When drugs or vaccines are being trialed for their effectiveness, there are typically several stages. Double-blind trials are seen as the most reliable type of study because they involve neither the participant nor the doctor knowing who has received what treatment. The aim of this is to minimize the placebo effect and minimize bias.
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How they work
In double-blind trials, the treatment patients have is unknown to both patients and doctors until after the study is concluded. This differs from other types of trials, such as simple blind trials where only the patients are unaware of the treatment they are receiving, whereas the doctors know.
Double-blind trials are a form of randomized trials and can be ‘upgraded’ to triple-blind trials, in which the statisticians or data clean-up personnel are also blind to treatments.
To be effective, it is generally recommended that double-blind trials include around 100-300 people. If treatments are highly effective, smaller numbers can be used but if only 30 or so patients are enrolled the study is unlikely to be beneficial.
The assignment of patients into treatments is typically done by computers, where the computer assigns each patient a code number and treatment group. The doctor and patients only know the code number to avoid bias, hence allowing the study to be double-blind.
Double-blind trials can come in different varieties. Double-blind, placebo-controlled studies involve no one knowing the treatment assignments to remove the chance of placebo effects. In a double-blind comparative trial, a new treatment is often compared to the standard drug. This allows researchers to compare an established drug to a new one to establish which one is more advantageous.
However, unlike double-blind, placebo-controlled trials, they are not very good at statistically evaluating if a treatment is effective overall.
Benefits of double-blind trials
Double-blind trials remove any power of suggestion, as no one involved knows the treatment patients receive. This means that doctors carrying out the study do not know and cannot accidentally tip off participants. Similarly, the doctors not being aware of the treatments means they do not unconsciously bias their interpretation of the study results.
The main principle behind double-blind and randomized trials, as opposed to simple blind trials, is to avoid bias in the treatment or experimental set-up. For example, if researchers are aware of the different treatment groups are getting, they may avoid assigning more unwell patients to the treatment group. Therefore, any effect seen by the treatment may have been related to how unwell a patient was to start with, rather than the efficacy of the drug.
Explaining Randomization in Clinical Trials
COVID-19 and double-blind trials
Double-blind trials are usually needed for drugs and treatments to get approval to be used in many countries. However, good, comprehensive double-blind trials take time and require many participants. This has been especially problematic during the COVID-19 pandemic, as the world has searched for pharmaceutical treatment options to improve survival and for vaccines to prevent the spread of this virus.
In terms of treatment, many drugs have been tested in double-blind trials. The antiviral nucleoside analog remdesivir has been tested in several double-blind trials and was the first drug to gain full FDA approval for use against COVID-19 in October 2020.
However, the results of trials have been conflicting, and some experts remained unconvinced of its benefits. In November 2020, the World Health Organization recommended against the use of the drug for COVID-19 and a global randomized trial came to the conclusion in February 2021 that remdesivir has little to no effect when used on hospitalized COVID-19 patients. The drug is still used in the US.
Multiple candidates for a COVID-19 vaccine have been identified and moved on to phase II and phase III trials, which often involve double-blind methods. These need to be conducted over meaningful timeframes to ensure any initial differences between the control and the treatment groups last in the long term.
Several different vaccines are now available (March 2021) due to mixed approval and emergency approval by governments and organizations. This has been an exceptional time for vaccine trials as the typical course of development has been sped up. What would usually take years has taken months.
Many countries have given limited or early approval to vaccines for emergency use before detailed phase III data has been publicized, based on preliminary evidence of effectivity and safety. This comes with some risks.
Another topic of discussion that has come about as a result of COVID-19 is the ethics of keeping patients blind during the trial as vaccine effectivity is supported. Whilst keeping the blind aspect is essential to achieving valuable and reliable information about long-term effects, there is an argument that blind participants who have received a placebo should be able to receive a vaccine as more become available.
References
- Cancer Research UK. 2019. Randomized Trials. [online] Available at: <https://www.cancerresearchuk.org/find-a-clinical-trial/what-clinical-trials-are/randomised-trials> [Accessed 25 July 2020].
- European Centre for Disease Prevention and Control. 2020. Vaccines And Treatment Of COVID-19. [online] Available at: <https://www.ecdc.europa.eu/en/covid-19/latest-evidence/vaccines-and-treatment> [Accessed 25 July 2020].
- Misra, S., 2012. Randomized double-blind placebo control studies, the "Gold Standard" in intervention-based studies. Indian Journal of Sexually Transmitted Diseases and AIDS, 33(2), pp. 131.
- The New York Times. 2021. Coronavirus Drug and Treatment Tracker [online] Available at https://www.nytimes.com/interactive/2020/science/coronavirus-drugs-treatments.html [Accessed 11 March 2020]
- The New York Times. 2021. Coronavirus Vaccine Tracker [online] Available at https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html [Accessed 11 March 2020]
- Wang, Y., Zhang, D., Du, G., Du, R., Zhao, J., Jin, Y., Fu, S., Gao, L., Cheng, Z., Lu, Q., Hu, Y., Luo, G., Wang, K., Lu, Y., Li, H., Wang, S., Ruan, S., Yang, C., Mei, C., Wang, Y., Ding, D., Wu, F., Tang, X., Ye, X., Ye, Y., Liu, B., Yang, J., Yin, W., Wang, A., Fan, G., Zhou, F., Liu, Z., Gu, X., Xu, J., Shang, L., Zhang, Y., Cao, L., Guo, T., Wan, Y., Qin, H., Jiang, Y., Jaki, T., Hayden, F., Horby, P., Cao, B. and Wang, C., 2020. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial. The Lancet, 395(10236), pp. 1569-1578.
- Winchesterhospital.org. 2020. Double-Blind Study. [online] Available at: <https://www.winchesterhospital.org/health-library/article?id=21861> [Accessed 25 July 2020].
- WHO Ad Hoc Expert Group on the Next Steps for COVID-19 Evaluation. 2021. Placebo-Controlled Trials of Covid-19 Vaccines — Why We Still Need Them. N Engl J Med, 384:e2.