The Quality of Clinical Trials

The historical medicinal procedures that all science enthusiasts recognize well—from the famous Babylonian experimentation of legumes and lemons in biblical times to the 1946 randomized controlled trial of streptomycin for pulmonary tuberculosis—have ultimately led to the development of the modern clinical trials that we see today (Bhatt, 2010). But what exactly are clinical trials? Clinical trials (CTs) are defined as studies and experiments conducted on human subjects in order to test a medical drug, treatment, or device before its release into the healthcare world. The main purpose of these clinical trials is to help create safe and effective products for professionals to use in the medical field. Government agencies such as the Food and Drug Administration (FDA) play a vital role in regulating ethical and safety standards within clinical trials for the most effective results.

Clinical trials generally consist of four phases. Phase I involves initial testing on small groups of people who are relatively healthy in order to find accurate dosages and monitor any side effects with an emphasis on safety. Phases II and III involve larger groups of people who are gathered based on preliminary conditions or diseases to analyze the effectiveness of a drug, compare it with other trials, and monitor short-term side effects. Phase IV, which only begins after the FDA gives approval and may last for several years, tests the products on even larger and more diverse populations to provide information on risks, best use, and long-term effects. These phases allow clinical trials to create transparent and accurate results that are regulated by the government. Once drugs are released upon completion of their clinical trials, drug efficacy is used to analyze how beneficial a certain drug is for the patient population. While clinical trials are becoming increasingly significant in the healthcare field, they have been subject to many regulatory and ethical problems. And despite the various actions and laws created over the years to combat these deficiencies, some controversy still remains.

Photo: Lupus Trials

The lack of reporting on outcomes and the potential presence of publication biases in clinical trials have been prevalent issues for decades. Research by PubMed Central has shown that about 15 to 20 percent of all clinical trials are never published. The group also found that studies with negative outcomes either go completely unpublished or get published in a misleading manner—more often than those with positive results (Zou, et al., 2018). This lack of published negative data, known as publication bias, has led to underreporting and inaccurate trial results that can not only create ineffective drugs, but also cause substantial harm to patients. The FDA Amendments Act (FDAAA) was enacted in 2007 to curb unpublished reporting and ensure that results from clinical trials are more transparent through the implementation of certain restrictions and requirements. However, the FDAAA is still widely ignored today. For example, one section of the law required researchers to report their trial data within a year of finishing; yet, “fewer than half of clinical trial sponsors reported their results” did so within that time frame (Steenhuysen, 2020). A study conducted by Ben Goldacre, a professor from Oxford University, analyzed 4,209 trials from ClinicalTrials.gov and revealed that almost one in three trials had gone unreported since the implementation of the FDAAA. This absence of telling negative data is detrimental since medical professionals, who refer to these biased studies, are at risk of being misinformed about treatments or drugs, ultimately undermining patient safety.

In addition, another major issue with clinical trials lies in patient participation. There have been many instances where drugs approved by the FDA, which claimed that they were completely safe and effective, have gone horribly wrong once real-life patients start buying them off the market. Since some clinical trials are excessively restrictive on who can participate, the sample featured in corresponding reports may be biased toward participants who are healthier than those who will truly benefit from using the drugs. Most clinical trials establish inclusion and exclusion criteria for their research, which essentially means setting certain standards—commonly based on age, gender, race, and/or pre-existing conditions—on who is eligible to participate in a clinical trial. When the criteria are too restrictive of characteristics that are highly common within the general population, such as being overweight or having diabetes, it may cause the pool of participants to be a misrepresentation of actual patients. A study by JAMA Dermatology in 2018 concluded that psoriasis patients, who were restricted from clinically participating in trials for a biological drug, were twice as more likely to undergo serious side effects after using the tested treatment than those who actually participated in those trials. Clinical trials for Cosentyx, another drug for psoriasis that was approved by the FDA in 2015, had excluded people with any sort of kidney, heart, liver, lung, hormonal, infectious, and/or gastrointestinal issues. After its release to the market, Cosentyx unsurprisingly caused “15,000 reports of serious adverse events… including 600 deaths” before it was pulled from public availability (Fauber, 2020). The importance of including diverse, representative populations based on gender, race, and preexisting conditions are evidently clear through these examples. With clinical participants receiving quality medical attention that is often unrepresentative of the real world, the drugs and other products tested in those trials also end up losing their quality.

With its importance in verifying drug efficacy, clinical trials are an indispensable aspect of the medical field. Yet, their few deficiencies can and are greatly affecting the potential these research reports hold for the future of healthcare advancements. It is imperative that scientists create stronger regulations to increase the inclusion of negative data and more diverse participants in clinical trials so that they can provide even more safe and effective products to the world.

Reference(s):

1. Bhatt, A. (2010). Evolution of clinical research: A history before and beyond James Lind. Perspective in Clinical Research, 1(1), 6-10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149409/

2. Fauber, J. (2020). New medications get tested on healthier people. The results don't always work on real-world patients. Milwaukee journal sentinel. Retrieved November 10, 2020, from https://www.jsonline.com/story/news/investigations/2019/08/07/clinical-drug-trials-choose-healthier-people-test-skew-results-prescription-medication-side-effects/1902260001/

3. Steenhuysen, J. (2020). Despite U.S. law, many clinical trial results go unreported. Reuters. Retrieved November 15, 2020, from https://www.reuters.com/article/us-health-research-reporting/despite-u-s-law-many-clinical-trial-results-go-unreported-idUSKBN1ZG2L0

4. National Institute on Aging. (2020). What Are Clinical Trials and Studies? Retrieved November 14, 2020, from https://www.nia.nih.gov/health/what-are-clinical-trials-and-studies

5. Zou, C., Becker, J., Phillips, A., Garritano, J., Krumholz, H., Miller, J., & Ross, J. (2018). Registration, results reporting, and publication bias of clinical trials supporting FDA approval of neuropsychiatric drugs before and after FDAAA: A retrospective cohort study. Trials, 19(1), 581. https://doi.org/10.1186/s13063-018-2957-0

6. Cover Photo: Everyday Health