Breaking Down the Stages of Clinical Trials, Their Challenges

September 08, 2020 - New drugs and therapies must undergo a series of tests and studies in order to help the individuals who need a cure or treatment for their conditions. These clinical trials are key to ensuring safety and efficacy of new treatments and cures.

But the process can be daunting for pharmaceutical companies and their researchers who dedicate significant time, money, and resources to developing and marketing a new prescription drug.

First, the investigational drug goes through pre-clinical studies to assess that it is likely safe and effective in individuals. 

Once cleared, researchers conduct up to four clinical trials to test the benefits and risks of a specific treatment or intervention. These trials consist of an investigator, usually a doctor, and a team of researchers. 

Clinical trials face various challenges and can cost pharmaceutical companies a lot more than initially planned.

READ MORE: Clinical Trial Design, Composition Has Undergone Major Changes

But because clinical trials are vital to get a drug to market, combating these challenges is extremely vital.

In the following article, PharmaNewsIntelligence explores the clinical trial phases and ways to combat some of the most pressing challenges that researchers face with getting their innovative treatments to market. 

Pre-Clinical Studies

While there are traditionally four stages of clinical trials, the process actually starts at ground zero: pre-clinical trials. 

Pre-clinical studies involve cell studies and animal studies and must be completed before clinical trials are launched. The results from pre-clinical studies suggest that the new product is likely to be safe and be effective in individuals. 

Cell studies, according to the American Cancer Society, are often the first tests done on a new treatment. Researchers look for effects of the new treatment on the cells of the disease they are studying.

READ MORE: Clinical Trial Finds Hydroxychloroquine Does Not Prevent COVID-19

Treatments that look promising in cell studies are then tested in animal studies. This step gives researchers a look into how safe the new treatment is in a living creature. 

Once pre-clinical studies are cleared, FDA must give the company permission before the treatment can move to the first stage of clinical trials. 

Pharmaceutical companies must then send an investigational new drug (IND) application to FDA before officially starting a clinical trial. 

FDA mentioned three IND types, including an investigator IND, emergency use IND, and treatment IND.  

An IND application must contain information in pharmacology and toxicology studies, manufacturing information, and clinical protocols and investigator information.

Phase 1 

READ MORE: 3 Principles for Patient-Centered Research Design, Clinical Trials

The official first stage of clinical trials is Phase 1. 

A Phase 1 clinical trial consists of 20 to 100 healthy volunteers or individuals living with the disease or condition that the product is being tested for, according to a guide from the FDA that details the four phases of clinical trials. 

In the first phase, trials focus on the safety and necessary dosage of the product without serious side effects. Researchers also look at the best way to administer the drug, such as orally, intravenously, or topically.

This phase usually lasts several months and 70 percent of drugs in Phase 1 move onto the next phase, FDA stated.

Phase 2 

In a Phase 2 clinical trial, up to several hundred people with the disease or condition being targeted be a treatment are enrolled and the efficacy or a drug or device is tested.

This phase is usually randomized where one group of patients receives the experimental drug, while a second “control” group receives a standard treatment or placebo.

A Phase 2 trial is also often “blinded,” which means that neither the patients nor the researchers know who has received the experimental drug. 

“This method allows the investigators to provide the pharmaceutical company and FDA with comparative information about the relative safety and effectiveness of the new drug,” according to a CenterWatch article. 

A Phase 2 trial generally lasts several months to two years, and just 33 percent of drugs move onto Phase 3.  

Phase 3 

A Phase 3 clinical trial typically enrolls up to 3,000 individuals who have the disease or condition. And most often, these clinical trials are launched globally at the same time. 

During this phase, trials are conducted to confirm and expand on safety and effectiveness from the previous two trial phases in order to compare the drug to standard therapies for the disease or condition being studied. 

Similar to a Phase 2 trial, study participants are often chosen at random to get either the standard treatment or the new treatment.

This is usually done because doctors do not yet know which treatment is better.

The American Cancer Society stressed that the main difference between a Phase 3 trial and a Phase 1 or 2 trial is that placebos may be used in some Phase 3 studies, but they’re never used alone if there’s a treatment available that works.

A Phase 3 clinical trial lasts one to four years, and only about 25 to 35 percent of the drugs move onto the final phase. 

Phase 4 

The final clinical trial stage is Phase 4, or the “post marketing surveillance” phase. These trials enroll the most individuals, usually several thousand. 

Phase 4 trials take place after the drug is already marketed and available to the general public. Once again, the main objective of the trial is to further test for safety and efficacy. 

But this time, the drug is tested in real life scenarios to study the long-term risks and benefits of using the drug and to uncover any potential side effects.

If researchers find that the drug reveals safety issues in an individual, it can either be modified or completely withdrawn from the market and no longer an available prescription. 

Additionally, pharmaceutical companies compare the drug with other drugs already in the market and determine the cost-effectiveness of a drug therapy relative to other traditional and new therapies. 

Overcoming Clinical Trial Challenges 

Clinical trials are vital in the drug development sector, so combating the challenges associated with the process is extremely vital.

One common challenge when conducting clinical trials is free medical care for trial-related injuries, a Nature article noted. 

The clinical trial sponsor is required to provide free medical care for all trial-related injuries in the participant as. And while at public hospitals it is possible to provide free care to all participants enrolled in a trial, private hospitals face challenges. 

For this reason, many private hospitals are unable to take part in clinical trials.

The authors recommended that compensation for trial-related injury or death must be adapted to specific contexts. Specifically, the presence of risk factors such as prematurity and co-morbid conditions must be factored in at the time of enrollment. 

Another roadblock when conducting a clinical trial is patient recruitment and access.  

The need to recruit and retain enrollment numbers is nothing new to researchers. Forty-eight percent of sites miss their enrollment targets and 80 percent of trials are delayed due to recruitment, according to researchers from TayganPoint Consulting Group. 

The drop-out rate of clinical trials is 30 percent, which adds a potentially substantial confounding factor.

But there are many ways to minimize the patient recruitment and dropout burden. 

The first way is to address patient burden by leveraging disease registries and patient advocacy organizations or populations through online surveys or focus groups to assess perceptions and implications of burden. 

This includes the number of required visits, length of visits, geographic distance, possibility of placebo, and potential degree of invasiveness, researchers said. 

Additionally, patient journey maps, electronic clinical outcomes assessment, use of today’s two-way smart technologies, and focusing on key geographies and “customer service” are additional ways to combat this burden. 

Clinical trials are vital to discovering new treatments for diseases and bring a product to market. Trials can give researchers insight into what does and doesn’t work in humans so that they can create the most effective drug possible. But the challenges associated with conducting a clinical trial must be addressed in order to speed up the drug development process and focus on patient-centered care.