Critique is an analytical process that aims to identify strengths and weaknesses of a study in an objective manner. Given that a study comprises abstract, hypothesis, aims, questions, sampling, methodology, data analysis, discussion, and conclusion, an objective analysis of each section offers coherency and flow of the paper. A central argument of an article should have its basis on facts obtained through the process of research and inference (Tappen, 2011). In this case, this paper critiques Efficacy of Quadrivalent HPV Vaccine against HPV Infection, a clinical study by Giuliano et al. (2011).
Abstract
The abstract comprehensively summarizes this study for it provides background information, methodology, results, and conclusion. In the background information, the article states that human papillomavirus (HPV) is common among men and boys, and the quadrivalent vaccine is not only effective but also safe in preventing anogenital infection and external genital lesions. In the section of methodology, the article shows that the study employed a randomized controlled double-blind study, by examining the efficacy of a quadrivalent immunogen against related HPV subtypes prevalent in male subjects.
The study sample comprised a representative sample of 4065 male subjects aged between 16-26 years. Its primary aim was to determine the efficacy of the vaccine in treating genital ulcerations resulting from persistent infection by HPV-6, 11, 16, or 18. The study’s results indicate that, in the ITT group, the placebo arm had 89 genital warts, while the vaccine arm had 36 such ulcerations, representing a 60.2% vaccination efficacy (Guiliano et al., 2011). In contrast, the pre-protocol group had 90.4% vaccine efficacy against all the HPV subtypes. Based on these findings, the researchers conclude that the quadrivalent HPV vaccine is effective against the four HPV subtypes that cause surface genital lesions in males. Therefore, by reading the abstract, I was able to determine the relevance and the scope of the study.
Hypothesis/Aims/Objectives
Although the researchers did not state the hypothesis clearly, the inferred hypothesis is that the tetravalent vaccine is effective in preventing infection of HPV-6, 11, 16, and 18 and the occurrence of external genital lesions and anogenital warts among men and boys. The study had three objectives, namely, the primary efficacy, the secondary efficacy, and composite efficacy objectives, which link to hypothesis and research design. The primary efficacy objective of the study was to demonstrate that vaccination with the tetravalent vaccine lowers the relative incidence of surface ulcerations in the anogenital regions due to related HPV subtypes.
This objective sought to evaluate the vaccine’s potency against HPV in males through a between-treatment comparison. Its efficacy would depend on the observed ulcerations detected over time in the vaccinated group versus the placebo group. Therefore, to achieve this objective, the researchers compared the lesions counted during anogenital examinations between the vaccine group and the placebo group in a blinded fashion. HPV DNA isolated from the lesions was used to distinguish the pre-protocol group from the ITT group.
The study’s secondary efficacy objective was to demonstrate that the tetravalent vaccine prevented chronic infection from the HPV subtypes relative to the placebo. Persistent infection represented the recurrent surface anogenital lesions counted at a six-month interval in a span of 36 months. The composite efficacy objective was to evaluate the combined efficacy of the immunogen against surface ulcerations associated with 14 assayed HPV types and the unidentified HPV subtypes. DNA detection through polymerase chain reaction was used to classify the HPV subtypes associated with the lesions. Hence, the hypothesis and objectives are relevant to the study because they have a concrete relationship.
Sample Size and Type
The study involved a sample of 4065 male subjects drawn from the 16-26 years age bracket. An initial sample of 4164 males was screened, but only 4065 qualified. The subjects were recruited from 71 places in 18 nations. The large sample size used in the study adequately represents the male population. Tappen (2011) argues that a large sample size has a high external validity because it sufficiently represents a study population. Moreover, the study used a stratified random sampling strategy to draw the subjects from the different locations for a double-blind study. In this method, a random sample was drawn from each population subset across 18 countries, which helped reduce selection bias. In stratified sampling, the target population (males aged between 16 and 26 years) is divided into subsets based on certain attributes or frame (region). A random sampling technique is then applied to the population subset to draw the desired number of subjects. This principle ensures that all eligible subjects have an equal chance of being picked, resulting in a more representative sample.
The sample size depends on various statistical considerations. Creswell (2009) observes that factors such as the desired level of precision, confidence level, and variability in the population determine the appropriate sample size. This study’s sample (n=4065) achieved a high level of precision because of the high confidence level used (95%). In addition, the degree of variability in multisite anogenital warts caused by the known HPV subtypes is low. Therefore, the sample was adequate to achieve a high level of precision, whereby the sample mean does not differ greatly from the population mean (μ). A small difference between the two values means the standard error is low.
The characteristics of the sample included heterosexual and homosexual subjects. Out of 4065 subjects, 3463 were heterosexual while 602 were homosexuals. The homosexual subjects had engaged in anal intercourse with other males over the past 12 months. The inclusion criteria for the heterosexual subjects included individuals aged between 16 and 23 and engaged in heterosexual relations with at least one partner. The sample was representative in terms of age, ethnicity, region, smoking status, and sexuality. On the other hand, all the homosexual subjects were aged between 16 and 26. They also indicated engaging in intercourse with at least one male/female partner. The subjects had no anogenital surface lesions related to other STIs. The inclusion criteria allowed the researchers to eliminate the effect of confounds such as herpes simplex that are known to cause genital warts.
Design of the Study/Study Level
The study used a “randomized, placebo-controlled double-blind trial” as the design (Guiliano et al., 2011, p. 402). The subject’s baseline HPV status was obtained for the pre-protocol group. This population comprised of consenting seronegative and PCR-negative people at baseline. Subsequently, they were randomly assigned to the vaccine group and the placebo group. The vaccine group had 2032 participants while placebo group had 2033 participants who received a 0.5ml of vaccine and placebo respectively in the musculus deltoideus of the arm. All subsequent injections were also administered in this muscle. The vaccine was a subunit immunogen with four HPV particles, namely, ‘HPV-6, 11, 16, and 18’, combined with the AAHS adjuvant (Guiliano et al., 2011, p. 403). In total, 4055 people were administered with at least one injection of either the quadrivalent HPV vaccine or a placebo. In this population, the pre-protocol group were 2805 who either received the vaccinations (n = 1397) or placebo (n = 1408).
The TTI population (n = 1250) comprised subjects injected with at least one dose of the HPV vaccine. This population consisted of males not immunized against any HPV subtype. Therefore, this group could have been seropositive at baseline or non-infected. The doses were injected to the subjects within a year and follow-ups made after the first day to determine the efficacy of the HPV vaccine based on the incidence of anogenital warts. In the TTI group, 175 did not complete the three doses after the first day. In contrast, all the pre-protocol subjects took the three doses within the 12-month period. Efficacy analysis commenced in the seventh month. This RCT provides a level I type of evidence. Thus, it enriches literature by providing substantial evidence that the quadrivalent HPV vaccine provides a cross-protection against HPV subtypes in males.
Data Collection Instruments
The data collection instruments that the study used are surveys, medical records, clinical observation, and specimen collection. Surveys and medical records provided information that the study used in determining the eligibility criteria of each participant and classified them according to different groups, namely, the placebo group, the vaccine group, heterosexual subgroup, homosexual subgroup, intention-to-treat subgroup, and per-protocol subgroup. Clinical observation allowed researchers to assess if a participant had genital lesions or anogenital warts associated with HPV infections or not.
In specimen collection, researchers obtained biopsies and pathologists analyzed to confirm presence or absence of HPV genetic material. The independent variable of the study was the treatments given to different groups, namely, vaccine and placebo. The level of measurement of the independent variable was categorical. The dependent variable of the study was the absence or the presence of genital lesions associated with HPV infections. The level of measurement of the dependent variable was categorical for the outcomes were either the presence or the absence of genital lesions. Thus, both the dependent and independent variables existed on a categorical scale appropriate for primary efficacy analysis and two-sided exact confidence interval test.
Procedure
To commence the study, which took place between 3 September 2004 and 29 August 2008, healthy male participants comprising 4065 boys and men aged between 16 and 26 were selected from 71 locations in various countries across the world. The first inclusion criteria were the ages of the participants as the heterosexual participants had ages between 16 and 23 while that of the homosexuals had ages between 16 and 26. The second inclusion criteria were that the participants should not have clinically detectable genital lesions associated with HPV. Out of 4065 participants who had met the inclusion criteria, 2033 and 2032 participants were randomly assigned to placebo group and vaccine group respectively (Giuliano et al., 2011). The random assignment of participants ensures that the vaccine and placebo groups reflect the diversity of participants in terms of race, age, location, smoking status, sexual history, and circumcision status.
The randomized participants then received one or three doses of placebo or vaccine, according to their respective groups in a blinded version. Further examination of the participants led to the selection of per-protocol population, which constitutes the participants who had no HPV during the enrollment. Out of 4065 participants, 2805 participants met the per-protocol criteria and received three doses of placebo or vaccine. Among per-population, 1408 participants received the placebo while 1397 participants received quadrivalent HPV at first day, second month, and sixth month (Giuliano et al., 2011). Subsequently, the discontinuing criteria were the same for both the vaccine group and the placebo group. The participants were then assessed for anogenital lesions on the first day and subsequently after every six months to 36 months. Clinical observation of genital lesions and detection of biopsies and swabs using multiplex polymerase chain reaction assay were used to confirm the presence of HPV lesions (Giuliano et al., 2011). The assessment of the participants by the pathologist was done in a blinded approach.
The assessment of the procedure shows that the study was done in a systematic process with coherent flow from the selection of participants to data collection. As the study commenced with the selection of participants based on inclusion and exclusion criteria, this procedure ensured that the participants had the required demographic variables and clinical conditions. The demographic variables of the participants comprised age, race, circumcision status, heterosexual, homosexual, location, and smoking status, which reflect the target population.
Since the participants had different clinical conditions, the study further selected per-protocol population, who had no HPV at the beginning of the study, to ensure that the study population had similar clinical conditions. The role of the per-protocol population was to ensure that there are no significant confounders, which would influence clinical outcomes of patients during the assessment (Shah, 2011). Therefore, the findings of the study have high internal validity because the procedure of selecting the participants eliminated possible confounders, which would have masked or magnify clinical outcomes.
Critical examination of the procedure shows that the study employed important procedures of clinical research, namely, randomization and blinding (Kent, 2012). In the selection of participants in the placebo group and the vaccine group, the study used randomization. The process of randomization ensured that the participants in each group reflect the diversity of participants in terms of age, race, circumcision status, heterosexual, homosexual, location, and smoking status. The diversity of participants is not only important in comparison of the groups but also in representation of the target population (Shah, 2011). Also, the double-blinding procedure employed was essential to account for placebo effects among the participants. Kent (2012) states that double-blinding procedure eliminated biases associated with clinical assessment and diagnosis.
Statistical Analysis
The study used primary efficacy analysis, which is a Bayesian method of assessing the differences in the incident rates of diseases over time, in determining the efficacy of HPV vaccine in the prevention of HPV infections among male participants. According to Giuliano et al. (2011), the primary efficacy was determined by dividing the incident rates of HPV in the vaccine group and the placebo group with the cumulative person-years in respective groups. Fisher’s exact test was used to compare the incident rates of HPV between the placebo group and the vaccine group (Giuliano et al., 2011). Thus, the article provides comprehensive and specific methods of statistical analyses, which gave robust outcomes.
The rationale for using the primary efficacy analysis is that the study focused on the primary endpoint of HPV genital lesions among the participants. Cheema and Burkes (2013) explain that primary endpoint is an appropriate parameter of survival analysis for maps the occurrence of signs, symptoms, disease, or death following a given intervention. The assessment of the participants over a period of 36 months is a short duration that is appropriate for primary endpoint analysis. Usually, secondary endpoint analysis examines post hoc clinical outcomes, which normal take long periods to occur.
Furthermore, as the study was randomized and powered, primary efficacy analysis was an appropriate test, which provides valid and reliable findings. In hypothesis testing, a two-sided exact confidence interval was used because the distribution of data points in both the placebo groups and the vaccine group followed the binomial distribution (Giuliano et al., 2011). In this view, ample evidence shows that the primary efficacy analysis was the appropriate test that the study used in the analysis of data obtained.
The study had some assumptions, which formed the basis of data analysis. One assumption, Giuliano et al. (2011) assume that the vaccine has 80% efficacy with a 0.025 one-sided alpha level, which means that 32 cases would have more than 20% efficacy and 23 cases would have more than 0% efficacy. Another assumption is that the distribution of endpoint cases in the vaccine group went after the binomial distribution. Thus, these assumptions ensured that the data analysis obtained valid and reliable outcomes, which meet the required criteria.
In data analysis, the study noted that it used one-sided alpha level of 0.025. This alpha level gives power to data analysis for it set limits within which data analysis occurs. Besides, the alpha level made sure that the hypothesis testing for endpoints occurred within the one-sided alpha level. The data analysis generated four statistical tables, which depicts the findings. The first table illustrates the distribution of HPV, types of genital lesions, and sexual orientation among intention-to-treat participants in the placebo group and the vaccine group. The second table depicts the distribution of HPV, types of genital lesions, and sexual orientation among per-protocol participants in the placebo group and the vaccine group. The third table shows the efficacy of HPV vaccine assessed using persistent infection and DNA detection methods. The fifth table summarizes the adverse events associated with the use of HPV vaccine. Fundamentally, these tables present outcomes of data analysis in summary and organized manner.
Conclusion
In concluding, the study reiterated the efficacy of quadrivalent HPV vaccine in preventing the infections of HPV -6, 11, 16, and 18 among males aged between 16 and 26 years. By identifying strengths and weaknesses, the conclusion effectively rates the validity of the findings. As the findings are valid, the conclusion suggests that vaccination of boys and men with quadrivalent HPV vaccine is essential to prevent the occurrence of genital lesions. Therefore, the conclusion provides meaningful information required in the understanding of the study and its application in line with hypothesis and objectives.
Quality of the Study
The study uses a rigorous design and sampling strategy. The randomization and double blinding used to assign the subjects to the vaccine and placebo groups for both the TTI and pre-protocol populations eliminated researcher bias. In addition, the study sample was drawn from multiple locations (71). Thus, efforts were made to draw a representative sample for enhanced external validity of the findings. The study fits into an RCT design, which gives level I evidence (Laurel, 2003). RCTs utilize randomization of the subjects to minimize bias during data collection and analysis. Overall, the study’s findings that the quadrivalent HPV vaccine is effective against several HPV subtypes are more reliable than those obtained from quasi-experiments.
References
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Giuliano, A., Palefsky, J., Goldstone, S., Moreira, E., Penny, M., Aranda, C., Vardas, E.,…Guris, D. (2011). Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. The England Journal of Medicine, 364(5), 401-411.
Kent, W. (2012). Randomization and blinding in clinical trials. Webmed Central Clinical Trials, 3(5), 1-8.
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