First experience of a fully decentralized clinical trial: The dawn of a new era in oncology

Herein, we report a fully remote clinical trial of an oral anticancer drug, which is the first of its kind in Japan. This framework is a breakthrough that allows patients to participate in clinical trials for investigational new drugs without having to visit distant trial sites.

Abbreviations

ACCH

Aichi Cancer Center Hospital

CGP

comprehensive genomic profiling

CT

computed tomography

DCT

decentralized clinical trial

D to P with D

doctor to patient with doctor

IND

investigational new drug

Dear Editor,

Herein, we report a fully remote clinical trial of an oral anticancer drug, which is the first of its kind in Japan. This framework is a breakthrough that allows patients to participate in clinical trials for investigational new drugs (INDs) without having to visit distant trial sites. It has potential benefits, including reduced time, financial and psychological burden of travel, lodging, time off work, and risk of coronavirus disease (COVID‐19) for patients and their families.

The COVID‐19 global pandemic has had a major impact on our lives and society, and clinical trials are no exception. Traditionally, in a clinical trial, patients must visit the trial site, undergo medical examinations, blood tests, and imaging tests, and receive medication according to the schedule in the study protocol. With the concept of patient centricity in drug development and the use of digital technology, clinical trial methods that do not rely on visits to clinical sites are attracting attention. This new clinical trial method is called decentralized clinical trial (DCT), which involves using telemedicine, mobile applications, wearable devices, eConsent, electronic patient‐reported outcome, delivery of investigational drugs to the home, and the use of alternative laboratories or imaging centers. ¹ Despite such innovations in other fields accelerating due to the COVID‐19 pandemic, the implementation of DCT in oncology remains rare because anticancer drugs generally require attention to adverse events and require blood tests and computed tomography (CT) scans to evaluate efficacy and safety. ²

After an ethical approval obtained by our institutional review board, we started an investigator‐initiated IND trial, named WJOG15221/ALLBREAK (jRCT2041210148), as the first fully remote cancer clinical trial in Aichi Cancer Center Hospital (ACCH) (Figure 1). This was an open‐label, phase 2 basket trial of the oral ALK inhibitor, brigatinib, in patients with ALK fusion‐positive tumors, an extremely rare subtype with a frequency of approximately 0.2%, except for non‐small cell lung cancer. ³ ALK fusions were identified in patients by performing a comprehensive genomic profiling (CGP) test nationwide, and physicians referred the patients to any of the 10 investigational sites listed in the CGP report. For patients with difficulty attending the sites, we considered remote patient enrollment conducted by ACCH. First, the clinical trial contract according to Article 39‐2 Outsourcing Duties of Ministerial Ordinance on Good Clinical Practice for Drugs was signed between the ACCH and a neighborhood hospital that the patient was currently attending. To become a partner, the hospital must meet several requirements including having experience in clinical trials, being able to conduct the examinations according to a defined schedule, and accepting an audit. The document described the delegation of blood, physiological, and imaging examinations in the protocol, while responsibilities for medical care of the patient are with the investigators in ACCH. Initial medical examination results and informed consent were remotely obtained by an ACCH doctor connected via a video conferencing system with the patient and the partner physician (doctor to patient with doctor style; D to P with D), and the obtained documents were delivered to the ACCH by mail and/or fax. If the eligibility criteria were met, brigatinib was delivered to the patient's home via specialized couriers from the ACCH. Regular blood tests and CT scans related to the clinical trial were performed at the neighborhood hospital, and the results were sequentially mailed to the ACCH. The results were used by the ACCH doctor to determine whether to continue treatment and assess its efficacy and safety.

FIGURE 1.

Schema of our decentralized clinical trial (DCT) framework in the WJOG15221M/ALLBREAK trial.

Prior to launching this initiative, revised documents of trial procedures and informed consent form were submitted to the ACCH Institutional Review Board. There was discussion about whether this scheme increases patient risk, but the approval was obtained without any problems because of the cooperation of the partner physician. Between May 2022 and December 2022, six patients were enrolled in the trial. Four (67%) were remote cases, who had difficulty in making regular visits to a nearby investigational site. These four patients would not have been enrolled without the remote framework, suggesting that the introduction of remote clinical trials is expected to promote enrollment. In addition, no major trial deviations have occurred to date through good cooperation between us and the partner physician. The patients can participate in clinical trials using promising agents and maintain their existing relationship with their primary physician to support receiving clinical trial treatment safely and with peace of mind. Therefore, we continued three‐way telemedicine (D to P with D) as much as possible even for routine online visits other than the initial examination.

Comprehensive genomic profiling tests were reimbursed by the National Health Insurance System in Japan in 2019. Although this major trend toward personalized cancer therapy is beneficial to patients, only approximately 4%–13% of patients receive genomically matched therapy. One reason for this low percentage is that access to early phase‐matched clinical trials is limited and is always performed in a very limited number of urban institutions. Moreover, the development of treatments for rare cancer subtypes identified by CGP is an area that pharmaceutical companies are not actively pursuing because of low profitability. Our DCT framework could overcome this issue by facilitating patient enrollment and reducing clinical trial costs by consolidating the trial sites and personnel.

While DCTs come with an array of benefits for patients and sponsors, they also come with a variety of challenges. If new wearable devices or computer applications are used in DCTs, it could be a burden to patients and partner physicians. Moreover, as for accidental protocol deviations, DCTs may have a higher risk of protocol deviations than traditional centralized trials. To safely expand our DCT framework, it may be necessary to initially work with experienced partner hospitals in limited trials using drugs with established safety profiles.

In addition, we believe that remote clinical trials utilizing satellite medical institutions will promote a new style of medical care (D to P with D) involving local communities, provide advanced medical care to rural areas, and serve as a model for equalization that improves the health and welfare of the entire nation, independent of the patient's place of residence. Ensuring universal access to healthcare opportunities is one of the international goals, including the Sustainable Development Goals, to achieve a better and more sustainable future for all. We look forward to the use of telemedicine, including DCT, following the Japanese government initiative.

CONFLICT OF INTEREST STATEMENT

Hiroya Taniguchi received lecture fees from Takeda, Ono, Eli Lilly, Merck Biopharma, and Chugai and research funds from Takeda, Daiichi Sankyo, and Ono. Toshiki Masuishi received lecture fees from Eli Lilly and research funds from Daiichi Sankyo, Amgen, and Syneos Health. Nobumasa Mizuno received research funds from MSD, Ono, Seagen, and Dainippon Sumitomo. Kei Muro received lecture fees from Eli Lilly, Daiichi Sankyo, Ono, Taiho, and Bristol‐Myers Squibb and research funds from Sanofi, Eisai, Astellas, Amgen, Daiichi Sankyo, Novartis, Taiho, MSD, Ono, and Chugai. Takatsugu Ogata and Masashi Ando have no conflicts of interest to declare.

ETHICS STATEMENTS

Approval of the research protocol by an Institutional Review Board: The trial was conducted in accordance with the Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board or Ethics Committee of Aichi Cancer Center Hospital.

Informed Consent: All patients provided written informed consent.

Registry and the Registration No. of the study/trial: jRCT2041210148.

Animal Studies: N/A.