Advanced Electronic Signatures (AdESs) require identification as long as is strictly necessary to fulfill the purposes for
and registration procedures that could be complicated for some which they were processed, unless that patient has explicitly
subjects: this could hamper, or even preclude, the access of consented to reuse the data for future research.
certain population groups. • Integrity and confidentiality: personal data must be
If the personal relationship with the healthcare professionals guaranteed adequate security.
is important in the information and conventional consent • Accountability: the controller must ensure that the data are
procedure, it is even more so in DCTs. Indeed, as DCTs processed in an appropriate manner.

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Data must be: Attributable, Legible, Contemporaneous (i.e., In addition to rigorous protection of privacy, the distribution
recorded at the time the activities are carried out), Original (or system must guarantee quality and efficiency, particularly for
true to the original), Accurate (ALCOA) (26). medicinal products requiring special storage and transportation
In order to allow the reuse of existing data and avoid useless conditions (for instance: maintenance of the cold chain).
duplications, data should also be made Findable, Accessible,
Interoperable and Reusable (FAIR) (27).
The accuracy of data recording is particularly important in Return of result
the case of active data collection by the patient. Therefore, the
subjects taking part in trials must be given adequate instructions Patients generally wish to know the results of the clinical
on this matter. investigations in which they are involved as soon as possible. In
There must be commensurate procedures in place to DCTs, given the way the studies are conducted, patients may be
ensure the integrity of the data during their transmission and even more eager to find out the results quickly.
management. Special attention must be given to the fact that Among other aspects, special attention must be paid to the
the data stored on personal devices can be easily linked to other occurring of any incidental findings, in other words, unexpected
personal data (contacts, location, microphone, video camera, results that are not related to the study and are not intentionally
purchases, etc.). Therefore, there must be adequate procedures sought. In the case of incidental findings that are clinically
in place to guarantee the effective protection of all personal data. relevant (for prevention and therapy) and actionable, it is
The risks of unintentional data disclosure or deliberate breach the physician’s duty not to overlook them: therefore, precise
of privacy go well beyond the scope of the DCTs. For example, procedures must be adopted for the management of any
health-related information can result in discrimination in the incidental findings (30–32).
workplace. In order to reduce this kind of risk, it may be useful to
use distributed ledgers, decentralized databases and blockchain
technology (28, 29). Discussion
The final use of the data must also be strictly governed: DCTs
favor the collection of a multitude of real-world data, which The DCT approval process deserves special attention,
in some cases go beyond the scope of the study. Therefore, it making the role of Ethics Committees (ECs) crucial.
is necessary to prevent their use in contexts other than those The procedures for conducting DCTs are such that the
envisaged by the study. It is also necessary to clearly establish current regulatory framework may be only partially adequate.
which data may be used after the end of the DCT. Patients must There are no detailed documents or reference standards
be adequately informed of this possibility and given the chance concerning the role of ECs in the oversight and evaluation
to grant or refuse their consent to such use. of DCTs (33). These bodies may encounter difficulties when
reviewing studies that involve significant complexities due
to the innovative approaches employed. Information on the
Study protocol flexibility decentralized activities should therefore be clear and justified
on a case-by-case basis in the clinical trial protocol (34). In a
Preferences vary from one person to another. For example, simulated survey on members of European ECs called on to
some may prefer direct personal interactions, without the review a DCT protocol, it was observed that the quality, safety,
mediation of technology. and organization of the DCT were perceived as being more
Flexible research programmes can make it possible to not problematic than those of conventional clinical studies. For
overlook differences in personal preferences. To this end, it instance, the members expressed concerns regarding the validity
would be useful to give patients the possibility to provide regular and accuracy of the data, in case the participating subjects were
feedback on their experience regarding the trial. However, responsible for measuring and inputting them (1). Although
flexibility may also introduce the risk of methodological biases the criteria used by ECs when analyzing a decentralized clinical
(see what previously reported on arterial blood pressure). study are the same as those for conventional studies, the
application of such criteria to the specific cases can be more
complex. Moreover, EC members may require supplementary
Provision of the IMP information in order to consider, for example, whether the
procedures for implementing the electronic informed consent
In planning a clinical trial, the sponsor and investigator may process are suited to guaranteeing a true personal data
consider whether the IMP is suitable for administration at home, communication, comprehension, and protection process.
and if the appropriate storage conditions of the IMP can be met. Aspects examined by ECs when reviewing new studies must
In DCTs, the medicinal product can be delivered to the subject’s be considered in the light of the DCTs as well. This scenario
home, usually by courier, under supervision and responsibility may be troublesome because of the numerous peculiarities DCTs
of the pharmacy of the healthcare facility and the investigator. show. One example regards the assessment of site suitability.

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DCTs are coordinated by trial sites, whose suitability can be - the healthcare personnel that design and conduct DCTs: all
assessed using the conventional criteria. However, DCTs are of them (including those that carry out home visits) must
conducted at the subjects’ home, which makes it difficult, if not be technically and ethically skilled;
impossible, to guarantee a priori that each home is fully suited to - the patients and their caregivers, who must be not only
the conduct of the DCT in question. informed, but also trained;
Another example regards the way in which devices are - the EC members, so that they can play their responsibility
used. Most (but not necessarily all) the devices used in DCTs for authorizing DCTs with competence and awareness.
are classified as medical devices. The medical devices must
be marked pursuant to regulations and used in compliance The planning and conduct of DCTs involve particularly complex
with their intended use. If this were not the case, the DCT matters: partnerships between sponsors, study sites and patient
would qualify as a clinical investigation on a medical device. advocacy groups must be favored to promote the best individual
This actually creates a intertwining between the regulations involvement of the patients themselves. General practitioners
governing clinical trials on medicinal products and those on should also be involved.
medical devices that is often difficult to manage, especially DCTs must be planned and conducted maintaining the
for ECs. standards for the production of evidence commonly adopted
More generally, adequate guidelines, recommendations and by the scientific community: although for DCTs changes in
regulations must be adopted in order to favor harmonization the organizational, administrative, regulatory and operational
of both DCT review and authorization procedures and foster conditions for the conduct are permitted, shortcuts and
virtuous implementation of these trials. exceptions in the scientific method and rigor are not acceptable.
At European level, an in-depth review of the ethical Groups that are unlikely to participate in DCTs because of
and legal framework is essential for establishing how digital divide (for example many elderly people) must be offered
the existing definitions and conceptual rules for clinical alternative options for trial participation, so that anyone who
trials are applicable to the decentralized activities of meets the eligibility criteria has the chance to take part. This
DCTs. As digital technologies gradually become more is a major challenge for clinical research in the near future:
extensively incorporated into clinical trials, the EU combining and harmonizing the need for equity of access,
regulatory framework for DCTs/hybrid trials will have to the procedural flexibility offered by the availability of different
evolve and the Good Clinical Practice (GCP) protocols methods of conducting studies, and the methodological rigor in
will have to be modernized. Modernizing GCP regulatory the production of reliable scientific evidence.
supervision in order to enable decentralized clinical Therefore, any decision to switch from a traditional trial
study models is currently an objective for the European to DCTs must be decided on a case-by-case basis: the
institutions (35). elements of decentralization must be justified in relation
The need for homogeneous safety standards that guarantee to the characteristics of the study, and balancing improved
patients a level of protection not lower than that adopted for access for patients, their safety, rights and dignity, with the
conventional trials, is particularly important: the fact that DCTs quality of collected data. Respect for the person, his/her
can allow real-time continuous monitoring is not, in itself, a wellbeing and his/her central role must always come first,
guarantee of adequate protection. It is also necessary to adopt taking precedence over any procedural consideration regarding
procedures that lead to timely intervention and, preferably, organization, quality, efficiency, effectiveness, and the progress
provide a remedy in the case of unforeseen circumstances, of knowledge.
incidents and adverse events. This calls for effective e-health
systems that are suited to the purpose, and above all a
health organization that guarantees 24/7 surveillance and Author contributions
possible assistance.
E-health systems must, in any case, offer patients the CP wrote the initial draft of the manuscript with the
possibility of direct contact with the healthcare facility and with contribution of CM. LR and SG contributed with insightful
the doctors and researchers conducting the trial. With a view feedback and integrations. GG provided critical revision. All
to this, in many cases, hybrid DCTs are appropriate as they authors approved the final manuscript.
alternate procedures at the subject’s home with procedures at the
trial site.
Considering the growing number of DCTs and their Conflict of interest
challenging implementation, adequate training - both on the
technical aspects, including digital skills, and on the ethical The authors declare that the research was conducted in the
implications resulting from the decentralized methods - should absence of any commercial or financial relationships that could
be provided to stakeholders, namely: be construed as a potential conflict of interest.

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Petrini et al. 10.3389/fpubh.2022.1081150

Publisher’s note organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
All claims expressed in this article are solely those of the claim that may be made by its manufacturer, is not guaranteed
authors and do not necessarily represent those of their affiliated or endorsed by the publisher.

References
1. van Rijssel TI, de Jong AJ, Santa-Ana-Tellez Y, Boeckhout M, Zuidgeest 15. Khozin S, Coravos A. Decentralized trials in the age of Real-World Evidence
MGP, van Thiel GJ, et al. Ethics review of decentralized clinical trials and inclusivity in clinical investigations. Clin Pharmacol Ther. (2019) 106:25–
(DCTs): results of a mock ethics review. Drug Discov Today. (2022) 7. doi: 10.1002/cpt.1441
27:103326. doi: 10.1016/j.drudis.2022.07.011
16. Price J, Goodson N, Warren EJ, Wicks P, Reites J. Resilient
2. Pfizer. Pfizer Conducts First “Virtual” Clinical Trial Allowing Patients design: decentralized trials recovered faster from the impact of CoViD-
to Participate Regardless of Geography (2011). Available online at: https:// 19 than traditional site-based designs. Expert Rev Med Devices. (2021)
www.pfizer.com/news/press-release/press-release-detail/pfizer_conducts_first_ 18:1–4. doi: 10.1080/17434440.2021.2014818
virtual_clinical_trial_allowing_patients_to_participate_regardless_of_geography 17. Ali Z, Anderson K, Chiriac A, Andersen AD, Isberg AP, Moreno FG, et al.
(accessed September 21, 2018). High adherence and low dropout rate in a virtual clinical study of atopic dermatitis
3. Orri M, Lipset CH, Jacobs BP, Costello AJ, Cummings SR. Web-based through weekly reward-based personalized genetic lifestyle reports. PLoS ONE.
trial to evaluate the efficacy and safety of tolterodine ER 4 mg in participants (2020) 15:5500. doi: 10.1371/journal.pone.0235500
with overactive bladder: remote trial. Contemp Clin Trials. (2014) 38:190– 18. Rogers A, De Paoli G, Subbarayan S, Copland R, Harwood K, Coyle J, et al. A
7. doi: 10.1016/j.cct.2014.04.009 systematic review of methods used to conduct decentralised clinical trials. Br J Clin
4. McKinsey&Company. No place like home? Stepping up the decentralization Pharmacol. (2022) 88:2843–62. doi: 10.1111/bcp.15205
of clinical trials (2021). Available online at: https://www.mckinsey.com/ 19. Mathieu E, Barratt A, Carter SM, Jamtvedt G. Internet trials:
industries/life-sciences/our-insights/no-place-like-home-stepping-up-the- participant experiences and perspectives. BMC Med Res Methodol. (2012)
decentralization-of-clinical-trials (accessed September 21, 2022). 12:162. doi: 10.1186/1471-2288-12-162
5. Oracle. The Accelerated Evolution of Clinical Trials in a Pandemic 20. Apostolaros M, Babaian D, Corneli A, Forrest A, Hamre G, Hewett J, et al.
Environment. Report. (2020). Available online at: https://go.oracle.com/ Legal, regulatory, and practical issues to consider when adopting decentralized
researchacceleratedtrials?elqCampaignId=257896 (accessed September 21, clinical trials: recommendations from the clinical trials transformation initiative.
2022). Ther Innov Regul Sci. (2019) 54:1–9. doi: 10.1007/s43441-019-00006-4
6. U.S. Food and Drug Admin. Guidance for Industry, Investigators, and 21. Rosa C, Campbell ANC, Miele GM, Brunner M, Winstanley EL. Using
Institutional Review Boards: Conduct of Clinical Trials of Medical Products e-technologies in clinical trials. Contemp Clin Trials. (2015) 45(Pt A):41–
During the COVID-19 Public Health Emergency 26 (2020). Available online at: 54. doi: 10.1016/j.cct.2015.07.007
https://www.fda.gov/media/136238/download (accessed September 21, 2022).
22. McDermott MM, Newman AB. Remote research and clinical trial
7. European Commission, Guidance on the Management of Clinical Trials integrity during and after the coronavirus pandemic. JAMA. (2021) 325:1935–
during the COVID-19 (Coronavirus) Pandemic (2022). Available online at: 6. doi: 10.1001/jama.2021.4609
https://health.ec.europa.eu/system/files/2022-02/guidanceclinicaltrials_covid19_
23. Coert RMH, Timmis JK, Boorsma A, Pasman WJ. Stakeholder perspectives
en_1.pdf (accessed September 21, 2022).
on barriers and facilitators for the adoption of virtual clinical trials: qualitative
8. SwissMedic, SwissEthics. Decentralised Clinical Trials (DCTs) study. J Med Internet Res. (2021) 23:e26813. doi: 10.2196/26813
with Medicinal Products in Switzerland. (2021). Available online at:
24. Van Norman GA. Decentralized Clinical Trials: the future
www.swissmedic.ch/swissmedic/en/home/humanarzneimittel/clinical-
of medical product development? JACC Basic Transl Sci. (2021)
trials/clinical-trials-on-medicinal-products/publikationen.html (accessed
6:384–7. doi: 10.1016/j.jacbts.2021.01.011
September 21, 2022).
25. Banks MA. Core concept: in the wake of COVID-
9. Danish Medicines Agency. The Danish Medicines Agency’s Guidance
19, decentralized clinical trials move to center stage. ProcNat
on the Implementation of Decentralised Elements in Clinical Trials with
Acad Sci USA. (2021) 118:e2119097118. doi: 10.1073/pnas.21190
Medicinal Products. (2021). Available online at: https://laegemiddelstyrelsen.
97118
dk/en/news/2021/guidance-on-the-implementation-of-decentralised-elements-
in-clinical-trials-with-medicinal-products-is-now-available/$\sim$/media/ 26. US Department of Health and Human Services. Data Integrity and
5A96356760ED408CBFA9F85784543B53.ashx (accessed September 21, 2022). Compliance with Drug CGMP. Questions and Answers. Guidance for Industry.
Washington DC: Food and Drug Administration (2018). Available online
10. de Jong AJ, van Rijssel TI, Zuidgeest MGP, van Thiel GJMW, Askin S,
at: https://www.fda.gov/media/119267/download
Fons-Martínez J, et al. Opportunities and challenges for decentralized clinical
trials: european regulators’ perspective. Clin Pharmacol Ther. (2022) 112:344– 27. Wilkinson MD, Dumontier M, Aalbersberg IJ, Appleton G,
52. doi: 10.1002/cpt.2628 Axton M, Baak A, et al. The fair guiding principles for scientific data
management and stewardship. Sci Data. (2016) 3:160018. doi: 10.1038/sdata.2
11. Moore J, Goodson N, Wicks P, Reites J. What role can
016.18
decentralized trial designs play to improve rare disease studies?
Orphanet J Rare Dis 17, 240. (2022). doi: 10.1186/s13023-022-0 28. See Hang L, Chen C, Zhang L, Yang J. Blockchain for applications of clinical
2388-5 trials: taxonomy, challenges, and future directions. IET Commun. (2022) 3:1–23.
12. Gussoni G. (editor). Implementing Decentralized Clinical Trials in Italy: Why 29. Maslove DM, Klein J, Brohman K, Martin P. Using
and How? Tendenze Nuove, Special Issue 2. Milan: Passoni Editore (2022). blockchain technology to manage clinical trials data: a proof-of-
concept study. JMIR Med Inform. (2018) 6:e11949. doi: 10.2196/
13. Gabbrielli F, Zibellini M, Triola R, Bocchino M (editors). Decentralized
11949
Clinical Trial e telemedicina: nuovo approccio alla sperimentazione clinica per
facilitare il paziente e velocizzare la ricerca. Rome: Istituto Superiore di Sanità 30. Cfr. Comitato Nazionale per la Bioetica. Gestione degli “Incidental
(2022). Rapporti ISTISAN viii, 22/4 135 p. Findings” nelle indagini genomiche con le nuove piattaforme tecnologiche, (2016).
Available https://bioetica.governo.it/media/1803/p123_2016_incidental_findings_
14. Josan K, Touros A, Petlura C, Parameswaran C, Grewal U, Senior M, et al.
it.pdf (accessed September 21, 2022).
Validation of a pandemic-proof, decentralized cardiovascular trial: scalable design
produces rapid recruitment, high engagement and protocol adherence in DeTAP 31. Commissione per l’Etica della Ricerca e la Bioetica del CNR. Incidental
(decentralized trial in Afib patients). Eur Heart J. (2021) 42(Supplement_1):12– Findings nella Ricerca Scientifica, (2018). Available online at: https://www.cnr.
9. doi: 10.1093/eurheartj/ehab724.3177 it/sites/default/files/public/media/doc_istituzionali/ethics/cnr-ethics-incidental-

Frontiers in Public Health 07 frontiersin.org

Petrini et al. 10.3389/fpubh.2022.1081150

findings-nella-ricerca-scientifica--scienze-e-tecnologie-omiche.pdf (accessed 34. de Jong AJ, van Rijssel TI, Zuidgeest MGP, van Thiel GJMW, Askin S,
September 21, 2022). Fons-Martinez J, De Smedt T, de Boer A, Santa-Ana-Tellez Y, Gardarsdottir H,
32. Saini KS. de las Heras B, Plummer R, Moreno V, Romano M, de Castro J, et al. the Trials@Home Consortium. Opportunities and Challenges for Decentralized
Reimagining global oncology clinical trials for the postpandemic era: a call to arms. Clinical Trials: European Regulators’ Perspective. Clinixcal Pharmacology &
JCO Glob Oncol. (2020) 6:1357–62. doi: 10.1200/GO.20.00346 Therapeutics (2022). Available online at: https://ascpt.onlinelibrary.wiley.com/doi/
abs/10.1002/cpt.2628 (accessed September 21, 2022).
33. Nebeker C, Harlow J, Espinoza Giacinto R, Orozco Linares R,
Bloss CS, Weibel N. Ethical and regulatory challenges of research using 35. European Medicines Agency. EMA Regulatory Science to 2025. Strategic
pervasive sensing and other emerging technologies: IRB perspectives. reflection. https://www.ema.europa.eu/en/documents/regulatory-procedural-
AJOB Empir Bioeth. (2017) 8:266–76. doi: 10.1080/23294515.2017.14 guideline/ema-regulatory-science-2025-strategic-reflection_en.pdf, pag. 21
03980 (accessed September 21, 2022).

Frontiers in Public Health 08 frontiersin.org