Article Critique
Summary
The pathogenic effects of sickle cell disease occur primarily due to the polymerization of deoxygenated HbS. Voxelotor is a drug that inhibits HbS polymerization at different dose levels, thus preventing red-cell sickling. The research question revolves around evaluating the safety and efficacy of voxelator in adults and children in the two doses of 900 mg and 1500 mg, in comparison to the placebo. The exposure variable was the voxalotor drug, while the outcome variables included hemoglobin levels, adverse effects, and markers of hemolysis (e.g., reticulocyte count, indirect bilirubin, and serum lactate dehydrogenase levels). An example of covariate variables included preexisting use of hydroxyurea, geographical area, and the age of the participants. The study is a multicenter, randomized, double-blind, placebo-controlled study that was conducted to compare the efficacy and safety of voxelator at two doses (900 mg and 1500 mg). 449 participants were identified as eligible for the study. Out of these, 175 were excluded due to the inability to meet the eligibility criteria (152 participants), withdrawal of consent (8 participants), presence of adverse events (11 participants), and other reasons (4 participants), leaving 274 participants. The 274 participants were later randomized for 900 mg, 1500 mg, and placebo in the ration of 1:1:1. 92, 90, and 90 participants were assigned to the 900 mg, 1500 mg, and placebo group, respectively. Among the various results, one of the most significant findings was that voxelotor led to significantly greater levels of increase in the hemoglobin levels in 51% of the participants receiving 1500mg ( 95% CI, P<0.001). 33% of those receiving 900 mg of voxelotor also showed significant improvements in hemoglobin levels ( 95% CI, P<0.001). The study concluded that voxelotor leads to significant increases in levels of hemoglobin and a significant reduction in markers of hemolysis in sickle cell patients.
Critique
The first critique will be made in the abstract. Vichinsky et al. (2019) present an abstract that is well-organized into sections including the background, methods, results, and the conclusion. These sections give a succinct summary of each stage of the research. The abstract communicates a concise background, thus allowing the reader to identify the objective and the rationale of the study. It further outlines the study design, interventions, description of the participants, interventions, and the dependent variables. The results of the study are also presented simplistically, allowing the reader to identify the most significant results. The abstract finally gives and clear conclusion that helps the reader to put the whole study into perspective.
Next, I will critique the introduction. The researchers give a well-detailed background on the topic under study. Vichinsky et al. (2019) begin the introduction section by succinctly identifying the under, which is sickle cell disease. They move on to present epidemiological data on the impact of the disease on the population. Next, they also present information in the manifestation of the disease and the available forms of treatment. This information is critical in building a strong argument on the need for conducting the study. The introductory information also validates the use of a quantitative approach towards investigating the aim of the study. Vichinsky et al. (2019) utilized a total of 18 sources, out of the total 20 sources utilized in the research article, to validate the information presented in the introduction section. The sources utilized in the introduction section were of high quality, and highly relevant since 14 of them were published within the last 5 years. The remaining sources had been published within the last 10 years (3 sources), while only one source had a publishing date older than 10 years. None of the reference sources were older than 10 years. The oldest source was 25 years old. Moreover, most of these sources were primary sources, thus further enhancing the quality of the sources. The introduction also captured the aim of the study clearly but did not state the hypothesis. Vichinsky et al. (2019) fail to present a theoretical framework. However, the nature of the study justifies the lack of a conceptual map of the research.
The next critique area is the methodology and design of the study. The research utilized a randomized, double-blind, placebo-controlled study design, which was appropriate for the study. This is a prospective study design. Randomized trials are the most effective study designs for determining causal relationships while eliminating biases between groups (McCoy, 2017). This was, therefore, in line with the aim and objective of the study. The use of double-blind research design was beneficial in reducing some of the biases and preventing the researchers from treating the participants differently (David & Khandhar, 2019). It also helped in reducing the placebo effect. The authors also vouched for the completeness and accuracy of the data that was collected. The process of recruiting the participants was not well described. For instance, the researchers do not describe how participants were contacted and the origin of the participants. Although 449 participants were eligible, only 272 participated in the study. However, the researchers gave clear reasons why the other 177 participants could not take part in the study. Moreover, the researchers did not describe the method of sampling that was employed to obtain the participants. The sample size (272 participants) was not sufficiently large enough to ensure safe generalization and replication of the results in sickle cell patients.
Also, the researchers fail to describe the different biases that can affect the sampling process. Despite using clinical assessments and observations as the main method of data collection, Vichinsky et al. (2019) fail to give a rationale for adopting these methods. However, the data collection methods are congruent with the research question. These data collection instruments are also suitable for the research sample. The research does not provide information as to whether these data collection methods yielded data that had high validity and reliability. This information would be critical in determining and facilitating the replication of the study by other researchers (Leung, 2015).
The researchers adhered to all ethical considerations such as consent, respect of persons, and justice, which protect the rights of the researchers (Das & Sil, 2017). For instance, informed consent was obtained from the parents or from the participants who were less than 18 years old and from adults (above 18 years). Participants also had the freedom to drop out at any time. A contract research organization, the IQVA, was conducting oversight over the research study, thus subjecting the study to external reviews. Periodic assessments were also conducted by an independent safety and data monitoring board, further increasing external review. The design of the study also aims at maximizing benefits while minimizing all effects. Moreover, the study does not provide any evidence that the participants can be identified. The intervention (administration of the drug, voxalotor) was also well described by the researchers and later applied accordingly.
The next area that will be critiqued was the result section. First, the research question and the design of the research fit into the analytical methods of the study. For instance, the researchers used a primary efficacy analysis, which was appropriate to analyze the primary outcomes of the study. The analysis of variables was also conducted using the intention-to-treat method, which helped in yielding significant results. This analytical method allowed the researchers to draw unbiased and accurate conclusions on the effectiveness of drug intervention (McCoy, 2017). The findings of the analysis were presented through easy explanations, which are easy to understand and interpret. This representation is also clear and accurate. The researchers also utilize simple and clear graphical displays (e.g., line graphs) and tabulations that capture all the necessary data while providing the reader with effective visual representations and data summaries. These tabulations and graphical displays are also accurate. The researcher also explains how the type I errors were controlled and minimized (approximately 5%). However, Vichinsky et al. (2019) do not explain the control of type II errors. Moreover, the findings are presented in a detailed fashion, which provided adequate data for synthesis and evidence-based practice (Noyes et al., 2019).
The next sections that will be critiqued are the discussion, limitations, and the conclusion section. First, Vichinsky et al. (2019) developed a comprehensive discussion that captures all the outcomes of the study. The discussion is also in line with the context, the research question and the objectives of the study. The researchers also make interpretations that are consistent with the findings of the study. However, the researchers fail to give the clinical implication of the research findings in clinical practice. This omission implies that the research lacks sufficient strength and support for clinical application. Moreover, the paper does not address how the results of the study can be generalized to sickle cell disease patients and the general population. This reduces the value of the study and shows that the study lacks external validity (Lesko et al., 2017). The researchers also fail to give the limitations and the assumptions of the study, thus limiting the replication of the study. This causes the reader to infer the assumption from reading the article. Vichinsky et al. (2019) also fail to make recommendations for future studies. Finally, the conclusion is short and does not capture all the important aspects of the research.
Reference
Das, N. K., & Sil, A. (2017). Evolution of ethics in clinical research and ethics committee. Indian Journal of Dermatology, 62(4), 373–379. https://doi.org/10.4103/ijd.IJD_271_17
Lesko, C. R., Buchanan, A. L., Westreich, D., Edwards, J. K., Hudgens, M. G., & Cole, S. R. (2017). Generalizing study results: A potential outcomes perspective. Epidemiology (Cambridge, Mass.), 28(4), 553–561. https://doi.org/10.1097/EDE.0000000000000664
Leung L. (2015). Validity, reliability, and generalizability in qualitative research. Journal of Family Medicine and Primary Care, 4(3), 324–327. https://doi.org/10.4103/2249-4863.161306
McCoy C. E. (2017). Understanding the intention-to-treat principle in randomized Controlled trials. The Western Journal of Emergency Medicine, 18(6), 1075–1078. https://doi.org/10.5811/westjem.2017.8.35985
Noyes, J., Booth, A., Moore, G., Flemming, K., Tunçalp, Ö., & Shakibazadeh, E. (2019). Synthesising quantitative and qualitative evidence to inform guidelines on complex interventions: clarifying the purposes, designs and outlining some methods. BMJ Global Health, 4(Suppl 1), e000893. http://dx.doi.org/10.1136/bmjgh-2018-000893
Vichinsky, E., Hoppe, C. C., Ataga, K. I., Ware, R. E., Nduba, V., El-Beshlawy, A., … & Diuguid, D. L. (2019). A phase 3 randomized trial of voxelotor in sickle cell disease. New England Journal of Medicine, 381(6), 509-519. http://dx.doi.org/10.1056/NEJMoa1903212