Are Clinical Trials in Oncology Biased?

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Varshit Dusad

Randomized controlled clinical trials (RCTs) are an important part of medical studies. Properly supervised trials act as the source of evidence for the safety and efficacy of new drugs, therapies, and medical devices. Hence, it is imperative that clinical trials are designed, conducted, and analysed in a robust and ethical fashion to ensure that they represent the true global burden of cancer without any systematic biases towards or against specific geographic, genetic, gender, or economic populations.

Conducting clinical trials is a costly and challenging affair that requires proper infrastructure, trained researchers, and strong collaboration between industry, medical centers, government, and regulatory bodies. Clinical trial studies sometimes can take years to complete depending on the nature of therapy and expected outcomes. Given that most trials are sponsored by industry (Well et al, 2021 noted that 70% of RCTs were funded by industry) whose major goal is to maximize profits, it can skew the goals away from a wholesome fight against cancer. For example, in recent years, Well et al, 2021 noted that only one-third of trials are focused on treatment endpoints that provide substantial clinical benefits such as increased overall survival, in comparison to two-thirds focused on marginal improvements such as progression free survival, disease free survival or events free survival. This is because such trials would be easier to conduct and will be able to meet expected outcomes easily and quickly.

Cancer treatment cost is rising globally, more so in the developed world as compared to low-income countries. Hence, it is important that patients are able to extract maximum enhancement to their quality of life and not just a mere extension of survival by a few months. 

In an ideal world, the distribution of oncology trials would be proportionate to the population subgroups as well as the incidence of the type of cancer. However, this is not the case in practice. For example, gastroesophageal, liver, pancreas, and cervical cancers are substantially under-represented in Randomly controlled Trials. Moreover, a large percentage of RCTs are funded by pharmaceutical industries in High-Income countries and are focused on systemic therapies in palliative settings. Also, as mentioned before, the putative surrogate endpoints are pervasively used in RCTs instead of actual endpoints that correspond with real clinical benefits to the patient. 

There is also a division in clinical trial studies between High-Income Countries (HICs) and Low-Middle Income Countries (LMIC). RCTs from LMICs were fewer and smaller, associated with positive results having a larger magnitude of benefit compared to HICs. There is also substantial publication bias in results arising from trials in LMICs vs HICs. RCTs from LMIC on average tend to be published in journals with much lower impact factors compared with trials originating in HICs. This bias can perpetuate the feeling that advanced oncology studies can be performed only in HICs and thus create a negative feedback loop of decreased funding in LMICs making high-quality oncology studies even more difficult.

Cancer is a global disease and 64% of global deaths occur in LMICs. In spite of this high burden, only 5% of global resources are allocated for LMICs. While profit-driven pharma companies have their place, the philanthropic and governmental organizations need to allocate more of their funding to realign the priorities of global healthcare from generating profit to improving public health. A positive example of the government stepping up to help alleviate the burden of cancer in LMIC is National Cancer Grid of India which maintains a tight network of 252 cancer centers across the country to establish a uniform standard of cancer care across the country.

For a sustainable fight against cancer, there has to be a truly united front against cancer. While it may be impossible to completely normalize the status of oncology studies and subsequent health care globally, it is worth investing in to minimize this gap. Each of the stakeholders – pharma companies, philanthropic organizations, public, publication venues and the government should play their part to democratize the healthcare burden of cancer.

Edited by Prathyusha Konda

Works Discussed

Wells JC, Sharma S, Del Paggio JC, et al. An Analysis of Contemporary Oncology Randomized Clinical Trials From Low/Middle-Income vs High-Income Countries. JAMA Oncol. 2021;7(3):379–385. doi:10.1001/jamaoncol.2020.7478

Hirsch BR, Califf RM, Cheng SK, et al. Characteristics of oncology clinical trials: insights from a systematic analysis of ClinicalTrials.gov [published correction appears in JAMA Intern Med. 2013 Sep 9;173(16):1560]. JAMA Intern Med. 2013;173(11):972-979. doi:10.1001/jamainternmed.2013.627