Are clinical trials safe?

For every big news story about breakthrough medical treatments, there is probably a clinical trial to thank.

Clinical trials are essential for discovering new treatments for chronic health conditions. From drug trials to experimental therapy options, clinical trials are also used to find new ways to detect, diagnose, and prevent the development of lifelong diseases. Clinical trials show our leading health and medical researchers what treatments work or do not work for the human body — information that cannot be learned from any lab-based trial.

Due to recent breakthrough findings in human genetics and medicine like the mapping of the human genome project, there has been a recent explosion in research for targeted therapies. These new treatment options are designed to target cells based on their genetic makeup and have been proven to target diseases more accurately and cause fewer side effects than traditional treatment options. But, for these groundbreaking discoveries to continue, increased participation in clinical trials is an absolute must.

As the interest in newer and better therapies continue to rise, so do the number of clinical trials available for participation. Because of this, more patients may find themselves in the position to participate in a clinical trial themselves, which in turn can come with many questions about safety and benefit.

So what are clinical trials, and how do I know they are safe for me?

Clinical trials, explained

Since the turn of the century, the number of clinical trials every year has been steadily on the increase around the world. With most regions of the world running fewer than 2000 clinical trials a year in 2001, the number has increased dramatically in the present day (1). The regions with the steepest growth are the Americas, Western Pacific, and Europe, which now all average over 11,000 clinical trials a year (1).

Clinical trials are an essential step to finding revolutionary medical treatments and medications to treat chronic diseases like cancer, diabetes, and neurological conditions. The field of medicine considers randomized-controlled trials, also known as “clinical trials,” as the gold standard for assessing the effectiveness of new treatments before they are approved for use. While the subject matter of each clinical trial is often vastly different, the basis of the scientific method behind the trial is often very similar.

Randomized-controlled trials are set up as fair tests for the new treatments, enabling researchers to determine the proper dosing of new drugs and compare how well they work with what’s already available. They also allow researchers to better understand why a treatment is not as effective, helping to rule out possible causes which leads to new findings and better treatments over time.

Clinical trials are so important because they prevent medical practitioners from wasting resources and time on ineffective treatments that, in the worst-case scenario, may even cause harm to their patients. Clinical trials are incredibly rigorous procedures designed to bring only the best and most effective treatments to market, with only 9.6% of human drug trials getting approved by The Food and Drug Administration (FDA) (2). In addition to this, completing all three stages of a clinical trial takes time — an estimated 10-15 years to be fully cleared for use (3).

So, what actually happens?

For every drug that makes it into a clinical trial, there are many more that don’t even make it out of the laboratory. Before a medication is even considered for human clinical trials, all medications must be evaluated in pre-clinical lab studies, some of which involve animal testing. If the medication is proven to have some positive health impact during this period, it may be cleared to enter the first stage of human clinical trials.

Clinical trials are conducted in stages called phases. During each phase, doctors closely monitor the participants to determine important information like maximum safe dosages, treatment duration, and severity of side effects. Here is what you need to know about each phase of a clinical trial (4):

Phase I — Small group participation

During this phase of the trial, the goal is to determine if the medication or treatment is safe to be used in humans. By nature, this phase of clinical trials has the most risk for adverse side effects, which is why the target group is typically very small (fewer than 50 people). Participants in these trials are most commonly healthy young individuals unless the trial is testing harmful therapies such as cancer chemotherapy medications.

Phase II — Determining treatment efficacy

If the drug makes it through phase I, the goal of phase II is to determine if the treatment is effective at treating the condition it is designed to help. Phase II trials are larger than phase I, typically studying up to 100 participants at a time. If an acceptable percentage of the patients respond well to the drug, it will go to a phase III trial.

Phase III — Comparing treatment to standard care

The final stage of the process, phase III of clinical trials takes the longest and utilizes the most number of participants. In this phase, the treatment or drug is compared to the current standard of care for that particular medical condition to determine if it is more effective. This phase of the process often involves several hundred participants to determine the treatment efficacy in a fair and unbiased way. During this phase, it is common for placebo (inactive ingredients or sugar pills) control groups to exist to test the validity of the treatment. Always randomly selected, patients do not know if they are part of the placebo or treatment group. To prevent additional harm, it is common for all patients to continue receiving the current standard of care during these tests. Additionally, some phase III trials include a double-blind aspect, where neither the participants nor researchers know who is getting the real treatment during the test.

As we can see, clinical trials are an exhaustive and involved process that truly tests the efficacy of new treatments. With each trial, the percentage of drugs that continues through gets smaller and smaller. It is estimated that of all phase I trials, roughly 63% make it to phase II, 31% make it to phase III, and only 9.6% make it through the entire three-stage trial (5). It is important to note that just because a trial fails, it does not mean it was not safe to participate in. On average, the limited efficacy of the treatment was the primary cause for failed trials in 48% of phase II trials, and 55% in phase III trials (6). While safety is a factor that contributes to the cancellation of trials, it is responsible for cancelling only 25% of phase II trials and less than 15% of phase III trials (6).

What are the risks?

With millions of people around the world participating in clinical trials every year, risk and safety is something that organizers take very seriously.

While every individual trial brings its own unique risks, the potential risks from participating in a clinical trial generally stem from the newness of the drug or treatment. Not knowing how it may interact with humans or how it will respond in combination with other treatments is where the largest source of risk presents itself. 

And while the fear of risk is a huge source of trepidation that prevents people from joining clinical trials, it is important to note that no medication is truly 100% safe for all users. Just like clinical trial drugs, all FDA approved drugs still come with risks and potential side effects. Despite being approved from a trial on a relatively small collection of people, it is common for the more severe and long term side effects of medications to come to light after they have been released on a wider scale by the FDA. Additionally, patients with additional medical problems or complex medical histories are generally excluded from these trials, so it is only after the wider release that these populations get exposed to these groups of people.

In general, phase I trials are tested on healthy volunteers rather than patients — excluding cases like cancer medications that would be unethical to give to a healthy individual. While it is not commonly expected for the participants of phase I trials to experience much of a health benefit from the treatment specifically, they do often experience health benefits from the additional care and medical monitoring from the trial. On the flip side, the extra monitoring does bring other negatives like time spent in the doctor's offices, time away from work and family, and occasional health insurance difficulties depending on the topic of the study. Just like everything else in this world, clinical trials are a grey zone of positive and negative impacts on your life and health that need to be balanced to determine if it is the right fit for you.

Potential side-effects

During all phases of any clinical trial, there are risks of any participant developing mild to severe side effects. In general, mild side effects like nausea, headaches, and diarrhoea are the most common (and still relatively rare) adverse effects of any clinical trial. But, in severe cases, patients may require hospitalization or can pass away as a result of participation in any stage of a clinical trial. As an additional note, the United States has no law that requires the manufacturing company to provide compensation for research injuries, so if a patient is injured or killed during a clinical trial, there is often little to no compensation. This is why incredibly close monitoring by highly trained medical professionals is mandatory throughout all stages of the trial.

Throughout every trial, statisticians review data on cure rates and side effects from every patient involved. If at any time the side effects go beyond the expected limits or the risks begin to outweigh the benefits of the experimental treatment, the study will be stopped or modified for patient safety.

Ethical considerations

Because of the nature of clinical trialling, ethics are deeply interwoven into every decision made throughout each phase. A common source of ethical controversy lies in the concept of therapeutic misconception (where people volunteer to participate believing that they will be guaranteed results, when in fact results and safety are not guaranteed in any trial.) Balancing this optimism is essential for trial runners — while they need to keep their participants hopeful and engaged in the process, they also need to outline the expectations and potential risks of the trial.

Getting informed consent

So participating in a clinical trial is a gamble: it may help, it may not help, or it may even cause some unpleasant side effects. Just like any medical procedure, before starting a clinical trial, a patient needs to be able to provide informed consent — consenting to participate in the trial understanding all of the benefits, risks, and possible outcomes available. Unfortunately, not all clinical trials can answer all of the questions that many people joining the trial may have because the therapy may have had minimal to no human testing done. Thankfully, many clinical trial leaders specialize in simplifying medical terminology and explaining concepts to a wide audience of participants, not just those who are medically literate. 85% of participants in recent clinical trials reported the informed consent form to be very easy to somewhat easy to understand, which is a shining positive for clinical trial sites (8).

Healthy volunteers are usually from a low-income background

Participation in a clinical trial is always voluntary, and participants can always withdraw at any given time throughout the process. While some people join trials as an altruistic act to help others, the majority of the healthy participants in early-stage trials are often low-income young people who are interested in the money they get paid for participating. The largest group of individuals partaking in clinical trials are unemployed people (32.6% of participants), with more than 46% of people participating making less than $25,000 a year (9). This group commonly includes minorities such as Black and Hispanic people who are vulnerable to chronic systemic exploitation in the medical system (9).

In the United States, volunteers are meant to wait at least 30 days in between trials — but there is no governing body to police this requirement. Without protective policies to prevent continued discrimination against these groups, many young people in this position participate in multiple phase I trials a year, earning money while also accumulating additional health risks. This poses many ethical questions about the ability of these people to provide true informed consent based on the many socioeconomic factors that drive this specific population to participate in these trials.

For the vast majority, the benefits outweigh the cost

So at the end of the day, is participation in clinical trials worth it? For most people, the data seems to indicate yes. 

With 90% of clinical trial participants in 2019 rating their treatment as the same or better than standard care options, getting access to quality medical care is a major advantage to partaking in clinical trials (8). Additionally, 96% of people said they would be willing to participate in another clinical trial, having had a positive overall experience during their trial(8).

For many, getting to be an active participant in their medical care is a huge benefit and driving factor to sign up for clinical trials. With increased access to state of the art medical facilities and medical experts, oftentimes clinical trial participants get incredibly high-quality care for very minimal risk.

As modern medical research continues to push the boundaries of what we once thought possible, clinical trial participants are truly the unsung heroes behind the scenes. As the number of clinical trials continues to increase, the opportunity to get involved in clinical trials has never been a more accessible or exciting opportunity for many to get involved in finding the cures for many chronic diseases.

Sources

1. Number of clinical trials by year, country, WHO region and income group (1999-2019) | World Health Organization

2. New study shows the rate of drug approvals lower than previously reported | Biotechnology Innovation Organization

3. How long a new drug takes to go through clinical trials | Cancer Research UK

4. International clinical trials day: The voyage of drug discovery | Alzheimer’s Research UK

5. Clinical development success rates 2006-2015 | Biotechnology Innovation Organization

6. Phase II and phase III failures: 2013–2015 (2016)

7. SAE rates in clinical trials | Applied Clinical Trials

8. Charts and statistics | CISCRP

9. Risk and emotion among healthy volunteers in clinical trials (2016)

The author, Claire Bonneau, is a medical writer and certified trauma operating room nurse.