The perspectives on the clinical trials in South Korea under ...

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The perspectives on the clinical trials in SouthKorea under the impact of the global COVID-19pandemic: the difference between trial site andsponsorsYoung-Sang Kim 

CHA Bundang Medical Center https://orcid.org/0000-0002-7397-5410Yil-Seob Lee  ( [email protected] )

CHA Bundang Medical Center

Research Article

Keywords: clinical trial, decentralized clinical trial, virtual trial, COVID-19, sponsor, site

Posted Date: May 13th, 2022

DOI: https://doi.org/10.21203/rs.3.rs-1461127/v1

License: This work is licensed under a Creative Commons Attribution 4.0 International License.  Read Full License

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Abstract

BackgroundDuring the COVID-19 pandemic, novel clinical trial methods known as decentralized clinical trials (DCTs)were rapidly introduced. The differences in operation of clinical trials including DCT perspectives duringthe pandemic between site and sponsors were investigated.

MethodsThe effect of the COVID-19 pandemic on clinical trials was investigated for a society of sponsors and atrial site in South Korea. The current di�culties and future perspectives on clinical trials were assessedand compared between the site and sponsors.

ResultsBoth the site and sponsors reported on their experiences with the challenges of conducting clinical trialsin the pandemic era. While 64% of personnel from the site judged that the di�culties were solved by theirown solution, 67.6% of personnel from sponsors considered cooperation with trial sites as a key solutionto overcome the di�culties. While half of the personnel from the site were skeptical of the changes in trialoperation methods, the sponsors expect the institutionalization of DCT elements.

ConclusionsWith varying attitudes, sponsors and sites attempted to overcome the challenges of conducting clinicaltrials during the pandemic era. To conduct clinical trials, both sponsors and sites must work closelytogether to �nd solutions with e�cient communication. For the successful implementation of new toolssuch as DCT, the government needs to solicit support from sponsors and sites and change regulations.

BackgroundIn 2020, the COVID-19 outbreak has compelled the governments of many countries to institute a full orpartial societal lockdown [1]. Korea also implemented various policies including social distancing andpartial lockdown [2]. The spread of COVID-19 gave rise to a burden in the healthcare system. The changesin the quarantine guidelines and people’s fear of infection minimized face-to-face contact, which resultedin the reduction in the use of healthcare units [3].

The COVID-19 pandemic also had an impact on clinical trials around the world [4]. Clinical trialparticipants tended to avoid face-to-face contact. The sponsors’ monitors had di�culty visiting the siteswhere clinical trials are taking place. Inspecting the sites was also di�cult in some ways. Changes in the

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clinical trial environment hastened the transition to new approaches to clinical trial operation [5]. Beforethis pandemic era, novel methods for clinical trials called decentralized clinical trials (DCTs), also termed“direct-to-participant trials” or “virtual trials,” were introduced [6]. DCTs are de�ned as studies “executedthrough telemedicine and mobile/local healthcare providers, using processes and technologies differingfrom the traditional clinical trial model [7]. Although the new approaches are interested in the era ofCOVID-19 pandemic, the new methods to the clinical trial in some countries seem to be di�cult to applydue to regulatory hurdles. In addition, the viewpoints of the new methods may be different between sitesand sponsors. Our study investigated the difference in the perspectives to the clinical trials under theimpact of the global COVID-19 pandemic between site and sponsors.

MethodsThe current study was conducted based on two surveys for Korea Society for Clinical Development(KSCD), a society of soponsor group, and a survey for a domestic trial site. The surveys were performedfor their own purposes. The ethics approval of this study was waived by the Institutional Review Board ofCHA Bundang Medical Center (2022-03-041). The original questionnares of the surveys and English-translated versions are provided in Supplementary Material.

Surveys of KSCD

In July 2020, KSCD surveyed the impact of the COVID-19 pandemic on clinical trials in South Korea. Atotal of 42 personnel from each member company voluntarily responded to the survey (Table 1). Thequestionnaire covers the di�culties caused by COVID-19, the solutions to the di�culties, and theprospects after the pandemic. Personnel from domestic and multinational pharmaceutical companies (N = 14 and 16, respectively) and domestic and multinational contract research organizations (CRO; N = 7and 5, respectively) responded. Half of the respondents (N = 22) were operation heads, managers, ordirectors. In 2021, KSCD surveyed post-COVID-19 DCT elements. A total of 36 businesses responded(Table 1). The survey included questions about the current state of DCT elements and their prospects.

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Table 1The general characteristics

Sites (N = 33)

Position

Professor 14 (42.4%)

Associate professor 13 (39.4%)

Assistant professor 4 (12.1%)

Clinical research coordinator 2 (6.1%)

Number of ongoing trials

20 or more 2 (6.1%)

10–20 1 (3.0%)

5–10 12 (36.4%)

1–5 15 (45.5%)

0 3 (9.1%)

The phase of clinical trials (N = 30; except for those without ongoing trial)

Phase 1 13 (43.3%)

Phase 2 16 (53.3%)

Phase 3 21 (70.0%)

Phase 4 10 (33.3%)

PMS 11 (36.7%)

Sponsors (year 2020; N = 42)

Characteristic

Domestic pharmaceutical company 14 (33.3%)

Multinational pharmaceutical company 16 (38.1%)

Domestic CRO 7 (16.7%)

Multinational CRO 5 (11.9%)

Position

Project manager 8 (19.0%)

CRA/PM line manager 6 (14.3%)

CRO, a contract research organization

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Sites (N = 33)

Operation unit head/manager/director 22 (52.4%)

General manager 6 (14.3%)

Sponsors (year 2021; N = 36)

Characteristic

Domestic pharmaceutical company 7 (19.4%)

Multinational pharmaceutical company 17 (47.2%)

Domestic CRO 5 (13.9%)

Multinational CRO 7 (19.4%)

CRO, a contract research organization

Survey of CHA Bundang Medical CenterIn August 2021, a survey on the impact of the COVID-19 pandemic on clinical trials was conducted atCHA Bundang Medical Center in South Korea. A total of 33 personnel participated in this survey (Table 1).This survey also consists of the questionnaires of di�culties due to COVID-19, the solution for thedi�culties, and the perspectives after the pandemic. Most responders were professors as investigators.

ResultsChallenges in conducting clinical trials due to COVID-19

In the pandemic era, personnel from both the site and sponsors face several challenges when conductingclinical trials (Table 2). Half of both sides’ respondents (43.3% from the site and 61.9% from thesponsors) thought that the clinical trials had been postponed, canceled, or discontinued. The site’s mostcommon response was that it was di�cult to enroll subjects (70.0%). Similarly, the most commonresponse from sponsors was a schedule delay due to enrollment di�culties (85.7%).

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Table 2Hurdles in conducting clinical trials due to COVID-19

Sites (N = 30)  

Postponement/canceler/discontinuation of trials 13 (43.3%)

Di�culties to enroll subjects 21 (70.0%)

Withdrawal of consents 1 (3.3%)

Di�culties to obey the protocol 11 (36.7%)

Di�culties to meet sponsor staff 16 (53.3%)

Sponsors (N = 42)  

Postponement/canceler/discontinuation of new trials 26 (61.9%)

Increment in budget for trials 11 (26.2%)

Di�culties to manage research manpower 19 (45.2%)

Di�culties in business management (e.g., rescission of contracts) 6 (14.3%)

Delay of schedule due to enrollment di�culty 36 (85.7%)

Di�culties to obey the protocol 23 (54.8%)

Low reliability on data quality 7 (16.7%)

Other responses 5 (11.9%)

None 2 (4.8%)

Overcoming di�culties in conducting clinical trialsTwenty-�ve from the site and 34 from sponsors responded with experiences of problem-solving (Table 3).Most of the personnel from the site (64%) judged that the di�culties were solved by their own solution.Although many personnel from sponsors (67.6%) considered cooperation of sites were helpful, theinvestigators who felt cooperation of sponsors were supportive were relatively infrequent (24%). Numbersof personnel from sponsors (61.8%) responded that companies provided revised guidelines to solve thedi�culties in conducting clinical trials.

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Table 3Experiences of problem-solving

Sites (N = 25, allowing duplicate responses) Sponsors (N = 34, allowing duplicate responses)

Mitigation of COVID-19 spread 7 (28.0%) Mitigation of COVID-19 spread 20(58.8%)

Cooperation of sponsors 6 (24.0%) Cooperation of sites 23(67.6%)

Support from site hospital 1 (4.0%) Provision of guidelines by thecompany

21(61.8%)

Investigator’s solution 16(64.0%)

Others 3 (8.8%)

Solutions to overcome di�culties Solutions to overcome di�culties

Phone contact instead of direct visit 10(47.6%)

Allowance of phone visit 19(45.2%)

Using e-consent 1 (4.8%) Introduction of e-consent 3 (7.1%)

Remote data collection 2 (9.5%) Telemetry/digital data collection 14(33.3%)

Use of local clinic 1 (4.8%) Direct-to-patient shipments of IP 15(35.7%)

Shipment of IP by parcel service 1 (4.8%) Central lab 5 (11.9%)

Visit by home health nurses 0 (0.0%) Home health nurse system 2 (4.8%)

Remote site contact without a directvisit

12(57.1%)

Remote site monitoring 26(61.9%)

Unsolved 1 (4.8%) Remote SDV/SDR 10(23.8%)

Wait until solved 1 (4.8%) None 6 (14.3%)

    Self-medication program 1 (2.4%)

IP, investigational product; SDV, source data veri�cation; SDR, source data review

 Sponsors tended to try to incorporate different types of DCT elements (Table 3). In contrast, siteinvestigators were far from DCT elements when attempting to solve the problems. The investigators’most common method of contact with the subjects (47.6%) was simply by phone.

The perspectives on the changes in the operation of clinical trials after the pandemic

The sponsors hoped that DCT elements are needed to be institutionalized soon. The sponsors lookforward to regulation changes accepting DCT tools (Table 4). In contrast, half of the personnel at the site

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never expected the changes in the methods of the clinical trial (45.5%, Table 4). While the personnel at thesite ranked direct contact with the aid of telemedicine tools including remote access, e-consents, andremote monitoring as new methods, methods to use home care nurses and another clinic instead of thereal sites were not favored. Furthermore, most of the personnel at the site were not aware ofterminologies indicating new trial methods such as DCT (Table 5).

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Table 4The site and sponsors’ perspectives on the changes in the operation of

clinical trials after the pandemicSurvey at the site

Changes in the operation of clinical trials after pandemic (N = 32)

No changes, return to the past 15 (45.5%)

New methods including telemedicine and intact trial 17 (51.5%)

No idea 1 (3.0%)

Kinds of elements in the changes (N = 20, allowing duplicate responses)

e-Consent 11 (55.0%)

Remote practice 14 (70.0%)

Direct-to-patient shipments of IP 9 (45.0%)

Remote assessment 12 (60.0%)

Visit by home health nurses 2 (10.0%)

Use of local clinic 5 (25.0%)

Remote site monitoring 12 (60.0%)

Survey for sponsors

Kinds of elements in the changes (N = 36, allowing duplicate responses)

Digital data collection tools 34 (94.4%)

Remote monitoring and sponsor visits to study sites 32 (88.9%)

Direct-to-patient shipping 30 (83.3%)

Electronic informed consent 29 (80.6%)

Electronic health records and electronic data capture 24 (66.7%)

Home health visits 23 (63.9%)

Telemedicine 20 (55.6%)

Local lab use 19 (52.8%)

IP, investigational product

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Table 5The investigators’ awareness of new

clinical trial methodsN = 25, allowing duplicate responses

Virtual clinical trial 7 (21.2%)

Decentralized clinical trial 5 (15.2%)

Remote clinical trial 9 (27.3%)

Direct-to-patient trial 1 (3.0%)

Unawareness 13 (39.4%)

No response 1 (3.0%)

DiscussionIn the pandemic era of COVID-19, both the site and sponsors have faced many challenges in conductingclinical trials. The most important tasks in resolving the issues are preventing the pandemic spread andcommunicating with sites and sponsors. While the site investigators favored indirect contact usingtelephone and email, the sponsors desired to introduce various tools of DCTs.

The investigators at the site strongly believed that the di�culties could be overcome by themselvesdespite the pandemic environment. In addition, half of the personnel at the site not only were unfamiliarwith the terminologies of novel methods on clinical trials but also had skeptical insights into them. Itadvocated for a cautious approach to the changes in clinical trial methods. With sposnors’ support, thesite investigators must take action against the changes [8]. Our study showed a gap between siteinvestigators and sponsors. Sponsors are more prepared to use DCT elements than site investigators. Assite investigators does not recognize the bene�ts of DCT in terms of patients perspectives, both partiesmust communicate more e�ciently with one another [9]. As the sponsors are required to train clinicalresearch associates (CRAs), CRAs need to play more roles to communicate with site personnel [10]. Eachsite needs to prepare a new standard operating procedure according to the government’s guidelines andto train the a�liated personnel.

As known well, the COVID-19 pandemic disrupted many clinical trials that were potentially bringing newtherapeutics to market [11]. As a result of this crisis, the US Food and Drug Administration, alongside itsinternational counterparts, has developed guidance to protect both research participants and trials byadvocating for remote data collection supplemented by telemedicine [12]. The regulatory authorities mustset the direction for resolving the issues by developing guidelines. According to global data 2021,digitalization of preclinical and clinical trials was viewed positively by 39% of healthcare andpharmaceutical professionals in North America, 39% in Europe, and 28% in the Asia-Paci�c region [13]. Inour study, clinical trial sponsors believed that DCT items, such as digitalization, were required forsuccessful clinical trials even after the pandemic era. However, some DCT items cannot be used in some

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countries including South Korea due to regulatory hurdles [14, 15]. Hence, regulatory authorities need to�nd hurdles with sponsors and sites and to solve those hurdles. In addition, trial sites also need tosupport remote monitoring performed by sponsors.

This study has several limitations. First, contrary to the sponsors, only one trial site was considered forthe survey. Although overestimation of our result is cautious, it is advisable to see a viewpoint of thepersonnel working at the site. Second, one of the surveys for the sponsors was conducted the previousyear; due to the interval between the surveys, the pandemic status, policy response, and social attitudemay be different from the two points. However, even in this advanced year, it is interesting to note thatmany site investigators remain unaware of new approaches to conducting clinical trials. Third, thesubjects who participated in clinical trials were not surveyed on. Changes in trial methods have a directimpact on the subjects. The changes must be geared toward the subjects’ bene�t and convenience.

ConclusionsDespite many common hurdles in conducting clinical trials during the pandemic era, sponsors and siteswere trying to overcome the hurdles with different attitudes. The COVID-19 pandemic has accelerated theimplementation of decentralized clinical trial solutions, and DCT will be used in clinical trials more andmore in the future, with bene�ts for sponsors and sites. Furthermore, decentralized solutions improve thepatient experience. Both sponsors and sites need to have close communication and �nd solutions whenthey face di�culties like COVID-19 in conducting clinical trials. In addition, sponsors and sites need toshare feasible solutions and coordinate to train the personnel involved in the clinical trial. Thegovernment needs to gather opinions from sponsors and sites and change regulations for the successfulimplementation of new tools like DCT.

List Of AbbreviationsCRA, clinical research associate

CRO, contract research organization

DCT, decentralized clinical trial

KSCD, Korea Society for Clinical Development

DeclarationsEthics approval and consent to participate

This study is based on the surveys performed for their own purposes. The participants answered to thequestionnaires of the surveys anonymously. In this reason, the need for consent to participate waswaived by the Institutional Review Board of CHA Bundang Medical Center (2022-03-041).

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Consent for publication

Both KSCD and CHA Bundang Medical Center agreed on the publication of the article.

Availability of data and materials

The datasets used and/or analysed during the current study available from the corresponding author onreasonable request.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or �nancialrelationships that could be construed as a potential con�ict of interest.

Funding

None

Authors' contributions

Substantial contributions to the conception or design of the work: YS Lee

interpretation of data for the work: YS Kim and YS Lee

Drafting the work or revising it critically for important intellectual content: YS Kim and YS Lee

Final approval of the version to be published: YS Lee

Agreement to be accountable for all aspects of the work in ensuring that questions related to theaccuracy or integrity of any part of the work are appropriately investigated and resolved: YS Lee

Acknowledgements

The authors thank to Korea Society for Clinical Development on conducting surveys and sharing theresults.

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