What are clinical trials and how do they work?

Scientists are discovering new cures for cancer, Alzheimer’s disease, and other diseases on a weekly basis; or at least that is what news headlines would suggest. Many of these press releases are based on preliminary research in cells or mice, while a majority of novel drugs end up showing no benefit when tested in people. Moving from cells to humans is the start of a highly-regulated and coordinated process called a clinical trial.

Clinical trials are designed to determine whether a medical, surgical, or behavioural intervention is safe and effective for people. Regulators and researchers are continually looking for ways to accelerate the speed and reduce overall costs of clinical trials with the goal of bringing life-saving treatments to patients sooner.

As of September 2022, there were over 420,000 studies registered on ClinicalTrials.gov, a database of privately and publicly funded clinical studies conducted around the world. These studies spanned 221 countries recruiting millions of volunteers worldwide, testing everything from simple behaviours like exercise routines to complex procedures like gene therapies, all following a similar multi-phase process to evaluate their effect on human health.

Basic research can often lead to the discovery of new drugs either intentionally or serendipitously. In between basic research and the start of a clinical trial is “preclinical research,” which involves lab experiments in cells or animal models to determine whether the drug is useful and if it is toxic before testing in people. This process takes multiple years and ends when researchers submit their data and detailed clinical trial plans to a regulatory agency like the US Food and Drug Administration (FDA).

Clinical trials are conducted in four phases, designed to evaluate a treatment, find the right dosage, and observe any side effects: Phase I usually involves a handful of people and judges a treatment’s safety and side effects; during Phase II and Phase III the number of participants increases and emphasis is given to the treatment’s effectiveness, after which the FDA may grant approval; Phase IV is designed to monitor long-term safety, identifying side effects that might not appear until years later.

While timelines greatly vary, the first three phases of clinical trials can take between 10-15 years to complete, costing companies anywhere from $1-2 million to more than $340 million. This process may appear overly complex for determining something as simple as a drug’s health impact but each step is carefully calculated, including sterile manufacturing practices, ethical patient consent, and clearly defined endpoints and measurements. Yet, even within this strict structure is room to experiment and try out new trial designs, with the goals of improving speed and reducing costs.

Approximately 86% of drugs that enter clinical trials do not receive FDA approval. This has significant implications for how pharmaceutical companies approach clinical trials considering that the average total cost of developing a new drug is estimated to be between $2-3 billion. Although clinical trials are highly-regulated processes, innovation in trial design and active engagement with regulators can create flexibility to try new ways of evaluating drugs.

Unlike conventional clinical trials that are fixed and unchanged throughout the study, adaptive trials are flexible and agile, sometimes testing multiple drugs at once. As new data comes in, adaptive trials can drop or add doses, change the trial’s duration, or change the patient populations, which proved critical in quickly responding to the COVID-19 pandemic.

Advances in wearable health devices and AI technologies to gather and store large amounts of real-world, health-related data is impacting the design and execution of clinical trials. Companies are working with regulators to turn this data into real-world evidence, providing new insights into a drug’s safety and long-term effects, which traditional trials may not observe with such detail.

The COVID-19 pandemic has accelerated the adoption of decentralized clinical trials, bringing a proportion of trial activities to the patients rather than bringing patients to a trial site. Virtual technologies and services like telehealth and remote patient monitoring has enabled decentralization, potentially broadening trial access and improving participant diversity, a long-standing issue in drug development.

While momentum is building to improve participant diversity, particularly in the US, for individual clinical trials, reaching communities with some of the highest-disease burdens requires moving clinical trials to other countries.

In 2021, the number of trials registered in high-income countries (HICs) was almost 100 times higher than in low-income countries, as reported by the World Health Organization.

Drugs developed in HICs should not be expected to work identically in low- and middle-income countries (LMICs) due to the vast biological diversity across regions. To identify and account for these differences, international collaborations and adaptive clinical trials are being used to create networks of sites across LMICs, helping to pool resources, share expertise, and accelerate data acquisition.

Long-term efforts to build clinical trial capacity (e.g. regulatory systems, manufacturing capabilities) in LMICs will be critical in developing drugs that are safe and effective for specific populations and deliverable within LMIC health systems.