Clinical trials(CTs) are the studies that involve humans for testing a new drug or medicament or any diagnostic tool or device to assess their safety and effect on human health. Clinical trials are carefully designed, reviewed, and completed because they provide information on the efficacy and safety of novel medications and equipment.
Why Clinical Trials are performed?
The primary method used by researchers to determine whether a new treatment, such as a new medication, diet, drug delivery methods, therapy modalities, or medical device(like neurostimulators and pacemakers), is safe and effective in humans.
To determine whether a novel treatment is more efficient than the standard treatment and/or has fewer adverse effects.
Assessing one or more interventions intended to detect or diagnose a certain illness or condition.
Investigating and evaluating methods to improve the quality of life for people who have chronic health issues or life-threatening illnesses.
NIH (National Institute of Health) Classification
Treatment Trials: In these studies, novel pharmacological combinations or experimental therapies are tested.
Prevention Trials: To discover a means of preventing an illness or preventing its recurrence.
Diagnostic trials: To discover more efficient methods or tests for disease diagnosis.
Screening trials: Test methods for detecting disease.
Quality of life trial: This experiment investigates how to increase the comfort and quality of life for those who have a chronic condition.
Phases of Clinical Trials
Phase 0 studies/Micro-dosing Studies: These studies aren't frequently performed and wouldn't be useful for all medications. These studies are very small, frequently involving fewer than 15 participants, and the drug is only administered for a brief period. They are not necessary for evaluating a new drug.
There is essentially no possibility that participants in the phase 0 trial will profit, in contrast to subsequent phases of clinical trials.
Phase I studies/Human Pharmacology phase: New medication on 20 to 80 healthy volunteers.
AIM: Finding the maximum dose of the novel medication that can be administered safely without having serious side effects i.e. determining the drug's safety profile.
About 70% of drugs in this phase move to the next stage.
Length of the study- Several months to a year.
Phase I clinical trial highlights:-
- MEC and MSC are determined.
- It involves studying the Pharmacokinetics and Pharmacodynamics profile of the drug.
Phase II studies/Therapeutic Exploratory phase: Controlled and closely monitored studies on 20-300 patients with disease or condition.
Aim: Obtaining preliminary data on the effectiveness/ efficacy of a drug for a particular disease/condition. To determine risks and short-term side effects of drugs under testing.
Length of the study- Several months to 2 years.
About 33% of drugs in this phase move to the next stage.
Phase III studies/Therapeutic Confirmatory phase: Involve expanded, controlled, and uncontrolled trials involving 300- 3000 people with disease/condition.
Aim: To collect additional information regarding the effectiveness of drugs and monitor adverse drug reactions.
Length of study: 1-4 years
Around 25-30% of drugs in this phase move to the next stage.
Phase IV studies/ Post Marketing Surveillance(PMS): Monitoring rare or long-term adverse effects of drugs once marketed over a large patient population across the world.
Aim: To establish the safety profile of the drug worldwide.
If phase IV trials reveal harmful side effects, a medicine/drug may be taken off the market or only allowed for specific applications.
Digital technological advancements in Clinical Trials
Digital technological advancements have changed the old idea of a clinical trial into a newer and underutilized approach like a digital/virtual/decentralized clinical study.
In the Covid 19 pandemic crisis, instead of the conventional method, virtual/digital/decentralized clinical trials were significantly increased due to travel restrictions and social isolation.
Advantages
Novel Technology like Telemedicine
Video visits
e-consenting, or
remote site monitoring techniques using electronic devices or app
Some terms may be used synonymously with each other but they are not the same such as Decentralized and Digital Clinical Trial as both used the same abbreviation ‘DCT’ which may lead to confusion sometimes. As Decentralized CTs may be digitalized but it is not necessary that digital clinical trials are decentralized.
Decentralized Clinical Trials
Such trials are conducted in remote areas away from the Central research center. Patients complete their clinical trial using either face-to-face interactions or virtual resources (such as video conferencing and patient-reported computerized assessments) depending on their location from the center. A decentralized trial can be carried out by mailing paper forms or by sending a remote healthcare provider to the patient's house.
The DCT model must be modified to meet the specific requirements of each trial setting and patient population in order to assure success.
Digital Clinical Trials
It is similar to conventional CTs but instead of using hard copies, all the data is collected in soft copies i.e. using only digital technology and no paper.
Any study can be conducted digitally, regardless of where the clinical visits take place.
For digital trials, data integrity is a top priority. This includes using systems that comply with regulations and have thorough audit trails that go back to source records (such as electronic patient reports medical records, and lab results).
Digital Clinical Trial Protocol
Before starting trials it is important to design a protocol. A digital clinical trial involves converting a written protocol into a collection of digital specifications and objects that are used to communicate with other digital systems.
This comprises:
Inclusion/Exclusion Criteria
Treatment Arms
Assessments
Visit Schedules
Safety Thresholds
The procedure can now be accessed digitally for modeling, optimization, and feasibility studies. There are tools and methods available to review the protocol's specifics, evaluate the effect of various eligibility requirements on enrolment, and find strategies to lessen the burden on patients by aligning clinical trials with industry standards of care.
Digital IRB (Institutional Review Board) submission
An electronic set of study documents from the digitized protocol are submitted for review and approval from IRB prior to patient screening and enrolment.
E-Screening Application
The E-Screening program, connected to the Electronic Medical Record (EMR) system at each research clinic, finds potential study participants at each location using the standards from the digital protocol.
The site research staff reviews these patient records, and those who qualify are invited to participate.
Challenge: Transforming unstructured data and physical documents into useful digital formats.
Solution: Use AI tools but they must only be utilized under the supervision of qualified personnel.
In accordance with the most recent FDA draught guidelines on the use of RWD, the FDA mandates that when using AI, the assumptions must be specified, the methodologies must be validated, and the data quality must be documented.
Electronic consent
It obtains patient consent using documents that have been approved by the IRB digitally. It describes the study and shows the risks, advantages, and alternatives. After the procedure is completed, this system can also be utilized to undertake post-study surveillance assessments, if necessary.
Other Systems
Every clinical trial employs a variety of methods to control the study's execution and data collection. Each of these systems generates clinical research data and related case report forms for a digital trial, which must be controlled through an integrated system.
These systems consist of:
Virtual Visit Systems
Electronic Clinical Outcomes Assessments (e-COA)
Medical Imaging Results
Clinical Trial Management System (CTMS)
Electronic Data Capture (EDC) system
Adverse Event Reports
Safety and Monitoring Systems
Digital Case Report Forms (e-CRFs)
A collection of digital case report forms are electronically filled out using the study's data.
These can be inspected and checked before being finalized and approved since they are consistent with the target EDC system and are linked with the study protocol.
The study's target EDC system will then be updated with the information from the digital case report forms, concluding the study's digital journey.
From this point, each source system and document of the digital clinical trial can be fully tracked back through the digital data path.
Advantage - Complete data monitoring and source data verification.
Advantages of Digital CTs
Identification of potential patients.
Efficient study site workflows.
Simplified study monitoring enhanced by artificial intelligence.
Reduced time.
Increase access to research studies and treatments.
Issues in designing Digital CTs
Lack of financial resources, infrastructure, and skilled personnel.
Patient compliance with digital tools as elderly people may be more comfortable with human interaction. Due to the tradeoff in patient acceptance, a time-consuming, multi-step verification process may result in a relatively small sample size.
Regulatory considerations to protect subject privacy: In the case of commercial providers of digital tools or health-related technologies, there is a lack of legal documentation or regulation. This may lead to such agencies sharing private information without participant's consent.
Complex design protocol.
Inference
Despite their underutilization, digital health technologies have the potential to revolutionize conventional CTs. For successful implementation in the near future, a number of limitations must be appropriately addressed.
To ensure greater dissemination of such design, a paradigm change toward improved participant-centric clinical trial experiences should be embraced rather than a research site.