What did trial participants in REMAP-CAP Japan experience during the COVID-19 pandemic? A qualitative study

Abstract

Background

Informed consent is crucial for clinical trial participation. However, there have been no qualitative studies of participants’ experiences in randomized control trials of acute and critical care, particularly during the COVID-19 pandemic, when clinical trials were significant public health measures. This study aimed to explore the experiences of critically ill patients in Japan who participated in an international clinical trial for COVID-19 therapeutics.

Methods

A qualitative research method using conventional content analysis was employed. Data were collected through semi-structured interviews of participants in the anticoagulation domain of the Randomized, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP). All participants had been hospitalized in a Japanese ICU due to severe COVID-19, been deemed competent, and given prospective informed consent to participate.

Results

Ten trial participants were recruited, and data saturation was achieved. Three categories emerged: (1) trial participation without awareness or adequate understanding, (2) interpretation of trial participation experience with reference to personal circumstances, and (3) emotions and thoughts evoked by trial participation. Details of the trials or interventions were poorly understood. Some participants were unaware they had consented to participate. While some expressed interest in future trials, others remained uncertain about their trial participation.

Conclusions

Critically ill trial patients struggled to understand trial details during the informed consent process. Future research should optimize this process and ongoing patient support to balance autonomy and public health needs in health emergencies.

Trial registration

Not applicable.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12910-026-01411-9.

Background

Informed consent to participation in clinical trials is fundamental to health research. While various experiences of trial participants have been described [1], most reports focus on those who participated in clinical trials for non-communicable diseases, such as cancers, connective tissue diseases, and diabetes mellitus, or on healthy volunteers. Due to the nature of disease processes, participants in clinical trials for these conditions are given time to process information and make informed decisions. Healthy volunteers, on the other hand, may participate regardless of comorbidities and often have different motivations for trial participation.

Timely enrolment is crucial in acute and critical care research. Patients are more likely to participate in clinical trials when they feel an urgent need to receive care [2]. While critically ill patients often have limited decision-making capacity at the time of eligibility assessment in clinical research, a certain proportion of patients deemed capable of making decisions do choose to participate in clinical trials [3]. However, it is difficult for acutely ill patients with a potentially fatal disease state to make an appropriate decision on trial participation [4].

The COVID-19 pandemic significantly increased the need for health research, including clinical trials such as randomized control trials and platform trials, to inform healthcare professionals about optimal clinical care [5–7]. Clinical trials in Japan are conducted in accordance with the Ethical Guidelines for Medical and Biological Research Involving Human Subjects [8]. The guidelines state that, for clinical trials involving drug administration, informed consent must be prospectively obtained directly from trial participants or a legally authorized representative (LAR) at the time of enrollment; this principle applies even for approved medications and critically ill patients. Consequently, it can be difficult to enroll participants in acute and critical care clinical trials during health emergencies in Japan, even though such trials can contribute to patient care by rapidly developing or optimizing treatment strategies.

Under such circumstances, not only the informed consent process but also participants’ trial experiences should be elucidated to ensure they are sufficiently protected. However, little is known about the experiences and perceptions of patients who participated in clinical trials during the pandemic amid the unprecedented scale of global clinical trials. This study aimed to explore the experiences of critically ill patients in Japan who participated in an international clinical trial for COVID-19 therapeutics. Amid the ever-present threat of pandemics caused by emerging and re-emerging infectious diseases [9], this patient population can offer valuable insights on the challenges of trial participation, informing future pandemic preparedness and responses and shaping acute and critical care clinical trials.

Methods

Study design

A qualitative research method was employed to gain deeper understanding of the current situation and capture individual experiences. Patients who participated in clinical trials reported difficulty responding to quantitative questions about their trial participation, as well as concerns about not being able to fully describe their experiences, which were either incompletely expressed or misinterpreted [10]. Therefore, our goal is to understand participants’ experiences in trials, focusing on the meaning and details of those experiences. To achieve this, we employed a qualitative approach based on constructivist epistemology. The study design and reporting followed the Standards for Reporting Qualitative Research [11]. This study was approved by the Ethics Committee of Tohoku University Graduate School of Medicine (No. 2021-1-865).

Participants

Potential study participants were inpatients who prospectively provided written and verbal informed consent to trial investigators and their treating physicians, and voluntarily participated in the Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) at participating sites in Japan.

The REMAP-CAP has been conducted globally since 2016, in compliance with the International Conference on Harmonization Good Clinical Practices (GCP). It aims to identify the optimal management strategies for respiratory infections, including COVID-19. This study participants all participated in the REMAP-CAP anticoagulation domain in Japan: on admission to ICU, critically ill patients with SARS-CoV2 infection were randomly assigned to receive either therapeutic anticoagulation or pharmacologic thromboprophylaxis in an open-label manner [12, 13]. Written, prospective informed consent from the participant or an LAR was required in Japan. Critically ill patients were defined as those requiring organ support, including non-invasive or invasive ventilatory support, vasopressor, or inotrope infusions, according to the REMAP-CAP protocol [14]. Participants were followed up by trial investigators via telephone for up to 90 or 180 days after enrollment, following the trial protocol. Notably, this domain was conducted as a comparative effectiveness study, rather than a clinical trial of investigational new drugs or medicinal products.

Sampling strategy

Participants were selected from among individuals who were enrolled in REMAP-CAP at the time of hospitalization and had been discharged for less than one year. Interviews were not conducted immediately after discharge to allow participants time to recover from critical illness and return to their daily lives. Those for whom an LAR gave informed consent were excluded from the study. The following factors were considered during sampling: the medical institutions where trial enrollment occurred, the trial investigators who obtained informed consent, and disease severity. Recruitment began with a follow-up phone call from the trial investigators, who explained the study and obtained permission to send further instructions. These instructions were then provided via mail or e-mail. Participants were informed that participation was voluntary, refusal would not result in any disadvantages, and their personal information would be strictly protected. After the instructions were sent, one author (YO) followed up via phone or email to confirm their willingness to participate. Written informed consent was obtained before the interviews. All participants received 2,000 Japanese yen gift cards as compensation, equivalent to around USD 15 and approximately twice the minimum wage per hour in Tokyo when the interviews were conducted. Sampling ended when data saturation was reached, with no new codes being extracted [15].

Data collection and analysis

Data were collected through semi-structured interviews conducted by two authors: YO (a licensed nurse) and KJ (a licensed physician). YO is currently affiliated with the medical institution where the REMAP-CAP was conducted, but did not work there during REMAP-CAP enrollment. KJ has no affiliation with the institution where the REMAP-CAP was conducted. No participants had met either interviewer before the study. Each interview lasted 30–60 min and was conducted individually via an online meetings or phone call. Given the sensitive nature of the interviews, which elicited painful memories of participants’ hospital stay, we allowed breaks or interview cessation if discomfort arose.

After inquiring about participants’ past medical history prior to their index ICU admission and their experience in other clinical trials, we asked them to share their experience in the REMAP-CAP trial, focusing on the following questions: “How was the trial explained to you?”; “What thoughts did you have at the time?”; “Why did you decide to participate in the trial?”; “How did you feel about the trial?” YO transcribed the recorded audio data verbatim.

We employed conventional content analysis to analyze the data [16]. In the first step, we repeatedly reviewed the verbatim transcripts, listening to the audio data to gain a holistic understanding of the interviews. We then summarized the narrative based on semantic units and recorded our impressions and thoughts (“primary code”). We ensured that the audio data and verbatim transcripts were fully aligned. In the second step, we grouped the primary codes from the individual transcripts and formulated secondary codes (hereafter, “codes”) based on the research objectives. In the third step, we organized the codes into meaningful clusters and subcategories according to their relationships. In the fourth step, we categorized the subcategories based on their interrelationships. Finally, in the fifth step, we refined the definitions of the categories, subcategories, and codes. Interviews, coding, and categorization were conducted with Japanese participants. The transcripts, codes, and categories were then translated into English with the assistance of a native English- and Japanese-speaking colleague to preserve the original meanings and nuances.

To ensure rigorous analysis [17, 18], we limited the semantic units for each primary code to one sentence. YO and YH independently analyzed all verbatim transcripts, cross-checking the results at each step. After each interview, we verified that no guiding questions were posed to participants. At each stage, the analysis results were shared with HS and KJ, who were not involved in the independent analysis, for critical discussion to reach a consensus within the research team. All authors have extensive experience in qualitative research and/or clinical trials. We aimed to present each narrative as fully as possible. MAXQDA 2022 software (VERBI GmbH, Berlin, Germany) was used to make the coding process more manageable.

Results

A total of 19 individuals were initially invited to participate, and study interviews were conducted sequentially as each individual agreed to participate. As no new codes were identified when analyzing data from the tenth participant, recruitment was terminated after 10 interviews. All participants had been enrolled into in the REMAP-CAP between July 2021 and February 2022, while the study interviews were conducted between February and August 2022. Each participant was interviewed 7–10 months after trial participation and 6–9 months after hospital discharge. Table 1 provides an overview of the study participants, who had been inpatients at two hospitals in Japan. Informed consent for the REMAP-CAP was obtained from all participants in person by three REMAP-CAP investigators, who were also treating ICU physicians. All participants were Japanese, with eight males and two females. Regarding age, two were in their 40s, four in their 50s, two in their 60s, and one in his 70s. At the time of REMAP-CAP enrollment, all were critically ill, initially requiring a high-flow nasal cannula, and six later required invasive mechanical ventilation after trial consent was obtained.

Table 1.

Characteristics of the participants of this qualitative study

Participants	Sex	Age	Hospital admitted	Physician who provided informed consent
A	Male	40s	Hospital A	Physician X
B	Male	50s	Hospital A	Physician X
C	Female	50s	Hospital A	Physician X
D	Male	40s	Hospital A	Physician X
E	Male	60s	Hospital A	Physician X
F	Male	40s	Hospital A	Physician X
G	Male	60s	Hospital A	Physician X
H	Male	50s	Hospital B	Physician Y
I	Female	50s	Hospital B	Physician Y
J	Male	70s	Hospital B	Physician Z

Three categories ([ ]), seven subcategories (< > ), and 17 codes (“ ”) were identified from the analysis (Table 2). Despite being unable to fully understand the physicians’ explanation, participants agreed to participate in the trial. Although they were aware of signing the consent form after the explanation, none fully understood the trial details or the interventions involved. Some participants were unaware of their trial involvement until later. Some interpreted the trial experience in relation to their personal context, which helped them better understand what the trial entailed and convinced them that trial participation was appropriate, in turn influencing their willingness to participate in future trials. By contrast, others remained uncertain about their participation. The results for each category are presented below.

Table 2.

Extracted codes, subcategories, and categories of the data

[Categories]	< Subcategories>	“Codes”	Narratives
[Trial participation without awareness or adequate understanding]	<Unable to comprehend the trial detail>	“Vague even before the trial was explained”	I was able to ride an ambulance, at least. [After arranging a hospital the patient would be hospitalized, the paramedics was about to take the patient to the hospital] (I heard (the paramedics say) “thank you” (to the hospital over the phone). That’s the only thing I remember. I don’t remember anything after that. But I believe I received some explanation. I just don’t remember it. (B)
		“Too fatigued to process the explanation”	I do remember (being explained), but my brain wasn’t processing the information at all. I was conscious, but my symptoms were severe. (D)
	< Declining the trial participation was not considered>	“This is not the time to refuse the doctor’s suggestion”	I wondered if I would become part of some research experiment or research data. My top priority was to have my body recovered. (J)
		“This is how things should be”	(The doctor said) there is a drug that prevents blood clotting, which they wanted to use on me, and asked if it’s ok with me. I thought it was just part of the [treatment] process and didn’t think it was something different. It’s hard to describe, but I had no opinions about it at that time, and I was fine with anything as long as my fever went down. (H) The process of the doctor explaining something and asking for my signature seemed like a normal process to me. I wasn’t paying much attention. (M)
	< Ambiguous consent process>	“I agreed with the doctor’s explanation, so I signed the consent form”	I was able to understand them even without any knowledge related to medicine or healthcare, so I believe (the explainer) was using plain language. Yes, I remember (the explanations) were very clear and easy to understand. (F)
		“I think I might have signed it after being told about it”	I was like “now that you mention it…” Now that people have mentioned it, I kind of remember writing (my name). I do kind of remember signing a form to cooperate in a clinical trial. Something like that. But I don’t remember any of the contents. (I)
		“I’m not sure if I signed it myself”	My daughter visited the hospital once after receiving a call from the hospital. She said I received some kind of explanation at the time from the doctor and signed. I think that’s it. I believe that’s true. (J)
		“I was surprised to learn I had consented to participate”	I have no memory (that I received any explanation). I learned (that I participated in the REMAP-CAP trial) after that phone call (the phone call to participate in this interview/study). Since I was critically ill (when I received the follow-up phone call from the doctor), I thought they wanted to know how I was doing. (C)
[Interpretation of trial participation experience with reference to personal circumstances]	< Interpret the trial by themselves>	“Drawing analogies from clues”	Even after my (endotracheal) tube was taken out, intravenous antibiotics and antiviral administration continued for a long time, and I thought perhaps those things might have been related. (A)
		“Identifying similarities with their own work experience”	Based on my experiences working (as a system engineer), the background is important when testing something, so I thought the decision would be made comprehensively. Rather than (sticking with) a specific drug, I thought it was a more comprehensive decision, where the drug was chosen based on the particular circumstance I was under. (G)
	< Find positive meanings to their participation in the trial>	“I am pleased that my participation helped in some way”	If I was able to contribute in at least one way, I’m happy with it, and it’s enough for me. I do feel that I was able to contribute to society to some extent. (H)
		“I was able to recover because I participated in the trial”	(I’m not sure what drug was used on me, but) I believe things are going in the right direction, given that I have recovered this much. (B)
[Emotions and thoughts evoked by trial participation]	< Shaped attitude toward trial participation in the future >	“I wouldn’t mind participating again”	I don’t really feel that I want to actively participate (in clinical trials again in the future), but it doesn’t mean I terribly don’t want to either. (A)
		“Hesitancy toward trial participation”	What is a clinical trial like? Is it like being administered some kind of drug? I don’t like the idea of it. (K)
	< Unexplainable trial participation>	“Anxiety arising after regaining their composure”	My participation won’t necessarily change the care I receive, right? It is safe to assume that I will not be tested for some other (random) drug or something like that, right? Though, it’s true that I am worried that by doing that (i.e., by participating), I may be tested for some weird drug which is totally unnecessary. (D)
		“Unsure of the nature of their involvement”	I’m not sure even at this point whether I’m participating or not (in a trial). The only thing I am aware of is that I am answering a questionnaire (Note: the questionnaire is for another study). (K)

[Trial participation without awareness or adequate understanding]

This category covers participants’ experiences regarding giving written informed consent for the trial. At the beginning of the consent process, participants answered questions from the investigators, but they had no clear recollection of this questioning. Their memories were often “vague even before the trial was explained,” or they felt “too fatigued to process the explanation” due to general fatigue and physical discomfort. Consequently, participants experienced <being unable to comprehend the trial detail>. All participants shared this experience, though to varying degrees. Simultaneously, participants were aware of the severity of their disease and felt that agreeing to the trial was necessary for their recovery. As one participant explained, “This is not the time to refuse the doctor’s suggestion”; another believed, “This is how things should be.” Therefore, the option of <declining trial participation was not considered>. Despite these circumstances, participants signed the consent form. Some stated, “I agreed with the doctor’s explanation, so I signed the consent form,” or “I think I might have signed it after being told about it,” while others expressed uncertainty, saying, “I’m not sure if I signed it myself,” or “I was surprised to learn I had consented to participate.” This suggests an < ambiguous consent process>.

[Interpreting of trial participation experience with reference to personal circumstances]

This category describes participants’ attempts to interpret their trial experience independently after realizing that they had participated. Some recognized their consent to participate when the trial was explained, while others did so during their study interview. Participants reconfirmed the informed consent form and recalled their responses to questionnaires in other studies during the interview. As they did so, they attempted to < interpret the trial by themselves > by “drawing analogies from clues” and “identifying similarities with their own work experience.” Some participants did < find positive meanings of their participation in the trial>, stating, “I am pleased that my participation helped in some way” and “I was able to recover because I participated in the trial.”

[Emotions and thoughts evoked by trial participation]

This category encompasses the emotions and thoughts experienced by participants regarding their involvement in a clinical trial. The interviews revealed that participants’ experiences had < shaped attitude toward trial participation in the future>, some participants expressed positive thoughts such as “I wouldn’t mind participating again,” citing either no particular reasons not to participate or a desire to cooperate with the healthcare professionals who helped save their lives. Conversely, other participants expressed “hesitancy toward trial participation,” not wanting to put themselves at risk and preferring to carefully consider their engagement. Furthermore, some participants voiced “anxiety arising after regaining their composure,” being concerned that unnecessary medication might have been administered because they participated in the trial. They described perceiving that their < participation in the trial remains in the dark>, acknowledging that they were “unsure of the nature of their involvement” and had vague memories of their decision to participate.

Discussion

This qualitative study explored the experiences of participants in REMAP-CAP Japan during the COVID-19 pandemic. Conventional content analysis of individual interviews identified three categories: (1) [trial participation without awareness or adequate understanding]; (2) [interpretation of trial participation experience with reference to personal circumstances]; and (3) [emotions and thoughts evoked by trial participation].

All study participants had consented to the clinical trial without clear understanding of the information provided by trial investigators; some were even unaware that they had given consent. These findings are consistent with insights from quantitative assessments of ICU patients’ awareness of their participation in clinical trials [19]. Participants lacked this understanding despite the trial investigators, who were also the treating physicians, determining their competency to make informed decisions regarding the trial. It is possible that participants were competent at the time they consented but suffered memory impairment while critically ill. Another possibility is that participants found it difficult to distinguish the REMAP-CAP anticoagulation domain, conducted as a comparative effectiveness study with approved drugs, from their usual care, and thus struggled to recognize that they were participating in a clinical trial. Prior studies have reported that the concept of randomization is difficult for potential trial participants to grasp [20–24]; doing so could be especially challenging for critically ill patients and their LARs. Consistent with the prior finding that patients are more likely to participate in clinical trials when they feel an urgent need to receive care [2], participants in this study did not consider declining the trial.

The pressing nature of care and narrow intervention windows in acute and critical research may pressure patients to consent, undermining the validity of their decision. According to a qualitative study on trial participation among cancer patients, providing sufficient time and advance notice is crucial to ensuring a rigorous informed consent process [25]. Furthermore, in the UK, practical guidance on obtaining consent in ICUs recommends repeated explanations when patient understanding is assessed as inadequate on the first attempt [26]. It also recommends introducing the research topic only after a clinical team has explained to the patient their condition. However, trial resources are relatively limited in Japan, making it difficult to consistently provide research explanations during off-hours or in emergency situations [27]. Similar challenges have been reported in other countries, necessitating a global discussion on how to ensure the practical feasibility and ethical validity of health research even in resource-limited settings, particularly in the pandemic context [3, 28, 29].

Some study participants positively interpreted their participation in the trial in light of their personal circumstances, despite lacking complete understanding. First, participants perceived that participating “helped in some way.” A major reported reason for ICU patients being willing to participate in clinical trials or feeling satisfied after participation is the benefit to future patients [30]. This study participants also felt a sense of contribution, leading to a positive attitude toward participating in future clinical trials. Second, participants perceived that trial participation led to their own recovery. Motivation to participate in clinical trials is likely to be higher when patients believe the medical intervention being trialed will benefit their health [31]. Regardless of whether they understand the details of a clinical trial, participants may naturally attribute their recovery to having participated. However, no participants in this study had experienced any adverse events attributable to the trialed anticoagulation medications. Paradoxically, trial participants who experience clinical deterioration may attribute this to their participation, potentially fostering an unduly negative perception of clinical trials. Among the general public and individuals who have never participated in clinical trials, insufficient understanding and persistent mistrust regarding the purpose, uncertainty, and safety of clinical trials have been reported as a societal risk [31, 32]. To promote a realistic and balanced understanding of clinical trials, it is important to continuously provide structured information about these trial aims and nature prior to participation, and to pursue patient and public involvement and engagement [24, 33, 34].

This study has some limitations. First, no study participants experienced serious adverse events related to the trial intervention, and all recovered from COVID-19 with few long-term sequelae, enabling them to resume their social lives. Some REMAP-CAP trial participants did suffer adverse events but were not included in this study to avoid the potential psychological burden of being interviewed about their experiences. These individuals are likely to express feelings and thoughts about trial participation that differ from those of this study participants. Second, interviews were conducted at least 180 days after trial participation, which might have introduced recall bias. However, this study was grounded in a constructivist epistemology, meaning it focused on how experiences were currently interpreted and given meaning, rather than on accurate memories of the past [35, 36]. Furthermore, many participants retained copies of the consent forms they had signed at the time of trial participation, and they were asked to review the consent forms and accompanying trial information documents during the interviews. Additionally, interviews were conducted as early as possible after allowing an appropriate period to avoid disrupting the REMAP-CAP protocol or patients’ recovery. Third, the study did not observe or evaluate the actual informed consent process conducted by trial investigators. There may have been variations in verbal and written information, time spent on explanations, or the context of the consent process. However, only three trial investigators were involved, all experienced board-certified ICU physicians with prior clinical trial experience and GCP training, and communication was consistent across the two trial sites under the same medical school affiliation. Accordingly, these variations are unlikely to have influenced the study results.

Conclusions

This study identified three categories of patient experiences of participating in the comparative effectiveness study of COVID-19 therapeutics conducted by REMAP-CAP Japan, including inadequate understanding of the trial and mixed interpretation and thoughts on the trial participation. Further research is needed to identify optimal approaches to informed consent and ongoing support throughout the trial to ensure patient-centeredness and address societal/cultural needs during health emergencies.

Abbreviations

COVID-19

Coronavirus Disease 2019

GCP

Good Clinical Practices

ICU

Intensive Care Unit

LAR

Legally Authorized Representative

RCT

Randomized Control Trial

REMAP-CAP

Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia

Authors’ contributions

Y. O. and H. S. are the guarantor of the manuscript content, including the data and analysis. Y. O., H. S., Y. H., N. I., and K. J. contributed to the study design. Y. O., H. S., Y. H., N. I., and K. J. contributed to data interpretation and drafting of the manuscript. Y. O., Y. H., and K. J. analyzed the data.

Funding

This work was supported by PRESTO, the Japan Science and Technology Agency (JPMJPR23R7), and JSPS KAKENHI (22K10382).

Data availability

All data and materials are available from the corresponding author on reasonable requests.

Declarations

Ethics approval and consent to participate

This study adhered to the Declaration of Helsinki, and was approved by the Ethics Committee of Tohoku University Graduate School of Medicine (No. 2021-1-865). Written informed consent was obtained before the interviews of each study participants.

Consent for publication

Written informed consent for publication was obtained before the interviews of each study participants.

Competing interests

The authors declare no competing interests.