In terms of the clinical trial share, Korea ranks eighth globally and is in third place in a single country clinical trial basis.1 The number of approved clinical trials for medical product conducted in Korea increased from 143 cases in 2003 to 679 in 2018.2 The Ministry of Food and Drug Safety (MFDS) has reported an increasing trend of trials for severe and rare incurable diseases.2 Anti-cancer clinical trials account for 36.4% of all clinical trials, and have been the most common indication of clinical trial for 3 consecutive years.2 The conduct of clinical trials consists of a series of processes and multiple parties are involved in the overall trial process.3 Accordingly, face to face contact, meetings and travel to designated places are required (Fig. 1).

Coronavirus disease 2019 (COVID-19) has spread globally since the first outbreak in December 2019 from Wuhan in Hubei Province, China.4 The first case in Korea was confirmed on January 20, 2020, in an individual who entered Korea from Wuhan.4 Compared to previous respiratory syndrome, Middle East respiratory syndrome (MERS) epidemic that occurred in 2012-2015, COVID-19 had greater community spread.5 The first case not linked with epidemiologic evidence, identified on February 16, 2020, accelerated increase in the number of confirmed cases due to community transmission.4 The Korea Centers for Disease Control and Prevention (KCDC) raised the disease alert to the highest level on February 23, 2020 to heighten the response (Fig. 2).4 As there was no available treatment approved for COVID-19 in Korea yet, the government emphasized prevention, to avoid the spread of infection. This strategy influenced not only personal lifestyles but also the conduct of clinical trials of medical products.

There were no exceptions made to compliance with KCDC guideline when conducting clinical trials, because of the concern about infection during the operation of trial. The guideline called on all citizens to maintain social distancing, refrain from visiting crowded places and reduce gatherings as well as outdoor activities.6 Conducting clinical trials results in an increased number of subject visits to hospitals, face to face contact and meetings. There was thus a conflict between being compliant with the KCDC guideline firmly and clinical trials activities, including encouraging subjects' continuous participation. New approaches were necessary in clinical trials to eliminate the risk of infection by complying with the guideline and enable subjects to continue to participate in trials if no better alternative treatment options were available, for protecting the subjects' safety and well-being.

The impact of the COVID-19 pandemic has not been addressed on clinical trials in Korea. The study evaluated the impact of the COVID-19 epidemic and the KCDC disease control guideline on the conduct of clinical research in Korea, on subjects, investigators, monitor, pharmaceutical companies, Institutional Review Boards (IRBs) and regulatory authorities (RAs), in order to suggest recommendations for conducting clinical trials during the pandemic.

To measure the impact of COVID-19, the study selected individual indicators for each involved party in clinical trials. To evaluate the impact on subjects' study visits and study major milestones, a questionnaire was administered. The survey was distributed to total 140 clinical project manager (CPMs) who were working at global clinical research organization and responsible for trials performed in Korea, according to method of simple random sampling from February 24, 2020 to March 7, 2020. The questionnaire included questions on whether COVID-19 had an effect on trial subjects' scheduled study visits and whether there was any major milestone influenced or expected to be delayed by COVID-19. The milestones could be described by the CPMs and in the process of data analysis, they were classified as site initiation, close out, first patients in/last patient in/last patient out, data cleaning and database lock. If a CPM reported that there was an impact on the milestone however did not provide details, they were contacted to try to obtain further information. If response was not received, the impact was classified as not specified.

The impact of the policy by trial sites on monitor's access to monitoring room and site initiation was investigated by contacting clinical trial center in 39 hospitals. Majority of hospitals (95%) were selected in Seoul and Gyeonggi-do where clinical trials were actively performed in Korea and Gyeongsangbuk-do and Daegu where high infection rate was shown. They were contacted for the week of February 24, 2020 to March 1, 2020, when the confirmed cases increased dramatically and the week of April 23 to 29, 2020, when the daily confirmed cases decreased less than 10 in Korea. The response on the access of monitor was classified as total closure, partially available and available, depending on the degree of access that monitors were permitted.

The official press statement of the top 25 pharmaceutical companies on the conduct of their clinical trials during COVID-19 pandemic were reviewed in April 2020 and their decision were classified.7 Clinical trials for COVID-19 listed in local and worldwide public clinical trial registry databases, provided by MFDS and the United States (US) National Institutes of Health were analyzed, during the week of June 22 to 28, 2020, according to the used investigational products, study status, phase and initiating parties, using the pivot table function.89 For investigational products-based analysis, drug intervention studies for COVID-19 from both database were included. The used drugs in each arm of individual trial were classified and if 2 or more products were being administered in the same arm as a combination, each product was counted separately.

The COVID-19 pandemic is having a global impact. Clinical trials are one of the areas that have been affected. Clinical trials are meaningful in that they provide patients with novel treatment options during the process, and if they lead to marketing of new treatments, they may be of benefit to many future patients. Moreover, considering that clinical trials are required for developing COVID-19 treatments, conditions should be established in which necessary clinical trials can be carried out smoothly even during the pandemic, while protecting all trial participants' safety. In Korea, all parties involved in the conduct of trials have been affected by COVID-19 pandemic. Various guidelines for conducting trials during the COVID-19 pandemic have been released both locally and globally for supporting the operation of trials. Guidelines developed by foreign countries should be considered and adopted in accordance with the situation in Korea if they are judged to be appropriate.

Twelve percent CPMs responded that subject study visits were not performed as planned according to the protocol. Although the proportion of trials not affected (55%) was higher, given that the provision of treatment is contingent on assuring the safety of subject, 12% is a sizeable proportion that cannot be overlooked. If the treatment that subjects receive through clinical trial participation cannot be replaced by the standard of care, action should be taken to maintain the treatment while complying with the KCDC guideline. Under the current Article 50 (1) of the Pharmaceutical Affairs Act, the sale of medicines outside pharmacies is prohibited in Korea, which makes it impossible to deliver medicines by courier.19 However, MFDS released a guideline that allows investigational products to be delivered to subjects directly on a temporary basis, to enable them to receive the products while reducing the risk of SARS-CoV-2 infection that they could face on their way to hospital.12 The guideline stipulates that the products be stored according to protocol requirements during the delivery process by a certified carrier.12

The US FDA guidance advises investigators to confirm that subjects voluntarily consent to receive investigational products via courier. The Italy RA, decrees of the Italian President of the Council of Ministers allow healthcare providers to provide an increased amount of investigational product, to cover an extended period of treatment if it is beneficial and safe for the subjects. For the products that are administered in a health care setting, the US FDA permits utilize home nursing services or healthcare professionals to serve as alternative sites, in order to keep access to medical products from being cut off even if the products needs to be administered by professionals with specialized skills.17 The guidance of the European Medicines Agency (EMA) states that it is acceptable for laboratory, imaging or other diagnostic tests to be conducted at a local laboratory or relevant clinical facility certified to perform such tests routinely.18 For the introduction of these foreign guidelines in Korea, policies on the supply and demand of necessary personnel or the designation criteria of alternative institutions must first be in place.

Comparing monitoring room availability for source data verification in February and April 2020, it is evident that it is affected by the number of COVID-19 confirmed cases per day. Given the possibility of worsening of the pandemic situation, monitoring rooms may be forced to close again and considering the limited seats available and the high demand on monitor to verify cumulative clinical trial data, measures should be introduced to verify clinical data efficiently with fewer site visits or the methods of obtaining clinical data that require less verification should be considered.

Risk-based monitoring can be recommended. It enables earlier detection of issues through focused centralized and remote monitoring activities, and targeted on-site visit only for key risk indicators. This can reduce the total number of on-site monitoring visits required. Association of clinical research organizations has suggested that even after routine monitoring is resumed, it is not necessary to perform 100% source data verification if remote monitoring was closely performed during the closure of monitoring room.20 Regulations in Italy have allowed remote source data verification exceptionally, limited to COVID-19 pandemic once these methods are described in a specific guideline by the sponsor and clinical research organization and approved by the Personal Data Protection Officer of the trial site.21 Once the research is equipped with a mechanism for collecting data remotely and directly from the patient or vendor, by using methods such as electronic questionnaires, centralized laboratories or electronic image data, remote verification can supplement on-site monitoring.

The increasing number of investigator-initiated trials and trials conducted under the auspices of US Federal Reserve and the US National Institutes of Health indicates that all parties are making concerted efforts to develop COVID-19 treatments and vaccines.9 Considering that the number of clinical trials of COVID-19 related products is rapidly increasing and that most patients are being recruited, measures are needed to ensure an ongoing supply of clinical trial drugs. It is necessary to diversify supply and demand channels for raw materials and to establish regular import and export channels between countries.

Given that the studies target patients with SARS-CoV-2 infection, relevant regulations should be implemented and facilities should be supported to use non-contact methods in order to protect investigators and trial staff. As one of non-contact approaches, telephone consent process is allowed for patients during isolation.12 Guidance on the management of clinical trials during the COVID-19 pandemic by EMA advises the presence of an impartial witness, if written consent by the trial participant is not possible.18 To enable trial facilities to maintain the non-contact between investigators and trial subjects, they should be well equipped for COVID-19 trials with capabilities such as electronic informed consent or device to electronically scan and save the signed informed consent without bringing the form out of the subjects' ward .

This study has some limitations. Although a single indicator was used to identify the impact of the COVID-19 pandemic on each party, the effects of more diverse areas needs to be assessed using a greater diversity of indicators. The analysis of COVID-19 related trials was based on a search of ClinicalTrials.gov, so the trials not registered in this database were not included in the analysis. We only consider the guidance from RAs in the US, Korea, European Union and the United Kingdom, so referring to the guidance of other RA could help to suggest more various measures.

All RA guidelines put patient safety first, and MFDS is making continuous efforts to conduct clinical trials that are beneficial to participants. Health authorities and policymaker should refer to various guidelines and consider alternative measures to conduct trials during this pandemic situation, taking the scope of the application into consideration while prioritizing subject safety, so that the most appropriate method can be implemented and adopted in Korea, in a timely manner. At this time, the impact of the COVID-19 pandemic on clinical trials in Korea has not been as marked as in some other countries. However, restrictions on subject study visits to hospital can directly impact on subject safety and monitor's restricted access to site caused a delayed safety review for subjects. Therefore all the lessons learned and policies implemented internally and externally should be evaluated, in order to be prepared for persistence of the COVID-19 pandemic or future pandemics. Development of the required regulations, strategies, facilities, and platform could help Korea not only adapt to the rapidly changed environments and protection of trial participants, but also emerge as a contributing country in the field of trials. In order to increase in the number of clinical trials for treatment of serious diseases, consideration should be given to developing regulations that will enable patients who have difficulty with visiting hospital physically even after pandemic is controlled, so that varying methods can be applied to patients with different clinical conditions.