Over the last decade, an important change in the approach to clinical trials has taken place, marking an incipient shift from traditional to decentralized trials. The first such initiative came in 2011, when Pfizer conducted a pilot decentralized study during an investigation of a new drug using smartphone- and web-based technology to collect patient data. In the last two years as the COVID-19 pandemic has limited on-site access, decentralized clinical trials (DCTs) have gained force, and it seems that this will be the main approach for future human clinical trials. Here, we will compare DCTs with traditional clinical trials (TCTs) and look at the factors that are driving the demand for DCTs, as well as considering the technical, logistical, and regulatory challenges faced by DCTs today.
What is a decentralized clinical trial?
DCTs, also known as “virtual” studies, can improve trials by guaranteeing interactions between physicians and patients as well as increasing the recruiting power of a diverse public and reducing withdrawal rates. There are many virtual technologies now available to enable DCTs. Depending on the type of study, investigators can choose from among telemedicine, wearable medical devices such as biometric sensors, other sensory-based technologies, home visits, and direct delivery of study drugs and materials to patients’ homes. Thus, clinical trials can be conducted either by investigators utilizing these virtual technologies or by trial participants themselves.
What are the main differences between TCTs and DCTs during each phase of a trial?
DCTs are smaller, fleeter, less costly, and more diverse than TCTs, principally due to their advantages in recruiting patients. Treatment and patient follow-up are also steps for which DCTs offer advantages. Below, we provide a side-by-side comparison between a traditional and decentralized clinical trial:
| Clinical study stage | Traditional | Decentralized |
|---|---|---|
| Patient recruiting | Doctors’ indications, social media advertising, and researcher center advertising | Digital advertising using ads or digital kiosks |
| Participant consent | In-person consent signature | Electronic consent signature (e-consent) |
| Screening | In-person physical exams | Electronic health record (e-screener) |
| Enrollment | In-person enrollment | Electronic enrollment |
| Treatment and follow-up | On-site treatment | Self-treatment or mobile healthcare providers |
| Retention | Scheduling in-person visits | Telemedicine |
| End of study | After the last in-person visit | Returning study equipment |
Patient recruiting:
- TCTs: After a patient enrolls, a study coordinator asks them—via a phone call or website interface—a series of questions about their medical conditions to verify if they meet the criteria of participation. Eligible patients are then directed to the research center to begin the consent process.
- DCTs: Once an individual sees the advertisement, they can self-register via a website using a computer or smartphone (pre-screening). After reading the detailed description of the study, they then respond to a medical conditions questionnaire, and within a few minutes, receive a notification regarding whether or not they match the inclusion criteria.
Participant consent:
- TCTs: The participants sign the consent during the clinic visit after reading all study descriptions and understanding all risks and benefits of the study as explained by the staff.
- DCTs: After pre-screening, the potential participants receive an email containing an electronic informed consent form (eConsent), which presents all study descriptions as well the risks and benefits they might face during the study. Any doubts they may have about the study can then be clarified by the staff on a phone call. Once the patients understand everything, they sign the electronic consent form and submit it.
Patient screening:
- TCTs: During the clinical visit, physicians examine the patients and verify all medical conditions that the patients must have to continue with the study.
- DCTs: After the submission of eConsent, the patients receive an online e-screener that contains electronic health records (EHR), outpatient data, and an electronic data capturing (EDC) system containing the medical information of the patient. All these parameters allow the provider to gain a broader view of the patient’s care.
Patient enrollment:
- TCTs: If participants complete all in-person stages, they are considered to be enrolled in the study.
- DCTs: Patients are enrolled via digital tools including a multifactor identification system.
Treatment and monitoring:
- TCTs: The treatment and monitoring of patients are carried out on-site by healthcare professionals.
- DCTs: Patients can take the medicine by themselves, following the provided instructions or, depending on the situation, mobile healthcare providers may be sent to their homes to administer the medications. For patient monitoring, the user-friendly Electronic Clinical Outcome Assessment (eCOA) and Electronic Patient-Reported Outcomes (ePRO) data can be used to record their vital signs and symptoms.
Patient retention:
- TCTs: The participants must schedule all their in-person visits and travel to the clinical center to continue their monitoring throughout the entire study.
- DCTs: The retention of patients is enhanced through virtual meetings or mobile healthcare providers.
End of the study:
- TCTs: The study is finished on the last visit of the patient after the investigators review all their results.
- DCTs: The patients return the study equipment back to the clinical site for the investigators to review all their results.
What is the current state of development of decentralized clinical trials?
At the time of publication, there are 69 decentralized clinical trials being conducted, ranging from observational to interventional studies. A few notable example include:
- In 2020, AOBiome LLC concluded a phase IIb/III, randomized, decentralized clinical trial (NCT02832063) evaluating the safety, tolerability, and efficacy of B244 compared to placebo in the treatment of acne vulgaris.
- In 2021, Sanofi Pasteur and Evidation Health finished a digital intervention (NCT04584645) in a decentralized randomized controlled trial where they observed an increase in influenza vaccination rates in Individuals with cardiovascular conditions.
- At the moment, Novartis is recruiting men and pre- and post-menopausal women with advanced breast cancer with a HR-positive/HER2-negative and with a PIK3CA mutation, for a phase II pilot decentralized clinical trial (NCT04862143) to test the drugs Alpelisib and Fulvestrant.
Moreover, there are more than 148 companies that provide digital health platforms to deliver solutions for companies to run a decentralized or hybrid clinical trial. For example, Halo Health Systems produces technological systems to coordinate trial sites, monitor patient safety, and assist active trials, while Right at Home focuses on providing home care services for older patients and individuals affected by poor mobility.
Anju Software is another company providing a platform for clinical trial management with a range of enhanced trial efficiency capabilities that includes the company’s technology for facilitating the reuse of edit checks for flagging inaccurate data across multiple clinical trials.
Future perspectives and challenges for decentralized clinical trials:
Increasing adherence to decentralized clinical trials is expected for the next few years. By the end of 2022, an increase of 28% is estimated, compared to 2021, and by the end of 2032, the market is expected to grow at a compound annual growth rate of almost 7%. This is because virtual interventions have numerous benefits over conventional trials, such as the reduction of recruitment timelines by 30–50% and a 90% increase in retention rates.
The success of a DCT will depend on the commitment of the investigators, because the challenges for introducing DCTs involve aspects that could influence the quality of clinical trials. As pharmaceutical companies must deliver validated results for approval by regulatory agencies, it is vital to ensure the technical quality of the electronic apps, making sure they are able to generate reproducible signals. In addition, investigators must receive technical support to ensure their capability to use different electronic platforms to monitor their patients. The patients themselves must also feel comfortable enough to participate through phone or video calls. Finally, the DCT must be in compliance with each regulatory agency involved in the study.
