Decentralized clinical trials and in silico clinical trials

These days, the buzzword in the clinical trial field is 'decentralized clinical trials' or DCTs. The Covid-19 pandemic seems to push the clinical trials toward 'decentralized' or 'hybrid' of decentralized and traditional clinical trials. 

Traditional clinical trials are 'centered' around the clinical trial sites and the investigators. The patients (clinical trial participants) are recruited by the investigators who are the medical doctors responsible for the conduct of the clinical trial at trial sites. The trial sites are the clinics, hospitals, and medical centers. The patients would need to visit the trial sites regularly to see the investigators for clinical trial activities (signing the informed consent, screening for eligibility, receiving study treatments, performing efficacy and safety measures,...). The clinical trial data will then be recorded and entered into the database (for example EDC) by the study coordinator or investigator at investigational sites.

Decentralized clinical trials are defined as the decentralization of clinical trial operations where technology is used to communicate with study participants and collect data and the data collection will not depend on the frequent patient's visits to the investigational sites. According to CTTI (clinical trial transformation initiative) Recommendations: Decentralized Clinical Trials: 

DCTs using telemedicine and other emerging and novel information technology (IT)
services offer the potential for local HCPs to participate in clinical trials. This may
provide several advantages compared to traditional clinical trials conducted at more
centralized clinical trial sites, including the following:

• Faster trial participant recruitment, which can accelerate trial participant access to important medical interventions and reduce costs for sponsors.
• Improved trial participant retention, which may reduce missing data, shorten clinical trial timelines, and improve data interpretability.
• Greater control, convenience, and comfort for trial participants by offering at home or local patient care.
• Increased diversity of the population enrolled in clinical trials.
• An opportunity for home administration or home use of the IMP, which may be
• more representative of real-world administration/use post-approval.

FDA's Advancing Oncology Decentralized Trials - Learning from COVID-19 Trial Datasets also listed the advantages of the DCTs: 

• Decentralized Clinical Trials (DCT) may have several potential benefits including reduced patient and sponsor burden and increased accrual and retention of a more diverse trial population.
• Use of full or hybrid DCT designs by commercial sponsors has been rare in oncology, in part due to uncertainty surrounding the effect of remote assessments on data quality and outcomes.
• COVID-19 has necessitated DCT-type trial modifications such as remote assessments to reduce patient exposure to COVID-19 infection from travel to trial sites.
• Many of these remote assessment modifications were deployed in the middle of large ongoing cancer trials.
• There is an opportunity to evaluate the effect of remote assessments on trial data to advance Decentralized Trials in oncology.
• Better understanding of the effect of DCT modifications can reduce uncertainty for sponsors and regulatory bodies, and identify mitigation strategies for future prospective DCT designs.

Historically, DCTs may be called differently: virtual trials, siteless trials, remote trials, digital trials, direct-to-patient trials. These different names may just describe one specific aspect of the DCTs and can cause confusion. For example, 'virtual trials' can be confused with the in silico trials which are based on computer models and do not use real participants (patients) but computer programs to model participants to assess drug efficacy and safety during the preclinical phase or before a traditional trial.

"Decentralized clinical trial" is a “Terrible Name for a Promising Innovation” and is not a best terminology for patients and study participants. Alternative names such as direct-to-patient trials, patient-centric trials, and home-based trials seem to be more straightforward and better terms.

In essence, in traditional clinical trials, we bring the trial to the patients; in DCTs, we bring the patients to the trial.

There are still a lot of challenges and obstacles to implementing decentralized clinical trials. Application of DCTs may be limited to some special situations (such as post-marketing studies with patient-reported outcomes and outcomes measured digitally). It is still rare for pivotal and registration studies to use full DCTs. It seems to be more appropriate to adopt hybrid trials - the combination of the traditional and the decentralized trials. For example, in clinical trials in the rare disease area, it is difficult for patients to travel to the investigational sites, the patients may visit the investigational sites for some important visits (in-clinic visits) and then the home health care nurses may be used for in-home visits to patient's home.  

In 2019, Janssen, PRA Launch a Fully Virtual Trial (it should be called the decentralized trial) "A Study on Impact of Canagliflozin on Health Status, Quality of Life, and Functional Status in Heart Failure (CHIEF-HF)". The study design was described in the Circulation: Heart Failure "Novel Trial Design: CHIEF-HF". CHIEF-HF seems to be the first phase III trial being fully decentralized.

 

Here are some references for DCTs:   

• Defining Decentralized Clinical Trials and Understanding Their Nuances
• Decentralized clinical trials: Collaboration is needed to drive their adoption and impact
• DTRA.org Decentralized Trials Research Alliance
• FDA Official Reviews “Challenges and Obstacles” to Decentralized Trials
• Decentralized Clinical Trials - Craig Lipset - Founder of Clinical Innovation Partners
• Is The Advent Of Decentralized Clinical Trials A Blessing Or A Curse?
• ACRO: decentralized clinical trials
• 
  

The decentralized clinical trials still collect the data from the patients and should not be called 'virtual clinical trials'. On the contrary, the 'In Silico clinical trials' is more appropriately called 'virtual clinical trials' or 'patientless clinical trials' and it simulates the virtual subjects for modeling and prediction. In Silico clinical trials may use the data from pre-clinical and historical clinical trials for simulation but involves no real patients in the study.  

According to the senator bill "AGRICULTURE, RURAL DEVELOPMENT, FOOD AND DRUG

ADMINISTRATION, AND RELATED AGENCIES APPROPRIATIONS BILL, 2016", In Silico clinical trials use computer models and simulations to develop and assess devices and drugs, including their potential risk to the public, before being tested in live clinical trials."

 

In Silico clinical trials are part of the model-informed drug development (MIDD). the FDA has a MIDD pilot program managed by the Division of Pharmacometrics. 

Dr. Yaning Wang has multiple presentations promoting the MIDD and In Silico clinical trials, for example, in his presentation at the 2021 FDA Science Forum "Regulatory Applications and Research of Model-Informed Drug Development (MIDD)" (Youtube video at 2:38:25) and in his presentation at PMDA "Application of MIDD in New Drug Development and Approval". 

Here are some additional references on In Silico clinical trials:

• Pink Sheet (2021) Why 2020 Saw The Steady Rise Of In Silico Trials
• Chao Liu at FDA Model-informed analysis during NDA/BLA Review - Insights from two FDA case reviews
• FDA-ISoP Public Workshop: Model Informed Drug Development (MIDD) for Oncology Products
• Scott Berry "In Silico Clinical Trial Design"
• Insilicotrials.gov blog