(ISSUE REPORT) Trends and implications of decentralized clinical trial regulations

DCT Definition

The U.S. Food and Drug Administration (FDA) defines DCT as a type of clinical trial in which some or all of the clinical trial procedures are conducted outside of the traditional clinical trial sites.

The expression ‘part or all’ does not mean that all of the DCT procedures are performed outside the clinical trial institution, but rather that a hybrid form of clinical trial is possible.

The FDA definition emphasizes procedures performed outside of clinical trial sites, and does not directly include characteristics of DCT such as digital, mobile, or remote.

However, as clinical trials include spaces other than existing clinical trial institutions, such as homes, workplaces, and local medical institutions, digital technologies are being widely used as tools to ensure data reliability and safety, so these are being focused on in the detailed element technology.

FDA’s DCT guidance is notable in that it specifically outlines the roles and responsibilities of personnel outside of clinical trial sites, thereby directly addressing regulatory issues related to Good Clinical Practice (GCP) that may arise in DCT.

The European Medicines Agency (EMA) published guidance in late 2022 using the term decentralised elements in clinical trials rather than using the term DCT directly.

EMA’s guidance is an outcome of Accelerating Clinical Trials in the EU (ACT EU), a joint initiative of the European Commission (EC), the European Medicines Agency (HMA) and the European Medicines Agency (EMA) that aims to advance the regulation of clinical trials.

EMA emphasizes that scientific validity, data integrity, benefit-risk, and patient rights protection should not be compromised by the introduction of dispersive elements, and that the risk-proportionate approach emphasized in ICH E8 should be followed to this end.

In particular, it specifically describes the precautions to be taken when directly delivering clinical trial materials, including pharmaceuticals, to clinical trial subjects from the perspectives of delivery, storage, and administration, and compares various pharmaceutical delivery regulatory cases in countries under EU jurisdiction.

Key DCT element technology

Electronic consent refers to obtaining consent required for clinical trials using electronic devices, and DCT is considering the use of remote electronic consent.

Electronic consent is also widely used in general medical settings, such as for consent forms for surgery, and guidance on electronic consent for clinical trials has been published by the FDA, EMA, and Korea.

However, remote electronic consent has not been introduced in Korea due to issues such as lack of understanding and experience of clinical trial subjects and regulatory issues. In foreign countries, most countries in the US and Europe allow remote electronic consent, but some countries require face-to-face confirmation.

In DCT, local healthcare facility and local laboratory refer to medical institutions or laboratories near the clinical trial subjects that perform general clinical trial procedures.

There are advantages in reducing the burden of patient movement and enabling efficient use of medical institutions. However, it has been pointed out that additional management burden may arise in order to secure and supervise the reliability of procedures performed at local medical institutions or local testing labs.

Electronic patient-reported outcome (ePRO) and wearable devices are widely used in DCTs because they can collect data outside of clinical trial sites without intervention by medical staff.

Patient-reported outcome (PRO) is the result of a patient’s self-report of his or her health status and treatment without intervention or interpretation by medical staff or a third party. This element technology has been widely used in existing clinical trials other than DCT, and its use is expected to become more widespread in DCT.

A home visit is an act in which medical staff visit a patient’s home in person to measure vital signs, collect blood, conduct tests, collect specimens, administer medication, etc. Home visits can enable patients who have difficulty moving around or live far from the clinical trial institution to participate in clinical trials, thereby implementing patient-centered clinical trials.

Televisit and direct-to-patient shipping are procedures for remotely checking the status of clinical trial subjects and delivering medicines or supplies needed for clinical trials. Televisit and direct-to-patient shipping are important elements that enable advanced DCT design, but they are also intertwined with discussions on the overall medical system, and are element technologies that are actively discussed in Korea and around the world.

Many regulatory issues that arise in DCT arise from the fact that medical practices and research practices coexist in clinical trials. Basically, clinical trials are defined as research practices to confirm the safety and efficacy of pharmaceuticals, but when conducting actual clinical trials, there are many elements that can be considered medical practices, such as medical treatment (in case of adverse events) and comparison with standard medical practices, which are giving rise to regulatory issues.

The Supreme Court’s decision 2007da3162 (October 14, 2010), which legally referred to the distinction between clinical trials and medical practices for patients, ruled that clinical trials “mean something whose safety and efficacy have not been sufficiently verified by knowledge and experience up to the time of the study.” However, there is an academic opinion that clinical trials and medical practices should be distinguished based on the subjective purpose of implementation.

In this way, clinical trials have elements that are difficult to clearly distinguish between medical practices and research practices, and as a result, discussions on medical practices in general, which are issues in medical law and pharmaceutical law, are mixed with discussions on DCT element technologies, requiring in-depth discussions and distinctions on terms and concepts.

As a typical example, in the case of ‘home visit’, one of the DCT element technologies, it is not clearly distinguished from ‘home nursing’, which is a medical practice stipulated in the Medical Act. Therefore, in order to achieve the level of home visit required by DCT, strict requirements for home nursing medical practice are applied, which has caused problems in practical introduction, making it difficult.

In addition, since clinical trials of current pharmaceuticals are to be conducted at clinical trial institutions designated under the Pharmaceutical Affairs Act, there is a possibility of regulatory conflict with clinical trial procedures outside of clinical trial institutions introduced by DCT.

However, the clinical trial institution designation system has significantly contributed to the qualitative improvement of the domestic clinical trial infrastructure, and many regulations and guidelines have been established based on the clinical trial institution designation system. Therefore, comprehensive discussions on the designation of clinical trial institutions should also be conducted along with the introduction of DCT.

In addition, the provisions on performing medical procedures in medical institutions under the Medical Act (Article 33 of the Medical Act) and the provisions on selling pharmaceuticals (Article 50 of the Pharmaceutical Affairs Act) are related to the elemental technologies of DCT, so discussions at a comprehensive institutional level are necessary.

The major regulatory issues currently under discussion are listed below by DCT element: <표 1>As summarized, additional considerations may arise depending on the actual implementation method.

<표1 DCT 요소기술별 주요 규제적 쟁점사항>

classification		Element technology	Key Regulatory Issues
data collection/agreement	1) Performed within a medical institution	Local medical institution	Regulations within the clinical trial institution(Pharmacy Act)
	2) Performed outside of medical institutions		Regulations within the clinical trial institution(Pharmacy Act)
	2-1) No medical staff required	WearableePRO	+ Whether medical treatment is performed within a medical institution(Medical law)
	2-2) Medical staff needed – Affiliation with clinical trial institution	Home visits by medical staff	+ Whether medical treatment is performed within a medical institution(Medical law) + Medical staff qualification requirements(Medical law)
	– WE ARE Affiliation with other implementing agencies		+ Whether or not it is a dispatch act(Dispatch method)
Direct delivery	1) Delivery outside medical institutions	Patient Direct Delivery	Performing all procedures for medicines in the pharmacy(Pharmacy Act)
Medical measures	1) Performed outside of medical institutions	Remote visit	Whether medical treatment is performed within a medical institution(Medical law) Regulations within the clinical trial institution(Pharmacy Act)

The US allows all the elements of DCT guidance, but there are differences in the specific requirements by state for direct patient delivery and remote visits. In Europe, the overall situation is similar to the US, but there are many countries that do not allow direct patient delivery, and there are differences in the methods allowed by each country.

In Korea, wearables and ePRO were introduced before DCT, and the regulatory basis for introducing local medical institutions and home visits in specific cases has been established recently. In the case of direct patient delivery and remote visits, discussions are underway from various perspectives due to the aforementioned regulatory issues.

Regulatory issues related to key elements of these technologies are examined in detail below. Patient direct delivery and remote visits are not included as they are still actively discussed.

Local medical institutions

Regional medical institutions are classified as medical institutions, but there are many cases where they are not clinical trial institutions (e.g., hospitals), so there are regulatory issues that may arise. What differentiates them from other element technologies is that since they are medical procedures within medical institutions, there is no problem with the spatial requirements for performing the medical procedure itself, and only whether they are clinical trial institutions is considered.

Accordingly, in the case of medical staff belonging to local medical institutions, although they are not considered sub-investigators under the current clinical trial management standards, there is a need for discussion on how to view them from a regulatory perspective in that they perform procedures related to clinical trials.

FDA has detailed the roles and responsibilities of community health care providers in its DCT guidance published in 2023. FDA requires that certain investigators be registered as investigators if they directly and significantly contribute to the clinical trial data, and should not be registered as investigators if the community health care provider performs clinical trial procedures as part of its routine practice.

Routine care means that there is no need for specific knowledge of the clinical trial plan, clinical trial drug, or clinical trial data booklet. However, the investigator is responsible for managing the task log for the medical staff of the local medical institution, and the task log is required to record ▲the name and affiliation of the medical staff ▲role and job ▲date the medical staff was registered ▲the location where the medical treatment is performed.

This is significant in that it minimizes the burden of education and training required to perform clinical trial work by separating medical staff participating in clinical trials through local medical institutions from the trial managers.

In Korea, the Ministry of Food and Drug Safety also established a basis for participation in clinical trials under the management and supervision of clinical trial institutions through the ‘Plan to Expand Participation in Clinical Trials by Regional Medical Institutions’ in April 2024, for ‘tests that do not require detailed knowledge of clinical trial drugs, clinical trial plans, or clinical trial data sets, and are performed in a general clinical setting as tests related to subject selection or monitoring.’

This is based on the case where participation in clinical trials by medical institutions other than clinical trial conducting institutions as described in Article 30, Paragraph 1, Subparagraph 2 of the ‘Rules on the Safety of Pharmaceuticals, etc.’ (Article 26 of the ‘Rules on the Safety of Pharmaceuticals, etc.’), and is significant in that it enables participation by regional medical institutions under the clinical trial conducting institution designation system.

In addition, it can be seen as a realistic plan that conforms to the international DCT regulatory harmonization trend by describing the level of obligations similar to the FDA’s DCT guidance regarding the management method of testers.

ePRO and wearable devices

Although ePRO and wearable devices are technologies that have been widely used in traditional clinical trials, they need to be discussed in the context of regulatory review of DCT as a whole.

The first thing to consider is whether the procedure in question constitutes a medical act. If it constitutes a medical act, it may need to be considered together with the regulations on performing medical acts within medical institutions (Article 33 of the Medical Act).

As a guideline related to this, the Ministry of Health and Welfare published the ‘Non-medical Healthcare Service Guidelines and Casebook’ in 2022, which specifically presents the concept and cases of ‘medical acts’ under the Medical Act and presents the concept of non-medical healthcare services that do not correspond to medical acts.

The guidelines state that simple confirmation of health checkup results and data collection based on individual consent (interpretation of checkup results, etc. is not allowed), and the measurement of health information, indicators, and values ​​using personal medical devices (electrocardiogram, blood pressure, blood sugar, etc.) are not medical acts and can therefore be provided by non-medical institutions.

Therefore, according to the definition of the guideline, it seems that ePRO and wearable devices used in DCT will not be considered medical procedures if they only perform the functions mentioned above.

However, since the above examples are limited to the act of confirming and checking health information, if it is accompanied by medical treatment at the level required by the clinical trial management standards, it can be viewed as a medical act, so there is a need to discuss this specifically from the DCT perspective.

Home visits by medical staff

Since home visits by medical staff are procedures outside of clinical trial institutions and are at the same time medical acts outside of medical institutions, they are subject to the Pharmaceutical Affairs Act and Medical Act-related regulations, and additionally, there are regulatory considerations regarding the qualifications of medical staff performing home visits.

Article 24 of the current Medical Act describes the scope and qualification requirements of home nursing, and stipulates that home nursing can only be performed by home nursing specialists who have home nursing specialist qualifications in accordance with the ‘Rules on Recognition of Qualifications of Professional Nurses, etc.’

Based on this, there are cases in which clinical trials conducted domestically have included home nursing-based medication and sample collection. However, home nursing professionals according to the ‘Regulations on Recognition of Qualifications of Professional Nurses’ generally have stricter qualification requirements than clinical trial workers (e.g., those who have completed a professional nurse training course of 2 years or more and have 3 years or more of professional nurse work experience), so there is a problem that it does not match the demand for personnel in the clinical trial field.

Therefore, it is thought that a detailed discussion is needed on whether home visits for clinical trials are considered home nursing acts under the Medical Act or should be viewed as separate acts, as well as the qualification requirements required for home visits for clinical trials.

In addition, if the medical staff performing the home visit is from an external organization other than the clinical trial institution, there is room to view it as dispatch under the Dispatch Act, so an interpretation of this is necessary.

The current dispatch law and enforcement decree stipulate that the work of medical personnel is not subject to dispatch, and there is an opinion that if medical staff belonging to a clinical trial support organization (site management organization, SMO) that is not affiliated with the clinical trial implementation institution performs a home visit, it can be viewed as an act of dispatch.

In fact, the Ministry of Employment and Labor’s administrative interpretation (Employment Discrimination Improvement Division-1331, May 31, 2017) states that clinical trial coordinators are not included in the dispatch target work stipulated in the Enforcement Decree of the Dispatch Act. Therefore, it seems necessary to review whether home visits by medical staff who are not affiliated with clinical trial implementation institutions constitute dispatch under the Dispatch Act.

Government

Domestic DCT-related regulations are intertwined with regulations on clinical trials and medical care in general, such as the Pharmaceutical Affairs Act and the Medical Act, and therefore require comprehensive and long-term discussions. In particular, they are related to the overall clinical trial system, such as the distinction between medical practices and research practices and the designation system for clinical trial institutions, and therefore require a multi-layered approach. The overall direction is similar to the changes in DCT-related regulations around the world (e.g., expanding the participation of regional medical institutions).

As regulatory changes related to DCT are taking place globally, it is necessary to pay attention to the establishment and revision of international guidelines and make efforts to comply with international standards.

As the ICH Good Clinical Practice E6 (R3), which is currently being revised, mentions DCT elements (e.g., remote electronic consent) and Annex 2 will cover DCT, efforts are needed to harmonize with the global clinical trial level.

In particular, considering the worldwide increase in clinical development strategies utilizing DCT, it is necessary to consider whether the introduction of DCT elements can affect the acquisition of safety and efficacy information in Korea, which is also related to the domestic introduction of cutting-edge new drugs.

Accordingly, our government is also establishing a foundation for domestic introduction of DCT by forming related business units and consultative bodies, drafting guidelines, and conducting R&D projects.

ARICTT (Advanced Regulatory Innovation for Clinical Trials Transformation) is a multi-stakeholder consultative body of the public, private, and academic sectors established in 2022 as a result of the Ministry of Food and Drug Safety-funded project, ‘Research on advanced regulations in response to changes in the post-COVID-19 clinical trial environment’, and is currently developing preemptive DCT guidelines.

The National Clinical Trial Support Foundation (KoNECT) was designated as the main organization of the Ministry of Health and Welfare’s ‘Smart Clinical Trial Technology Development Research Center’ in May 2023 to support the development of new clinical trial technologies. The center operates a public-private consultative body to promote DCT and is promoting a project to conduct clinical trials applying DCT element technologies.

Company

As the introduction of DCT elements is expected to become more widespread, it is possible to consider participating in government policy proposals and discussions on element technologies expected to be utilized, establishing internal policies, and creating guidelines or manuals accordingly.

Since various digital technologies are expected to be utilized in clinical trials, it is necessary to provide training to increase researchers’ understanding of clinical trial digital technologies.

Clinical trial trends are changing rapidly, and discussions are actively underway on clinical trials utilizing not only DCT but also real-world data (RWD) and AI, so it is necessary to keep an eye on changes in clinical trial technology from a long-term perspective and maintain an open attitude. (Article by Professor Kyung-Sang Yoo, Department of Clinical Pharmacology, Seoul National University College of Medicine)

※ The contents of this report were published with the author’s consent and may differ from the editorial direction of this publication.

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