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Implications of the licensure of a partially efficacious malaria vaccine on evaluating second-generation vaccines.

Fowkes FJ, Simpson JA, Beeson JG - BMC Med (2013)

Bottom Line: The Malaria Vaccine Technology Roadmap's goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%'.To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%).However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future.

View Article: PubMed Central - HTML - PubMed

Affiliation: Macfarlane Burnet Institute of Medical Research, 85 Commercial Road, Melbourne, Victoria 3004, Australia. fowkes@burnet.edu.au.

ABSTRACT

Background: Malaria is a leading cause of morbidity and mortality, with approximately 225 million clinical episodes and >1.2 million deaths annually attributed to malaria. Development of a highly efficacious malaria vaccine will offer unparalleled possibilities for disease prevention and remains a key priority for long-term malaria control and elimination.

Discussion: The Malaria Vaccine Technology Roadmap's goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%'. To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%). However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future. In this opinion piece we discuss the methodological, logistical and ethical issues that may impact on the feasibility and implementation of superiority, non-inferiority and equivalence trials to assess second generation malaria vaccines in the advent of the licensure of a partially efficacious malaria vaccine.

Conclusions: Selecting which new malaria vaccines go forward, and defining appropriate methodology for assessment in logistically challenging clinical trials, is crucial. It is imperative that the scientific community considers all the issues and starts planning how second-generation malaria vaccines will advance in the advent of licensure of a partially effective vaccine.

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Sample size estimates for superiority, non-inferiority and equivalence trials of second-generation malaria vaccines, according to different incidence risk of malaria in the first-generation vaccine group. The figures show the estimated sample size required to detect a range of differences in the efficacy (margin %) between a second and first-generation malaria vaccine. The margin represents the absolute difference in the efficacy between the two vaccines for active-controlled trials; the relative difference for each value of absolute risk difference will therefore be greater for areas with a lower transmission (for example, absolute risk difference of 10% units equates to a relative risk of 0.67 and 0.80 when the baseline risk is 30% and 50%, respectively). The different incidence risks of malaria (proportion of individuals with malaria outcome during follow-up) in the first-generation vaccine groups corresponds to the approximate baseline risk observed in RTS,S phase II and III trials (that is, 30% and 50%) [4,5]. Sample sizes are calculated with 90% power at the 5% significance level by the authors using STATA (StataCorp; College Station, TX, USA). Note, as the incidence risk approaches 0.5, the standard error gets marginally larger; this explains why the sample size for the same absolute risk difference is bigger for a baseline risk of 50% compared with 30% (for example, total sample size required for a superiority trial with risk difference of 10% units is 778 and 1,030 for a baseline risk of 30% and 50%, respectively).
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Figure 2: Sample size estimates for superiority, non-inferiority and equivalence trials of second-generation malaria vaccines, according to different incidence risk of malaria in the first-generation vaccine group. The figures show the estimated sample size required to detect a range of differences in the efficacy (margin %) between a second and first-generation malaria vaccine. The margin represents the absolute difference in the efficacy between the two vaccines for active-controlled trials; the relative difference for each value of absolute risk difference will therefore be greater for areas with a lower transmission (for example, absolute risk difference of 10% units equates to a relative risk of 0.67 and 0.80 when the baseline risk is 30% and 50%, respectively). The different incidence risks of malaria (proportion of individuals with malaria outcome during follow-up) in the first-generation vaccine groups corresponds to the approximate baseline risk observed in RTS,S phase II and III trials (that is, 30% and 50%) [4,5]. Sample sizes are calculated with 90% power at the 5% significance level by the authors using STATA (StataCorp; College Station, TX, USA). Note, as the incidence risk approaches 0.5, the standard error gets marginally larger; this explains why the sample size for the same absolute risk difference is bigger for a baseline risk of 50% compared with 30% (for example, total sample size required for a superiority trial with risk difference of 10% units is 778 and 1,030 for a baseline risk of 30% and 50%, respectively).

Mentions: Sample size requirements of superiority, non-inferiority and equivalence trials will vary according to the assumed true difference between the second and first-generation malaria vaccine, the maximally tolerated difference required to reach a conclusion of superiority/non-inferiority/equivalence (Δ) and incidence of the malaria outcome [24]. Taking RTS,S as an example, and assuming a modest true VE of 30% or 50% [4,5], Figure 2 shows the range of sample sizes for differences in incidence risk of malaria between a new malaria vaccine and first-generation vaccine (for example, RTS,S) for superiority, non-inferiority and equivalence trials. The margin represents the absolute difference between the two vaccines; for non-inferiority and equivalence trials it is common practice to state a priori an 'absolute risk difference margin’ and base resulting sample size calculations on this absolute difference [25]. The figure shows that as the maximum acceptable clinical difference decreases the required sample size to determine superiority/non-inferiority/equivalence increases (Figure 2). The level of malaria transmission in a population has an impact on sample size, but counter intuitively, sample sizes will increase for a given absolute margin (Δ) when incidence risk of malaria (transmission) approaches 50% in active controlled trials (Figure 2). For example, a 5% margin and a baseline risk of 30% or 50%, gives sample size estimates for superiority trials of 3,678 and 4,182, for non-inferiority trials 2,878 and 3,426, and for equivalence trials 4,368 and 5,198, respectively.


Implications of the licensure of a partially efficacious malaria vaccine on evaluating second-generation vaccines.

Fowkes FJ, Simpson JA, Beeson JG - BMC Med (2013)

Sample size estimates for superiority, non-inferiority and equivalence trials of second-generation malaria vaccines, according to different incidence risk of malaria in the first-generation vaccine group. The figures show the estimated sample size required to detect a range of differences in the efficacy (margin %) between a second and first-generation malaria vaccine. The margin represents the absolute difference in the efficacy between the two vaccines for active-controlled trials; the relative difference for each value of absolute risk difference will therefore be greater for areas with a lower transmission (for example, absolute risk difference of 10% units equates to a relative risk of 0.67 and 0.80 when the baseline risk is 30% and 50%, respectively). The different incidence risks of malaria (proportion of individuals with malaria outcome during follow-up) in the first-generation vaccine groups corresponds to the approximate baseline risk observed in RTS,S phase II and III trials (that is, 30% and 50%) [4,5]. Sample sizes are calculated with 90% power at the 5% significance level by the authors using STATA (StataCorp; College Station, TX, USA). Note, as the incidence risk approaches 0.5, the standard error gets marginally larger; this explains why the sample size for the same absolute risk difference is bigger for a baseline risk of 50% compared with 30% (for example, total sample size required for a superiority trial with risk difference of 10% units is 778 and 1,030 for a baseline risk of 30% and 50%, respectively).
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Related In: Results  -  Collection

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Show All Figures
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Figure 2: Sample size estimates for superiority, non-inferiority and equivalence trials of second-generation malaria vaccines, according to different incidence risk of malaria in the first-generation vaccine group. The figures show the estimated sample size required to detect a range of differences in the efficacy (margin %) between a second and first-generation malaria vaccine. The margin represents the absolute difference in the efficacy between the two vaccines for active-controlled trials; the relative difference for each value of absolute risk difference will therefore be greater for areas with a lower transmission (for example, absolute risk difference of 10% units equates to a relative risk of 0.67 and 0.80 when the baseline risk is 30% and 50%, respectively). The different incidence risks of malaria (proportion of individuals with malaria outcome during follow-up) in the first-generation vaccine groups corresponds to the approximate baseline risk observed in RTS,S phase II and III trials (that is, 30% and 50%) [4,5]. Sample sizes are calculated with 90% power at the 5% significance level by the authors using STATA (StataCorp; College Station, TX, USA). Note, as the incidence risk approaches 0.5, the standard error gets marginally larger; this explains why the sample size for the same absolute risk difference is bigger for a baseline risk of 50% compared with 30% (for example, total sample size required for a superiority trial with risk difference of 10% units is 778 and 1,030 for a baseline risk of 30% and 50%, respectively).
Mentions: Sample size requirements of superiority, non-inferiority and equivalence trials will vary according to the assumed true difference between the second and first-generation malaria vaccine, the maximally tolerated difference required to reach a conclusion of superiority/non-inferiority/equivalence (Δ) and incidence of the malaria outcome [24]. Taking RTS,S as an example, and assuming a modest true VE of 30% or 50% [4,5], Figure 2 shows the range of sample sizes for differences in incidence risk of malaria between a new malaria vaccine and first-generation vaccine (for example, RTS,S) for superiority, non-inferiority and equivalence trials. The margin represents the absolute difference between the two vaccines; for non-inferiority and equivalence trials it is common practice to state a priori an 'absolute risk difference margin’ and base resulting sample size calculations on this absolute difference [25]. The figure shows that as the maximum acceptable clinical difference decreases the required sample size to determine superiority/non-inferiority/equivalence increases (Figure 2). The level of malaria transmission in a population has an impact on sample size, but counter intuitively, sample sizes will increase for a given absolute margin (Δ) when incidence risk of malaria (transmission) approaches 50% in active controlled trials (Figure 2). For example, a 5% margin and a baseline risk of 30% or 50%, gives sample size estimates for superiority trials of 3,678 and 4,182, for non-inferiority trials 2,878 and 3,426, and for equivalence trials 4,368 and 5,198, respectively.

Bottom Line: The Malaria Vaccine Technology Roadmap's goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%'.To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%).However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future.

View Article: PubMed Central - HTML - PubMed

Affiliation: Macfarlane Burnet Institute of Medical Research, 85 Commercial Road, Melbourne, Victoria 3004, Australia. fowkes@burnet.edu.au.

ABSTRACT

Background: Malaria is a leading cause of morbidity and mortality, with approximately 225 million clinical episodes and >1.2 million deaths annually attributed to malaria. Development of a highly efficacious malaria vaccine will offer unparalleled possibilities for disease prevention and remains a key priority for long-term malaria control and elimination.

Discussion: The Malaria Vaccine Technology Roadmap's goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%'. To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%). However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future. In this opinion piece we discuss the methodological, logistical and ethical issues that may impact on the feasibility and implementation of superiority, non-inferiority and equivalence trials to assess second generation malaria vaccines in the advent of the licensure of a partially efficacious malaria vaccine.

Conclusions: Selecting which new malaria vaccines go forward, and defining appropriate methodology for assessment in logistically challenging clinical trials, is crucial. It is imperative that the scientific community considers all the issues and starts planning how second-generation malaria vaccines will advance in the advent of licensure of a partially effective vaccine.

Show MeSH
Related in: MedlinePlus