Implementation status and consideration for the globalisation of decentralised clinical trials: a cross-sectional analysis of clinical trial databases

Abstract

Objective

To comprehensively elucidate the current landscape of decentralised clinical trials (DCTs) and identify notable aspects that can facilitate DCT implementation.

Design

Cross-sectional analysis.

Setting

Data were extracted using selected DCT-specific search terms on 4 June 2022, from the ClinicalTrials.gov database and on 2 September 2022, from the Japan Registry of Clinical Trials and Japic Clinical Trials Information.

Primary outcome measure

We characterised trials based on the four components of DCT: telemedicine, home healthcare, direct-to-patient and the Internet of Healthcare Things (IoHTs)/Internet of Medical Things.

Results

Data obtained from ClinicalTrials.gov indicated that the number of DCTs has increased annually and exponentially since 2020. DCTs for cardiovascular diseases are the most common, and the digital platform for patient monitoring is used the most in DCTs. The Japanese databases also showed that DCTs have increased in recent years, and the data on disease areas and IoHTs were similar to those obtained from the ClinicalTrials.gov database, except for the number of studies. Approximately 9.2% of DCTs were conducted across multiple regions, whereas over 80% were conducted within a single country.

Conclusions

This study revealed the comprehensive trend of DCTs in the USA and Japan and helped identify widely implemented DCT components and the therapeutic areas in which they are implemented. International consensus guidelines for DCTs are necessary to promote multiregional clinical trials with DCT components.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• The world’s largest clinical trial database, ClinicalTrials.gov, and major Japanese databases, Japan Registry of Clinical Trials (jRCT) and Japic Clinical Trials Information (JapicCTI), were searched.

• The current landscape of decentralised clinical trials (DCTs) was comprehensively analysed, including the therapeutic areas and types of Internet of Healthcare Things used.

• The data sources were limited to the ClinicalTrials.gov, jRCT and JapicCTI databases.

• We excluded non-industry-sponsored studies and those without phase information.

• Despite using an exhaustive list of search terms, DCT-related studies not using these terms during registration may not have been identified.

Introduction

Decentralised clinical trials (DCTs) are characterised by reduced dependence on traditional research facilities and increased use of innovative technologies and approaches, such as digital health technology, including wearable devices and telemedicine, which allow patients to participate from anywhere in the world.^{1 2} The Group of Seven, an intergovernmental organisation comprising the world’s largest developed economies, has specified the need for an international clinical trial network to respond to future pandemics.³ DCTs can enable the international conduct of clinical trials, even in the event of another pandemic. We previously studied the development trends of the Internet of Medical Things (IoMTs)/Internet of Healthcare Things (IoHTs), which are expected to be used in DCTs, through a bibliographic citation network analysis and text mining. We identified the relevant regulatory considerations and the disease areas and technical fields in which DCT is expected to be widely used.⁴ Rogers et al quantitatively and qualitatively evaluated published data on DCT design and implementation, and de Jong et al reported on the implementation of decentralised activities in registered clinical trials.^{5 6} However, it is necessary to comprehensively assess the implementation status of existing DCTs to identify and address the challenges associated with their global conduct. Therefore, we analysed studies extracted from the ClinicalTrials.gov, Japan Registry of Clinical Trials (jRCT) and Japic Clinical Trials Information (JapicCTI) databases to elucidate the current implementation status of DCT components and IoHT trends in DCTs with a focus on the USA and Japan.^7–9 Furthermore, we attempted to identify the likelihood of the global popularisation of multiregional DCTs considering the trend of globalisation in pharmaceutical drug development.

Methods

Data extraction from the ClinicalTrials.gov database

Data were extracted through ClinicalTrials.gov on 4 June 2022, using the following keywords related to DCTs: ‘remote’, ‘site less’, ‘home-based’, ‘web-based’, ‘internet-based’, ‘virtual trial’, ‘location flexible’, ‘direct to patient’ or ‘decentralized’. ClinicalTrials.gov is the world’s largest clinical trial registration site and is operated by the US National Institute of Health and the US Food and Drug Administration through the National Library of Medicine. The search yielded 12 140 studies, which were extracted in a Microsoft CSV file format. The data collection flowchart is presented in figure 1A. To observe the trend of the implementation of DCT components specifically in pharmaceutical drug development, we focused on studies sponsored or supported by the industry, resulting in the exclusion of 10 149 studies that were not sponsored or funded. Sixty-eight duplicate studies were removed, and we retrieved 1923 studies aligned with the scope of this review. Of them, 543 involved the use of DCT components. To evaluate the relationship between the implementation of DCT components and the study phase, we excluded articles without information on the study phase. The total number of studies was defined as those published between 1 January 2001 and 4 June 2022, which were extracted using the advanced search feature. The extracted studies were independently reviewed by authors TS, SM and M.O to ensure they were related to DCTs and relevant trials were included in the analysis.

Figure 1.

Flowchart of the data collection process. (A) Data extraction from the ClinicalTrials.gov database. (B) Data extraction from the Japan Registry of Clinical Trials (jRCT) and Japic Clinical Trials Information (JapicCTI) databases. DCT, decentralised clinical trial.

Data extraction from Japanese clinical trial databases

JapicCTI was established by the Japan Pharmaceutical Information Center, with study registration starting in July 2005. jRCT was established by the Ministry of Health, Labor and Welfare based on the Clinical Trial Act (Law No. 16 of Heisei 29) that took effect in April 2018. Clinical trials conducted based on the Clinical Trial Act must be registered on the jRCT website. Clinical trial databases in Japan, including JapicCTI, were merged with jRCT as of 20 February 2023. Data published until 2 September 2002 were extracted from the JapicCTI and jRCT databases using the same keywords as those for the ClinicalTrials.gov database: ‘remote’, ‘site less’, ‘home-based’, ‘web-based’, ‘internet-based’, ‘virtual trial’, ‘location flexible’, ‘direct to patient’ or ‘decentralized’. These keywords were translated into Japanese for data extraction from Japanese databases. The data collection flow chart is illustrated in figure 1B. The studies were independently reviewed by authors SM and MO to ensure they were related to DCTs, and the relevant trials were included in the trend analysis.

Data characterisation for trend analysis

We characterised the studies extracted from ClinicalTrials.gov and Japanese clinical study databases according to the study descriptions. DCT was defined as a clinical trial that implemented the four components of DCT: telemedicine, home healthcare (HHC), direct-to-patient (DTP) and IoHT/IoMT (IoHT). Below is the definition of the component of DCT in our study.

1. Telemedicine: patients were evaluated based on video or phone interactions with healthcare practitioners.

2. HHC: healthcare and services, such as blood sample correction and medication administration, were provided by a nurse or healthcare provider at the patient’s home.

3. DTP: shipping of investigational medicinal products administrable in an at-home setting or other study-related materials to the participant.

4. IoHT: application of IoMT/IoHT.

In addition, IoHT was categorised based on the Institute of Electrical and Electronics Engineers’ (IEEE) classification.¹⁰ To focus on DCTs with study phase information for the analysis of study type and location, 76 studies from the ClinicalTrials.gov database were included after excluding 467 studies without study phase information.

Patient and public involvement

Neither patients nor the public were involved in the design, conduct, reporting, or dissemination plans of our research.

Results

Trends in the number of DCTs over the years

Figure 2A presents data on the start year and status of the 543 extracted studies and the total number of studies registered with ClinicalTrials.gov. Since the first study in 2001, the number of trials incorporating DCT components has increased steadily; in 2020, it increased drastically (1.7-fold year-on-year increase). The total number of clinical trials has also increased annually, but without a rapid increase in 2019 and 2020; the total number of studies in 2020 increased by 1.03 year-on-year, with the slowest increase from 2001 to 2021. Figure 2B illustrates the data on the start year and status of the 43 studies extracted from the Japanese clinical trial databases. The first DCT-related study was performed in 2013, with a gradual increase in the number of trials implementing DCT components since 2019; this number increased notably in 2020 and 2021 by 2.4 and 1.3 times, respectively, as compared with that in the previous year.

Figure 2.

Number of DCTs by start year from the ClinicalTrials.gov. and Japanese databases. (A) The number of clinical trials with DCT components by start year and study status. The status refers to the category outlined in the ClinicalTrials.gov database. *Data published until 4 June 2022 are included. (B) The number of clinical trials with DCT components by start year and study status. The status refers to the category outlined in the database. **Data published until 2 September 2022 are included. DCT, decentralised clinical trial.

Number of studies with DCT components by disease area

Table 1 shows the number of studies with DCT components by therapeutic area. The studies obtained from the ClinicalTrials.gov database (table 1A) indicated that the disease areas with the largest number of studies involving DCT components were diseases of the circulatory system (124 studies), followed by endocrine, nutritional and metabolic diseases (70 studies), diseases of the nervous system (61 studies) and mental and behavioural disorders (46 studies). The Japanese database (table 1B) yielded studies on mental and behavioural disorders (11 studies), followed by endocrine, nutritional and metabolic diseases (seven studies), diseases of the circulatory system (six studies), and diseases of the nervous system (three studies).

Table 1.

Studies with decentralised clinical trial components by therapeutic area

(A) Data from the ClinicalTrials.gov database
	Total study number	Telemedicine* (%)	HHC† (%)	DTP‡ (%)	IoHT§ (%)
Diseases of the circulatory system	124	35 (28)	3 (2)	0 (0)	117 (94)
Endocrine, nutritional and metabolic diseases	70	32 (46)	2 (3)	1 (1)	62 (89)
Diseases of the nervous system	61	22 (36)	1 (2)	0 (0)	50 (82)
Mental and behavioural disorders	46	15 (33)	2 (4)	1 (2)	36 (78)
Diseases of the respiratory system	36	22 (61)	3 (8)	1 (3)	27 (75)
Neoplasms	33	17 (52)	5 (15)	2 (6)	19 (58)
Diseases of the musculoskeletal system and connective tissue	31	16 (52)	2 (6)	1 (3)	21 (68)
Certain infectious and parasitic diseases	26	11 (42)	3 (12)	0 (0)	19 (73)
Factors influencing health status and contact with health services	24	9 (38)	1 (4)	0 (0)	21 (88)
Healthy individual	15	5 (33)	1 (7)	0 (0)	11 (73)
Diseases of the genitourinary system	12	7 (58)	0 (0)	1 (8)	8 (67)
Symptoms, signs and abnormal clinical and laboratory findings not elsewhere classified	12	5 (42)	0 (0)	1 (8)	10 (83)
Diseases of the digestive system	11	6 (55)	2 (18)	1 (9)	5 (45)
Others	7	1 (14)	2 (29)	0 (0)	5 (71)
Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism	6	1 (17)	0 (0)	0 (0)	6 (100)
Diseases of the eye and adnexa	6	0 (0)	0 (0)	0 (0)	6 (100)
Injury, poisoning and certain other consequences of external causes	6	4 (67)	0 (0)	0 (0)	4 (67)
Diseases of the skin and subcutaneous tissue	5	3 (60)	0 (0)	0 (0)	3 (60)
Pregnancy, childbirth and the puerperium	5	3 (60)	1 (20)	0 (0)	3 (60)
Diseases of the ear and mastoid process	3	3 (100)	0 (0)	0 (0)	2 (67)
Aged person	2	0 (0)	0 (0)	0 (0)	2 (100)
People with chronic diseases	2	2 (100)	0 (0)	0 (0)	1 (50)
Total	543	219 (40)	28 (5)	9 (2)	438 (81)

(B) Data from Japanese databases
	Total study number	Telemedicine* (%)	HHC† (%)	DTP‡ (%)	IoHT§ (%)
Mental and behavioural disorders	11	5 (45)	0 (0)	1 (9)	8 (72)
Endocrine, nutritional and metabolic diseases	7	0 (0)	1 (14)	0 (0)	6 (86)
Diseases of the circulatory system	6	1 (17)	0 (0)	0 (0)	6 (100)
Diseases of the nervous system	3	2 (67)	0 (0)	0 (0)	3 (100)
Others	2	0 (0)	0 (0)	0 (0)	2 (100)
Diseases of the respiratory system	2	1 (50)	0 (0)	0 (0)	2 (100)
Healthy individual	2	1 (50)	0 (0)	0 (0)	2 (100)
Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified	2	2 (100)	0 (0)	0 (0)	2 (100)
Neoplasms	2	0 (0)	0 (0)	0 (0)	2 (100)
Diseases of the musculoskeletal system and connective tissue	1	0 (0)	0 (0)	0 (0)	1 (100)
Factors influencing health status and contact with health services	1	0 (0)	0 (0)	0 (0)	1 (100)
Diseases of the genitourinary system	1	0 (0)	0 (0)	0 (0)	1 (100)
Diseases of the digestive system	1	0 (0)	0 (0)	0 (0)	1 (100)
Aged person	1	1 (100)	0 (0)	0 (0)	1 (100)
Certain infectious and parasitic diseases	1	0 (0)	0 (0)	0 (0)	1 (100)
Total	43	13 (30)	1 (2)	1 (2)	39 (91)

*Patients were evaluated based on video or phone interactions with healthcare practitioners.

†Healthcare and services, such as blood sample correction and medication administration, were provided by a nurse or healthcare provider at the patient’s home.

‡Shipping of investigational medicinal products administrable in an at-home setting or other study-related materials to the participant.

§Application of IoMT/IoHT.

DTP, direct-to-patient; HHC, home healthcare; IoHTs, Internet of Healthcare Things; IoMTs, Internet of Medical Things.

Data extracted from the ClinicalTrials.gov database (table 1A) show that IoHT was used in trials from all disease areas, with 438 (81%) of 543 studies using IoHTs, which is close to the overall average of 80% for studies in all disease areas. IoHTs were used most in trials for cardiovascular system disorders (117 studies, 94%) and all trials on diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism (six studies, 100%), diseases of the eye and adnexa (six studies, 100%) and elderly individuals (two studies, 100%), although a small number of studies were conducted. Telehealth was used in 219 (40%) studies. Regarding disease areas, IoHTs were used in clinical trials on diseases of the respiratory system (22 studies, 61%), neoplasms (17 studies, 52%) and musculoskeletal and connective tissue diseases (16 studies, 52%) at a high rate. In contrast, the implementation of HHC was limited to 28 (5%) studies and DTP to 9 (2%) studies. HHC and DTP components were most commonly used in the trials on neoplasms (five and two studies, respectively). Based on the results from the Japanese database (table 2B), IoHTs were used in 39 (91%) studies, telehealth in 13 (30%) studies and HHC and DTP in 1 (2%) study each.

Table 2.

IoHTs used in decentralised clinical trials in the therapeutic areas

Data from the ClinicalTrials.gov database
	Number of studies with IoHTs	Remote healthcare monitoring* (%)	Ambient-assisted living† (%)	Healthcare solutions with smartphones‡ (%)	Wearable devices§ (%)
Diseases of the circulatory system	117	89 (75)	15 (13)	12 (10)	34 (29)
Endocrine, nutritional and metabolic diseases	63	42 (67)	4 (6)	15 (24)	9 (14)
Diseases of the nervous system	50	14 (28)	21 (42)	10 (20)	26 (52)
Mental and behavioural disorders	36	3 (8)	10 (28)	21 (58)	8 (22)
Diseases of the respiratory system	27	13 (48)	4 (15)	7 (26)	13 (48)
Neoplasms	21	6 (29)	6 (29)	7 (33)	4 (19)
Diseases of the musculoskeletal system and connective tissue	21	2 (10)	14 (67)	5 (24)	6 (29)
Certain infectious and parasitic diseases	17	6 (35)	2 (12)	8 (47)	4 (24)
Factors influencing health status and contact with health services	21	13 (62)	4 (19)	4 (19)	0 (0)
Healthy individual	11	5 (45)	2 (18)	4 (36)	5 (45)
Diseases of the genitourinary system	8	3 (38)	3 (38)	2 (25)	1 (13)
Symptoms, signs and abnormal clinical and laboratory findings not elsewhere classified	10	4 (40)	3 (30)	3 (30)	0 (0)
Diseases of the digestive system	5	4 (80)	0 (0)	1 (20)	0 (0)
Others	5	4 (80)	0 (0)	1 (20)	2 (40)
Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism	6	5 (83)	0 (0)	1 (17)	0 (0)
Diseases of the eye and adnexa	6	3 (50)	1 (17)	2 (33)	0 (0)
Injury, poisoning and certain other consequences of external causes	4	0 (0)	4 (100)	0 (0)	2 (50)
Diseases of the skin and subcutaneous tissue	3	3 (100)	0 (0)	0 (0)	0 (0)
Pregnancy, childbirth and the puerperium	3	2 (67)	0 (0)	1 (33)	0 (0)
Diseases of the ear and mastoid process	2	0 (0)	1 (50)	1 (50)	0 (0)
Aged person	2	0 (0)	2 (100)	0 (0)	0 (0)
People with chronic diseases	1	1 (100)	0 (0)	0 (0)	0 (0)
Total	439	222 (51)	96 (22)	105 (24)	114 (26)

Data from Japanese databases
	Number of studies with IoHTs	Remote healthcare monitoring* (%)	Ambient-assisted living† (%)	Healthcare solutions with smartphones‡ (%)	Wearable devices§ (%)
Mental and behavioural disorders	8	0 (0)	3 (38)	3 (38)	3 (38)
Endocrine, nutritional and metabolic diseases	6	1 (17)	0 (0)	5 (83)	0 (0)
Diseases of the circulatory system	6	4 (67)	1 (17)	1 (17)	1 (17)
Diseases of the nervous system	3	0 (0)	1 (33)	1 (33)	2 (67)
Others	2	0 (0)	1 (33)	0 (0)	1 (67)
Diseases of the respiratory system	2	1 (50)	0 (0)	0 (0)	1 (50)
Healthy individual	2	0 (0)	2 (100)	0 (0)	1 (50)
Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified	2	0 (0)	0 (0)	2 (100)	0 (0)
Neoplasms	2	1 (50)	0 (0)	1 (50)	1 (50)
Diseases of the musculoskeletal system and connective tissue	1	0 (0)	1 (100)	0 (0)	0 (0)
Factors influencing health status and contact with health services	1	0 (0)	1 (100)	0 (0)	0 (0)
Diseases of the genitourinary system	1	0 (0)	0 (0)	1 (100)	0 (0)
Diseases of the digestive system	1	0 (0)	0 (0)	1 (100)	0 (0)
Aged person	1	0 (0)	1 (100)	0 (0)	0 (0)
Certain infectious and parasitic diseases	1	1 (100)	0 (0)	0 (0)	1 (100)
Total	39	8 (23)	11 (28)	15 (38)	11 (28)

*Remote healthcare monitoring can be performed using applications that acquire patients’ health data. Remote health monitoring technologies are normally adopted in in-home care and hospital environments to remotely monitor patients’ vital signs and indicate any abnormalities to patients, families and physicians in real-time, aiming to reduce clinical time, decrease hospital costs and improve quality of care.

†An Internet of Things-based service that supports the care of elderly or incapacitated patients. These solutions are aimed at extending the independence and safety of individuals at home through blood pressure and motion sensors.

‡Web-based applications or platforms that support diagnosis, clinical communication, drug prescription or medical education are healthcare solutions and require the use of smartphones.

§Wearables are smart devices that can be attached, for example, to the body, such as watches, shoes or body sensors. These devices connect to physiological transducers to display signs such as body temperature, heart rate and blood pressure.

IoHTs, Internet of Healthcare Things.

Types of IoHTs used in DCTs by disease area

Table 2 presents the IoHT types by disease area. Based on the IEEE classification, IoHT was categorised as remote healthcare monitoring, healthcare solutions with smartphones, ambient-assisted living and wearable devices. Studies from the ClinicalTrials.gov database (table 2A) indicate that remote healthcare monitoring was used in half the trials (222 studies, 51%), 96 (22%) studies, 105 (24%) studies and 114 (26%) studies, provided healthcare solutions with smartphones, ambient-assisted living and wearable devices, respectively. Regarding disease areas in which more than 50% of the trials used any IoHT type, remote healthcare monitoring was used in trials on diseases of the circulatory system (89 studies, 75%), endocrine, nutritional and metabolic diseases (42 studies, 67%), factors influencing health status and contact with health services (13 studies, 62%), diseases of the digestive system (four studies, 80%), other diseases (four studies, 80%), diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism (five studies, 83%), diseases of the eye and adnexa (three studies, 50%), diseases of the skin and subcutaneous tissue (three studies, 100%) and pregnancy, childbirth and the puerperium (two studies, 67%). Ambient-assisted living was used in trials on diseases of the musculoskeletal system and connective tissue (14 studies, 67%) and injury, poisoning and certain other consequences of external causes (four studies, 50%). Healthcare solutions with smartphones were implemented in trials on mental and behavioural disorders (21 studies, 58%) and diseases of the ear and mastoid process (two studies, 50%). Wearable devices were used in trials on mental and behavioural disorders (26 studies, 52%) and injury, poisoning and certain other consequences of external causes (four studies, 50%).

Among the studies retrieved from the Japanese database (table 2B), studies aimed at developing and validating healthcare solutions with smartphones, the so-called ‘digital therapeutics’, accounted for the highest proportion (15 studies, 38%) among those utilising IoHTs. In terms of disease areas, studies on endocrine, nutritional and metabolic diseases accounted for a high percentage of the trials using smartphones (five studies, 83%). Remote healthcare monitoring, ambient-assisted living and wearable devices accounted for 8 (23%), 11 (28%) and 11 (28%) studies, respectively. Remote healthcare monitoring was most frequently used in studies on circulatory system diseases (four studies, 67%), while ambient-assisted living and wearable devices were most frequently used in trials on mental and behavioural disorders (three studies, 38%).

Study type and location by study phase

The type and location of studies obtained from the ClinicalTrial.gov database are presented in table 3 by study phase. For all phases, single-country trials were the most common (n=61, 80.3%). Multiregional trials (n=7, 9.2%) were limited to late phases, such as phases II/III, III and IV. Most studies were conducted in the USA, regardless of the study phase. In Europe, single-country trials were conducted in Finland, France, Germany, the Netherlands, Sweden and the UK. In the Asia-Pacific region, DCTs from India, Japan, Korea, Taiwan and Australia were identified, with early development phase DCTs, such as phase I and II, conducted in Australia. The Japanese database search yielded one multiregional trial from among 43 studies. It was an international phase III trial (NCT04379050) on patients with Parkinson’s disease and was also identified through the ClinicalTrials.gov database search (data not shown).

Table 3.

Study type and location of decentralised clinical trials by study phase

		Phase I	Phase I/II	Phase II	Phase II/III	Phase III	Phase IV
		n=13 (17.1%)	n=2 (2.6%)	n=21 (27.6%)	n=3 (3.9%)	n=10 (13.2%)	n=27 (35.5%)
Study type	Single-country trial	12	2	18	2	6	21
	Single regional trial	1		3			4
	Multiregional trial				1	4	2
Study location*	North America			2			2
	Canada	1				(1)	3 (1)
	USA	7	2	15	2 (1)	3 (3)	13 (2)
	Europe	1		1			2
	Belarus					(1)
	Belgium					1 (2)
	Bulgaria					(1)
	Denmark					(1)	(1)
	Finland						1
	France					1 (2)	1
	Germany					1 (2)	1 (1)
	Israel						(1)
	Italy					(1)
	Netherlands					1 (2)
	Poland					(1)
	Rumania					(1)
	Russian Federation					(2)
	Spain				(1)	(1)
	Sweden	2		1		(1)
	Turkey					(1)
	Ukraine					(1)
	UK	1		1		(1)	1 (1)
	Asia-Pacific
	Australia	1		1		(2)	(1)
	India					(1)
	Korea, Republic					(1)	1
	Japan					(1)
	Taiwan					(1)

*The number in parentheses indicates the number of multiregional studies.

Discussion

Trends in the number of studies with DCT components

The number of clinical trials registered with the ClinicalTrials.gov database has increased each year, along with the number of trials with DCT components; however, we observed a decrease in the number of trials initiated in 2020 other than those related to COVID-19. The year 2020 had a year-on-year ratio of 1.03, the lowest year-on-year ratio since 2001.¹¹ In contrast, the number of clinical trials involving DCT components increased 1.7-fold in 2020, the year of the COVID-19 pandemic, compared with that in 2019. As shown in table 1, our search also yielded a few trials with COVID-19-eligible patients (included in certain infectious and parasitic diseases) and those evaluating home rehabilitation and home self-administration under behavioural restrictions associated with COVID-19. The Japanese clinical trials database also showed a 2.4-fold increase in clinical trials with DCT components initiated in 2020 as compared with those in 2019, despite the fewer studies. In 2019, the Clinical Trials Transformation Initiative recommendation paper was published, and Trial@Home was established, suggesting that with these initiatives and the subsequent COVID-19 pandemic, the popularisation of DCTs began in earnest after 2019–2020. Results from the Japanese and US databases suggest that IoHTs are widely used regardless of disease area and that the widespread use of IoHTs has contributed to the recently increased use of DCT.^{12 13} Conversely, the present results indicate that HHC and DTP have a relatively poor track record of use, and caution is warranted when considering the potential utility of these tools in DCTs. The low level of DTP application was contrary to expectations, as major regulatory authorities had allowed its use during the COVID-19 pandemic.^14–16 The reasons for this discrepancy could not be elucidated based on the study information within the selected databases. Furthermore, the application of HHC would be limited during an epidemic of infectious disease or when movement restriction is required.

Data characterizsation by disease area

A previous study reported on IoHTs that are expected to be used in DCTs through bibliographic citation network analysis and text mining.⁴ The results of using clinical trial databases as the source of information are consistent with those of the previous study. As shown in table 1, the largest number of trials with DCT components were related to diseases of the circulatory system (124 studies), followed by endocrine, nutritional and metabolic diseases (70 trials), diseases of the nervous system (61 studies) and mental and behavioural disorders (46 studies). Among these trials on circulatory system diseases, 94% used IoHT, often for remote monitoring through pacemakers. With the increased use of wearable devices, such as the Apple Watch, and the accumulation of evidence on symptom detection through wearable devices, this disease area is expected to remain highly compatible with DCTs in the future.¹⁷

Diabetes mellitus was central among endocrine, nutritional and metabolic diseases, and studies involving remote monitoring of blood glucose through monitoring devices were the most frequent (42 studies, 67%), as shown in table 2A. In addition, the number of trials using IoHTs, categorised as healthcare solutions with smartphones, was second only to that of trials involving telemonitoring (15 studies, 24%). For example, digital therapeutics and web-based platforms, such as BlueStar, the first digital therapeutic approved by the US FDA in 2010, which aims to achieve therapeutic effects through lifestyle interventions and an application aimed at ensuring timely intake of hypoglycaemic medication by patients, are categorised as these types of IoHTs.¹⁸ The Japanese clinical trial database results also yielded five trials involving smartphone applications in the endocrine, nutritional, and metabolic disease areas.

Following diseases of the circulatory system and endocrine, nutritional and metabolic diseases, nervous system diseases and mental and behavioural disorders were the second most common disease areas using DCT components. Remote patient monitoring through telemedicine has been reported in these disease areas.¹⁹ In this study, trials categorised as using telemedicine or IoHTs remote healthcare monitoring were identified in both USA and Japanese databases. However, the 22 (36%) studies on diseases of the nervous system and 15 (33%) on mental and behavioural disorders retrieved through the ClinicalTrials.gov database search did not indicate notably higher rates than those in other disease areas. However, this database indicated that the rate of studies using IoHTs categorised as healthcare solutions with smartphones was the most frequent (21 studies, 58%) for mental and behavioural disorders than for other disease areas. Several digital therapeutics in this area have been approved in the US,²⁰ and the continued conduct of DCTs in the areas of nervous system diseases and mental and behavioural disorders is anticipated.

Another disease area that has attracted attention as having high compatibility with DCTs is dermatology. Ali et al reported on the visual nature of dermatological conditions, the relative ease of virtually evaluating skin diseases and the fact that skin diseases are often not life-threatening and rarely require complex examinations.²¹ These factors can favour the use of DCTs in dermatological research. However, our search yielded only five studies from the ClinicalTrials.gov database and none from the Japanese database in the dermatology area. This may also be because all trials with DCT components could not be identified from the information available in the databases, which is a limitation of the present study. DCTs are also attracting attention in oncology, a recent mainstream area in drug development.²² In this study, 33 and 2 oncology-related trials from the ClinicalTrials.gov and Japanese databases, respectively, were identified. Interestingly, trials on neoplasms involved HHC and DTP, which are DCT components rarely used in other disease areas. In the oncology field, measures to reduce patient visits through blood collection (NCT0467676386) and drug administration by visiting nurses (NCT01473563, NCT04395508) and the application of DCT components are expected to reduce patient burden considering the disease severity.

Thus, the present database results indicate that trials with DCT components will continue to focus on cardiovascular, endocrine, psychiatric and central nervous system diseases. The Japanese database yielded no study results in the field of dermatology, which is otherwise considered compatible with DCTs; further, DCT elements in the field of oncology, such as HHC and DTP, commonly observed in the US database, were not found in the Japanese database. These findings indicate regional differences in the prevalence of DCT elements for specific diseases, which may be a rate-limiting factor for multiregional collaboration.

Trends by IoHT subtype

This study attempted to classify IoHTs into four groups based on the IEEE classification. Remote healthcare monitoring was the most commonly used IoHT in DCTs, and it aims to maintain and manage patient conditions through remote and real-time biometric monitoring by physicians and healthcare professionals using pacemakers, automated blood glucose metres and other wearable devices included in the other IoHT groups. IoHTs in the form of remote healthcare monitoring are used in a wide range of disease areas and are expected to continue to play a central role in IoHT in DCTs. Ambient-assisted living is an IoHT that enables the elderly and disabled to lead safe and healthy lives. In this study, its use was more frequently observed in trials on diseases of the musculoskeletal system and connective tissue (14 studies, 67%) and injury, poisoning, and other consequences of external causes (4 studies, 50%). This comprehensive study identified trials validating platforms that remotely support rehabilitation for treatment and recovery from trauma and musculoskeletal conditions. Providing healthcare solutions with smartphones is a digital therapeutic modality that uses the smartphone camera, microphone and speedometer to collect and analyse health data and support diagnosis, communication with the hospital and education regarding healthcare. According to the present results, this modality was mostly used in trials on mental and behavioural disorders (21 studies, 58%) retrieved from the ClinicalTrials.gov database and trials on endocrine, nutritional and metabolic diseases retrieved from the Japanese databases. In the USA, several aids, including the aforementioned BlueStar and digital therapeutics for mental disorders, have been approved, and CureApp for smoking cessation has been approved in Japan.²¹ A variety of other digital therapeutics are expected to follow suit. The development of these aids may require data collection and validation through DCTs, which can help simulate a home-based environment for use.

Of the four IoHTs categories, wearable devices, represented by smartwatches, are the most familiar to patients and are gaining wide popularity. However, the present results indicate that their utilisation in DCTs was biased towards specific disease areas. In the field of mental and behavioural disorders, where wearable devices were most frequently used (26 studies, 52%), the administration of virtual reality (VR) therapy with VR goggles was found in several studies (data not shown). VR therapy has already been approved in the USA, and it also has potential utility in managing chronic pain (symptoms, signs and abnormal clinical and laboratory findings not elsewhere classified) and sleep disorders (diseases of the nervous system).²³ Moreover, DCT is expected to be used during the development of VR therapy for these disorders. Four clinical trials using VR were identified in the Japanese database (data not shown). Further use of DCT in the development of digital therapeutics, such as smartphone applications and VR therapy, is anticipated.

Study locations and types of DCTs

The ClinicalTrials.gov and Japanese database searches showed that trials with DCT components were predominantly conducted in a single country, and international collaborative trials were limited to later study phases. This is contrary to the increasing prevalence of multiregional clinical trials in recent years.²⁴ Given the need to explore international clinical trial networks for efficient and harmonised diagnostics, therapeutics and vaccines under regular conditions instead of those in pandemics or as part of 100-day missions,³ immediate action is required for the implementation and dissemination of international collaborative DCTs. Guidelines for DCTs are being developed, particularly in Europe^25–27; however, the formulation of international consensus guidelines for DCT by the International Conference on Harmonization (ICH) is desirable considering that the introduction of ICH-E5 (R1) in 1998, the Q&A addendum to E5 in 2006 and the E5 and E17 guidelines in 2017 were the catalysts for the spread of multiregional trials in the past.^28–30 In fact, DCT has been discussed among the activities of ICH E6 (R3) in Annex 2. In the future, the inclusion of additional considerations for non-traditional interventional clinical trials and the revision of the existing guidelines are expected.³¹

Limitations and future research

We used the ClinicalTrials.gov, JapicCTI and jRCT databases in this study. However, other databases, such as the European Union Drug Regulating Authorities Clinical Trials Database and other clinical trial registration databases in Japan (JMACCT and UMINCTR), should also be considered to comprehensively understand the global landscape of DCTs. Furthermore, despite using an exhaustive list of search terms, we may have been unable to identify DCT-related studies that did include the search terms during registration. This may have resulted in an underestimation of the number of relevant studies as compared with that in a previous study using a different search strategy.⁶ Third, we included only studies sponsored or funded by industry, resulting in the exclusion of non-industry studies, which accounted for approximately 50%–70% of studies registered with ClinicalTrials.gov.^{32 33} Therefore, caution is warranted when generalising the present results. In the future, the landscape of non-industry-sponsored studies and trends in the post-COVID-19 era should be evaluated.

Conclusion

In summary, our findings indicate that the number of clinical trials with DCT components has increased every year, and in 2020 it was 1.7 times higher than that in the previous year (before the COVID-19 pandemic). The largest number of trials with DCT components were conducted in the fields of cardiovascular diseases, endocrine, nutritional, and metabolic diseases and neurological and psychiatric diseases. The use of DCT components HHC and DTP was lower than that of other DCT components. Further, the conduct of DCTs may have regional differences in some disease areas, which may prevent their worldwide implementation. In contrast to conventional clinical trials, DCTs were mainly conducted in a single country, and multiregional studies were limited. Multiregional DCTs and relevant international consensus guidelines are therefore necessary for the global conduct of DCTs.

Data availability statement

Data are available upon reasonable request.

Ethics statements

Patient consent for publication

Not applicable.