CONSIDERATIONS OF DECENTRALIZED CLINICAL TRIALS
Introduction: What randomized controlled trials are and the PROs and CONs related to them
Randomized controlled trials (RCT) are defined as prospective studies that evaluate the effectiveness of a new intervention or treatment [1]. The main advantage associated with RCTs design relies on the reduction of bias, providing at the same time an accurate instrument to analyze cause-effect relationships between an intervention (e.g. drug) and a consequence (e.g. disease) [1]. The randomization balances participant characteristics, regardless if observed or not, between the groups thereby permitting the impact of any changes in outcome to the study intervention [1]. RCTs should be designed to have pre-specified primary outcomes, must be registered in a clinical trial database, and have specific ethical approvals [1]. Although RCTs are characterized by many PROs, there also few CONs, such as their high economic and time costs, the issues related to the generalizability of the cohort, as the volunteer enrolled subjects could not be representative of a specific population, and loss to follow up [1]. Recruitment and maintenance of study subjects still represent crucial challenges in RCTs; it has been shown that between 50% and 60% of RCTs do not achieve their original enrollment target, or are burdened with important delays [2], [3]. Furthermore, in recent years, the RCTs designs became more and more complex in terms of procedures and planned visit numbers [4]. All these issues taken together could have a negative influence on both patients' and physicians' willingness to enter RCTs or to enroll patients for RCTs respectively [5].
For example, in global trials, most of the participants mentioned the location of a center as a crucial factor in the decision to take part in a research study [6], indicating the physical distance to the trial center a limit to their participation [7], [8].
In addition to these difficulties, it is necessary to mention the disruption and chaos that the health care system is facing since the beginning of the ongoing pandemic caused by the acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for COronaVIrus Disease-2019 (COVID-19) [9]. COVID-19 epidemic emerged in December 2019 in China and rapidly spread all over the world, evolving in a pandemic, as stated by the World Human Organization (WHO) on 11 March 2020 [9]. The ongoing pandemic is creating significant pressure on hospitals and healthcare systems, as conventional resources should be redistributed. Furthermore, movement restrictions, and possible drug supply interruptions, are complicating the possibility to administer standard therapies and running clinical trials.
SARS-CoV-2 outbreak, with its destroying power, is inevitably impacting on research activities: start-up activities for new trials may be postponed and recruitment to ongoing trials should be suspended [10]. Many regulatory organizations, such as the Food and Drug Administration (FDA) [11], the European Medicines Agency (EMA) [12], have established guidelines on how to manage clinical trials during this situation. These guidelines outline possible difficulties in keeping the adherence to protocol-defined studies and proper contingency actions, to maintain patient safety and, at the same time, trial integrity [13].
Another limit imposed by the current pandemic situation is the rarefaction of close and frequent meetings between investigators, sponsors, and review boards to guarantee patient safety and clinical trial [13].
In this paper we are going to discuss different important aspects in adapting the conduct of clinical trials in the upcoming years, also considering the influence played by the COVID-19 pandemic, to identify the future direction for trials.
Decentralized clinical trials and their challenges
The decentralization of clinical trials has the potential to decrease barriers to participation and to reduce the early abandon from a study, moving the trial experience from a site-centric to a more patient-centric approach. Nowadays conventional clinical studies have decentralized elements in regards to locality and data collection strategies [14]. The development of remote or decentralized clinical trials (DCTs) has been possible as technology, infrastructure, and knowledge have in parallel advanced to support their use.
DCTs are defined as clinical trials performed through telemedicine, mobile/local healthcare providers, and/or mobile technologies, quite completely free from barriers that affect traditional trials, such as physical distance.
The first benefit is that DCTs allow to enroll participants from anywhere, resulting in a faster enrollment phase, thus with participants more representative of a target population. Not only physicians benefit from a decentralized approach, which also permits trial participants to join clinical research from anywhere, with the experimental activities better integrated into their daily home routine [15]. DCT method is intended to reduce participant burden both in terms of time waste and travel costs, thus amelioration retention during the all trial phase, and facilitate certain research that may otherwise be excessively onerous under traditional conditions.
Since the measurements are not limited to scheduled site visits, the new technologies lead to the opportunity to perform more frequent or even continuous measurements [15].
Telemedicine refers to the use of information and communications technology to make available health care services when the physician and the patient are not physically present with each other [16]. Currently, most Countries have telemedicine protocols and norms that regulate the use of mobile medicine in DCTs by different stakeholders, such as researchers, sponsors, and intermediaries [17].
Duke University and the United States (US) FDA co-founded the Clinical Trials Transformation Initiative (CTTI) [18], a public-private company, whose aim is to develop and encourage the implementation of practices that will upsurge the quality and effectiveness of clinical trials, highlighting the need to adopt a broader use of DCTs. With this purpose, the CTTI promoted the Decentralized Clinical Trials project, with these main objectives: (1) detect the existing legal and practical barriers for wider use of DCTs and (2) identify the resources that can implement DCTs [15].
One of the first initiatives carried out by CTTI between October 25, 2016, and January 20, 2017, was a group consultation with trial sponsors from 7 different pharmaceutical or biotechnology industries to recognize the main legal and regulatory challenges related to the conduct of DCTs, to find possible solutions [15].
The challenges perceived by the interviewed representatives are mainly related to factors involved in the scheduling and conduct of DCTs, such as guaranteeing that protocol-defined procedures are completed in a reliable way throughout the study. An important concern refers to the trial participants’ identities verification process, and the measures to adopt to ensure their privacy and confidentiality when the trial is remote.
It is important to implement strategies to monitor safety with telemedicine in the context of remote clinical research, to reduce to the minimum extent patients’ risks. Although many stakeholders refer that employing telemedicine in research could be difficult and perceived as a significant time wasting due to state of the art of actual telemedicine technology and regulation. Other issues are related to the shipment and receipt of investigational study drugs or other medical devices, some states, do not permit direct shipment of investigational medical products. Even the accountability of the received drug could be difficult and mainly based on what patients refer [15].
Possible solutions to implement decentralized clinical trials
The solutions proposed to overcome the obstacles currently limiting the wider spread of DCTs include the need to start the trial planning early, recruiting in this initial phase sponsors, researcher, and legal and regulatory stakeholders. To speed up the procedures and avoid slowdowns or blocks of the trials is crucial to identify and understand as soon as possible the specific national regulations that manage clinical trials, distribution of investigational medical products, and telemedicine. It would be crucial to develop accurate systems for tracking delivery, receipt, and drug accountability. Since in DCTs the mobile devices are fundamental to monitor patients’ data and, thus, patients’ safety, it would be necessary to enhance the available training and assessment systems for mobile healthcare providers. A useful approach is represented by the patient-centered one, which allows receiving participants’ feedback throughout the trial.
Based on these issues and proposals that emerged from these first qualitative interviews and stakeholder expert meetings, the CTTI established consensus recommendations about 6 DCTs topics [19]:
DCTs approaches and trial design
Telemedicine state licensing issues
Drug supply chain
Mobile healthcare providers
Investigator delegation and oversight
Safety monitoring.
DCT Approaches and Protocol Design
Initially, it has been suggested that the design and application of DCTs should use an “all-or-nothing” approach, thinking that a fully decentralized method may not comprise a physical trial site, but include trial visits ran through telemedicine or by mobile or local healthcare providers and the use of mobile devices to register data.
Actually, the CTTI recommends that the design of DCTs does not have necessary to be an all-or-nothing approach. A partially decentralized approach, also called hybrid, should be used if applicable. This method combines the features of decentralized studies with more conventional approaches. These approaches may employ for example, a designated trial site in which specific trial-related procedures take place (e.g. radiology tests), allowing other procedures (e.g., vital signs recording) to be carried out somewhere else. Enrolled participants and researchers may interact both in a physical site and via video or teleconferencing. This flexible approach may allow investigators to achieve logistics experience more gradually, with better outcomes.
Telemedicine state licensing
The term telemedicine encompasses a group of technologies fundamental to consent the development of DCTs even between different countries, it is thus necessary to know the licensure requirements of telemedicine of a specific Country [15]. Sponsors should examine the laws of country or state in which they intend to run a trial to certify compliance with existing laws. Patients’ enrollment could be limited by difficulties with obtaining informed consent, mainly because of physical distance; for this reason, tele-consent represents a telemedicine-based approach to achieve informed consent with the potential to eliminate these barriers [20].
Drug supply chain
Investigational medical product delivery and accountability are crucial safety procedures, it is thus important to have a deep knowledge of their regulations according to local regimentation and the product’s registration status with the FDA [15]. Also, practical considerations should be considered in the delivery process of a medical product directly to the patient, including the product’s nature and conservation methods. Some investigational drugs cannot be directly delivered to study participants as of the route of administration or the safety profile [15]. A possible solution provides the engagement of a vendor, possibly with a pharmacy license in different Countries, experienced in direct shipment to participants [15].
Mobile Healthcare Providers
Visits provided by mobile healthcare providers may promote patients’ adherence, since this approach can enhance comfort in particular settings, such as home or office, reducing the movement time. In a dislocated setting, researchers can perform many procedures, as clinical evaluation, blood withdrawals, drug administration, and compliance verification [15]. Mobile healthcare providers may ease the participation in prospective trials nevertheless of study length since this approach reduces the frequency of visits, and the distance to travel, and harmonizes with work or family duties [15].
Investigator delegation and oversight
It is fundamental that DCTs using mobile and telehealth tools and practices should be run in the same way as conventional trials regarding the researcher's delegation and oversight.
Safety Monitoring
As in conventional trials, remote safety monitoring procedures must be deeply considered in remote trials. Clinical researchers and participants should be trained on safety procedures related to specific DCTs, to be sure, for example, that the patients in a remote setting can inform about possible adverse events rapidly [15]. It is recommended that inclusion and exclusion criteria are explicit in the protocol, ensuring that enrolled participants have sufficient technological abilities to share data and report possible adverse events.
Conclusion
As anticipated, conventional clinical trials have several limits, such as high costs and complex procedures that require the presence of the patients in a physical clinical site to perform visits and tests. This delicate scenario has recently been complicated by the COVID-19 pandemic, which required social distancing and limitation of travel for everyone and in particular for those suffering from chronic diseases.
The decentralization of clinical trials is meant to improve the logistics of clinical trials, with a more patient-centric approach, with a reduced burden for both patients and caregivers, without sacrificing security monitoring and a rich data collection, and creating new ways to capture the health status of patients in a real-world scenario. In consideration of the mentioned difficulties in running and complete a traditional clinical trial, the decentralization could enhance patients’ enrollment and retention, and permit a more continuous data monitoring and collection using innovative telemedicine devices.
The decentralization of clinical trials is a new perspective, much effort is required to achieve more acceptance and to spread the development of DCTs. Some already existing hurdle is represented by undeveloped digital infrastructure, inadequate experience by researchers, and legal barriers linked to privacy management and drug delivery.
References
[1] E. Hariton and J. J. Locascio, “Randomised controlled trials – the gold standard for effectiveness research: Study design: randomised controlled trials,” BJOG: An International Journal of Obstetrics and Gynaecology. 2018, doi: 10.1111/1471-0528.15199.
[2] B. G. O. Sully, S. A. Julious, and J. Nicholl, “A reinvestigation of recruitment to randomised, controlled, multicenter trials: A review of trials funded by two UK funding agencies,” Trials, 2013, doi: 10.1186/1745-6215-14-166.
[3] S. J. Walters et al., “Recruitment and retention of participants in randomised controlled trials: A review of trials funded and published by the United Kingdom Health Technology Assessment Programme,” BMJ Open, 2017, doi: 10.1136/bmjopen-2016-015276.
[4] K. A. Getz and R. A. Campo, “Trial watch: Trends in clinical trial design complexity,” Nature Reviews Drug Discovery. 2017, doi: 10.1038/nrd.2017.65.
[5] R. Kadam, S. Borde, S. Madas, S. Salvi, and S. Limaye, “Challenges in recruitment and retention of clinical trial subjects,” Perspect. Clin. Res., 2016, doi: 10.4103/2229-3485.184820.
[6] “Report from CISCRP. Perceptions & Insights Study Report on the ParticipationDecision-Making Proces,” 2017. https://www.ciscrp.org/download/2017-perceptions-insights-study-the-participation-decision-making-processs/?wpdmdl=8768, (accessed Mar. 16, 2021).
[7] E. J. Mills et al., “Barriers to participation in clinical trials of cancer: A meta-analysis and systematic review of patient-reported factors,” Lancet Oncol., 2006, doi: 10.1016/S1470-2045(06)70576-9.
[8] F. Legge et al., “Participation of patients with gynecological cancer in phase I clinical trials: Two years experience in a major cancer center,” Gynecol. Oncol., 2007, doi: 10.1016/j.ygyno.2006.09.020.
[9] E. Mahase, “Covid-19: WHO declares pandemic because of ‘alarming levels’ of spread, severity, and inaction,” BMJ, 2020, doi: 10.1136/bmj.m1036.
[10] The Lancet Oncology, “COVID-19: global consequences for oncology,” The Lancet Oncology. 2020, doi: 10.1016/S1470-2045(20)30175-3.
[11] Food and Drug Administration, “Food and Drug Administration. FDA guidance on conduct of clinical trials of medical products during the COVID-19 pandemic,” 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents (accessed Mar. 20, 2021).
[12] E. M. Agency, “European Medicines Agency. Guidance on the management of clinical trials during the COVID-19 (Coronavirus) pandemic,” 2020. .
[13] A. C. Tan, D. M. Ashley, and M. Khasraw, “Adapting to a pandemic - Conducting oncology trials during the SARS-CoV-2 pandemic,” Clinical Cancer Research. 2020, doi: 10.1158/1078-0432.CCR-20-1364.
[14] S. Khozin and A. Coravos, “Decentralized Trials in the Age of Real-World Evidence and Inclusivity in Clinical Investigations,” Clin. Pharmacol. Ther., 2019, doi: 10.1002/cpt.1441.
[15] M. Apostolaros et al., “Legal, Regulatory, and Practical Issues to Consider When Adopting Decentralized Clinical Trials: Recommendations From the Clinical Trials Transformation Initiative,” Ther. Innov. Regul. Sci., 2020, doi: 10.1007/s43441-019-00006-4.
[16] R. Roine, A. Ohinmaa, and D. Hailey, “Assessing telemedicine: A systematic review of the literature,” CMAJ, 2001, doi: 10.1136/bmj.323.7312.557.
[17] C. Scan and C. August, “State Telehealth Laws and Medicaid Program Policies: A Comprehensive Scan of the 50 States and District of Columbia,” Public Heal. Inst. Cent. Connect. Heal. Policy, 2016.
[18] “Clinical Trials Transformation Initiative.” www.ctti-clinicaltrials.org (accessed Mar. 22, 2021).
[19] C. T. T. Initiative, “Clinical Trials Transformation Initiative. CTTI recommendations: decentralized clinical trials,” 2018.
[20] B. E. Bunnell et al., “An Exploration of Useful Telemedicine-Based Resources for Clinical Research,” Telemed. e-Health, 2020, doi: 10.1089/tmj.2018.0221.