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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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Related in: MedlinePlus

Defining superiority, equivalence and non-inferiority in clinical trials of second-generation malaria vaccines. Summary of the possible trial types, outcomes and considerations when testing second-generation malaria vaccines compared to a partially efficacious first-generation licensed vaccine. Error bars correspond to possible trial outcomes and indicate two-sided 95% confidence intervals (CI). Δ (the superiority margin (+Δ), non-inferiority margin (-Δ) and equivalence margin (-Δ to +Δ) can be defined by an absolute or a relative difference in actual malaria outcomes. Interpretation of trials depends on where the CI for the true difference in outcome falls relative to Δ and the  effect (0). For superiority trials, to conclude superiority, the trial effect may be bigger or smaller than Δ but the 95% CI must be above 0 (scenarios A and B). For equivalence trials, equivalence requires the CI to lie wholly within a bidirectional symmetrical equivalence margin (-Δ and Δ, scenarios C and D). If the effect estimates lie outside the bidirectional symmetrical equivalence margins, the second-generation malaria vaccine is either better or worse than the first-generation vaccine [16]. In a non-inferiority trial, the prime interest is determining whether the new malaria vaccine is no worse than the non-inferiority margin (-Δ) which, if exceeded, defines the new treatment as being inferior to RTS,S. For non-inferiority trials, if the CI lies completely to the right of the prespecified margin (-Δ) a conclusion of non-inferiority of the second-generation malaria vaccine is reached (scenarios E and F). If the CI includes -Δ it is concluded that the new malaria vaccine is inferior to the first-generation malaria vaccine.
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Figure 1: Defining superiority, equivalence and non-inferiority in clinical trials of second-generation malaria vaccines. Summary of the possible trial types, outcomes and considerations when testing second-generation malaria vaccines compared to a partially efficacious first-generation licensed vaccine. Error bars correspond to possible trial outcomes and indicate two-sided 95% confidence intervals (CI). Δ (the superiority margin (+Δ), non-inferiority margin (-Δ) and equivalence margin (-Δ to +Δ) can be defined by an absolute or a relative difference in actual malaria outcomes. Interpretation of trials depends on where the CI for the true difference in outcome falls relative to Δ and the effect (0). For superiority trials, to conclude superiority, the trial effect may be bigger or smaller than Δ but the 95% CI must be above 0 (scenarios A and B). For equivalence trials, equivalence requires the CI to lie wholly within a bidirectional symmetrical equivalence margin (-Δ and Δ, scenarios C and D). If the effect estimates lie outside the bidirectional symmetrical equivalence margins, the second-generation malaria vaccine is either better or worse than the first-generation vaccine [16]. In a non-inferiority trial, the prime interest is determining whether the new malaria vaccine is no worse than the non-inferiority margin (-Δ) which, if exceeded, defines the new treatment as being inferior to RTS,S. For non-inferiority trials, if the CI lies completely to the right of the prespecified margin (-Δ) a conclusion of non-inferiority of the second-generation malaria vaccine is reached (scenarios E and F). If the CI includes -Δ it is concluded that the new malaria vaccine is inferior to the first-generation malaria vaccine.

Mentions: The choice of superiority, non-inferiority or equivalence trial depends on the objective of the new malaria vaccine. A superiority trial would be suitable if the desire was to replace the first-generation vaccine with a more efficacious vaccine, and the aim would be to demonstrate that the new malaria vaccine was better by a predefined clinically accepted margin (Δ) (Figure 1). This is the same principle as a placebo-controlled trial, except the placebo is replaced with an active control. Conversely, if a new malaria vaccine was predicted to have a similar VE to the first-generation vaccine but had longer duration, was cheaper, had favorable logistics or contained additional lifecycle stages or antigens, these would provide the rationale for a non-inferiority or equivalence trial. The objective of non-inferiority and equivalence trials is to determine whether the effects of the new malaria vaccine stay within or go beyond a predefined clinically acceptable margin (Δ) relative to the standard licensed vaccine (Figure 1). After clinical trials, the new malaria vaccine may be recommended if it has a VE that is similar, but not inferior, to the first-generation vaccine. The choice of non-inferiority or equivalence trial will depend on the scientific question being asked. The hypothesis being tested in a non-inferiority trial is that the second-generation vaccine is as good as, or better than, the first-generation vaccine. Non-inferiority trials are used to show that a minimum level of efficacy has been achieved by the new vaccine. This trial would therefore be favorable for vaccines that seek to advance first-generation vaccines by being more efficacious or have longer duration. In an equivalence trial, the hypothesis being tested is that the second-generation vaccine cannot be worse than or better than the first-generation vaccine. Equivalence trials would be used to demonstrate that a new vaccine is clinically equivalent to a current vaccine in its efficacy, and they are used in the registration and approval of vaccines that have been shown to be bioequivalent.


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

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

Defining superiority, equivalence and non-inferiority in clinical trials of second-generation malaria vaccines. Summary of the possible trial types, outcomes and considerations when testing second-generation malaria vaccines compared to a partially efficacious first-generation licensed vaccine. Error bars correspond to possible trial outcomes and indicate two-sided 95% confidence intervals (CI). Δ (the superiority margin (+Δ), non-inferiority margin (-Δ) and equivalence margin (-Δ to +Δ) can be defined by an absolute or a relative difference in actual malaria outcomes. Interpretation of trials depends on where the CI for the true difference in outcome falls relative to Δ and the  effect (0). For superiority trials, to conclude superiority, the trial effect may be bigger or smaller than Δ but the 95% CI must be above 0 (scenarios A and B). For equivalence trials, equivalence requires the CI to lie wholly within a bidirectional symmetrical equivalence margin (-Δ and Δ, scenarios C and D). If the effect estimates lie outside the bidirectional symmetrical equivalence margins, the second-generation malaria vaccine is either better or worse than the first-generation vaccine [16]. In a non-inferiority trial, the prime interest is determining whether the new malaria vaccine is no worse than the non-inferiority margin (-Δ) which, if exceeded, defines the new treatment as being inferior to RTS,S. For non-inferiority trials, if the CI lies completely to the right of the prespecified margin (-Δ) a conclusion of non-inferiority of the second-generation malaria vaccine is reached (scenarios E and F). If the CI includes -Δ it is concluded that the new malaria vaccine is inferior to the first-generation malaria vaccine.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4225678&req=5

Figure 1: Defining superiority, equivalence and non-inferiority in clinical trials of second-generation malaria vaccines. Summary of the possible trial types, outcomes and considerations when testing second-generation malaria vaccines compared to a partially efficacious first-generation licensed vaccine. Error bars correspond to possible trial outcomes and indicate two-sided 95% confidence intervals (CI). Δ (the superiority margin (+Δ), non-inferiority margin (-Δ) and equivalence margin (-Δ to +Δ) can be defined by an absolute or a relative difference in actual malaria outcomes. Interpretation of trials depends on where the CI for the true difference in outcome falls relative to Δ and the effect (0). For superiority trials, to conclude superiority, the trial effect may be bigger or smaller than Δ but the 95% CI must be above 0 (scenarios A and B). For equivalence trials, equivalence requires the CI to lie wholly within a bidirectional symmetrical equivalence margin (-Δ and Δ, scenarios C and D). If the effect estimates lie outside the bidirectional symmetrical equivalence margins, the second-generation malaria vaccine is either better or worse than the first-generation vaccine [16]. In a non-inferiority trial, the prime interest is determining whether the new malaria vaccine is no worse than the non-inferiority margin (-Δ) which, if exceeded, defines the new treatment as being inferior to RTS,S. For non-inferiority trials, if the CI lies completely to the right of the prespecified margin (-Δ) a conclusion of non-inferiority of the second-generation malaria vaccine is reached (scenarios E and F). If the CI includes -Δ it is concluded that the new malaria vaccine is inferior to the first-generation malaria vaccine.
Mentions: The choice of superiority, non-inferiority or equivalence trial depends on the objective of the new malaria vaccine. A superiority trial would be suitable if the desire was to replace the first-generation vaccine with a more efficacious vaccine, and the aim would be to demonstrate that the new malaria vaccine was better by a predefined clinically accepted margin (Δ) (Figure 1). This is the same principle as a placebo-controlled trial, except the placebo is replaced with an active control. Conversely, if a new malaria vaccine was predicted to have a similar VE to the first-generation vaccine but had longer duration, was cheaper, had favorable logistics or contained additional lifecycle stages or antigens, these would provide the rationale for a non-inferiority or equivalence trial. The objective of non-inferiority and equivalence trials is to determine whether the effects of the new malaria vaccine stay within or go beyond a predefined clinically acceptable margin (Δ) relative to the standard licensed vaccine (Figure 1). After clinical trials, the new malaria vaccine may be recommended if it has a VE that is similar, but not inferior, to the first-generation vaccine. The choice of non-inferiority or equivalence trial will depend on the scientific question being asked. The hypothesis being tested in a non-inferiority trial is that the second-generation vaccine is as good as, or better than, the first-generation vaccine. Non-inferiority trials are used to show that a minimum level of efficacy has been achieved by the new vaccine. This trial would therefore be favorable for vaccines that seek to advance first-generation vaccines by being more efficacious or have longer duration. In an equivalence trial, the hypothesis being tested is that the second-generation vaccine cannot be worse than or better than the first-generation vaccine. Equivalence trials would be used to demonstrate that a new vaccine is clinically equivalent to a current vaccine in its efficacy, and they are used in the registration and approval of vaccines that have been shown to be bioequivalent.

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