Article type
Year
Abstract
Background: in 2019, Zolgensma® was approved in the United States for treating spinal muscular atrophy (SMA), based on two open-label (unmasked), non-comparative studies. Some methodological criticisms have been raised from this decision. In contrast, facing both a rare disease and an orphan drug has been a justification for accepting less robust and reliable evidence.
Objectives: to discuss the methodological issues related to regulatory process of drugs for rare diseases, based on the Zolgensma® case for treating SMA.
Methods: critical appraisal study carried out at the Centre of Health Technology Assessment (HTA), Hospital Sírio-Libanês (São Paulo, Brazil).
Results: open-label, unmasking and single-arm studies are far from the methodological rigor of a randomized double-blind clinical trial, considered the most appropriate primary study to assess the effects of healthcare interventions. Firstly, the presence of a similar comparator group is essential to estimate the real effect of the intervention and to assess if these effects are different from those observed with the use of best available option, placebo or natural course of the disease. Secondly, the similarity between the comparison groups helps to ensure that the effect observed can be exclusively attributed to the intervention, eliminating any other factor that differentiates the groups, such as disease severity, sex, age or comorbidities. The use of an adequate randomization method would certainly achieve this goal. Thirdly, the lack of allocation concealment can overestimate the size of the intervention effect by 37% to 41%1,2. This means that, depending on the point estimate of the effect, an intervention that, in reality, has no benefits, may prove to be falsely beneficial. Fourthly, unmasking participants, personnel and outcome assessors lead to deviations in the process of conducting the study, such as adherence to treatment, reporting of adverse events, and also biased judgement of the outcomes. Here we pointed out four of the various biases 3 to which these studies may be exposed, impacting the direction and size of the findings, thus decreasing their reliability.
Conclusions: the case of Zolgensma® raises a debate about the methodological criteria adopted by global regulatory agencies for approving the marketing of drugs, specifically in the rare disease scenario, and orphan drugs, at extremely high costs. Critical points related to the methods for planning and conducting the clinical studies that supported the regulatory process for drugs must be identified and revised.
Patient or healthcare consumer involvement: it is essential that patients, managers and health decision makers understand the process of drug regulation in their country, as well as know the uncertainties related to the findings of pivotal studies used to support approvals.
References:
1. Moher 1998
2. Schulz 1995
3. Catalogue of Bias Collaboration. Catalogue Of Bias. [Internet]. Catalogue Of Bias. 2019. Available from: https://catalogofbias.org/biases/attrition-bias.
Objectives: to discuss the methodological issues related to regulatory process of drugs for rare diseases, based on the Zolgensma® case for treating SMA.
Methods: critical appraisal study carried out at the Centre of Health Technology Assessment (HTA), Hospital Sírio-Libanês (São Paulo, Brazil).
Results: open-label, unmasking and single-arm studies are far from the methodological rigor of a randomized double-blind clinical trial, considered the most appropriate primary study to assess the effects of healthcare interventions. Firstly, the presence of a similar comparator group is essential to estimate the real effect of the intervention and to assess if these effects are different from those observed with the use of best available option, placebo or natural course of the disease. Secondly, the similarity between the comparison groups helps to ensure that the effect observed can be exclusively attributed to the intervention, eliminating any other factor that differentiates the groups, such as disease severity, sex, age or comorbidities. The use of an adequate randomization method would certainly achieve this goal. Thirdly, the lack of allocation concealment can overestimate the size of the intervention effect by 37% to 41%1,2. This means that, depending on the point estimate of the effect, an intervention that, in reality, has no benefits, may prove to be falsely beneficial. Fourthly, unmasking participants, personnel and outcome assessors lead to deviations in the process of conducting the study, such as adherence to treatment, reporting of adverse events, and also biased judgement of the outcomes. Here we pointed out four of the various biases 3 to which these studies may be exposed, impacting the direction and size of the findings, thus decreasing their reliability.
Conclusions: the case of Zolgensma® raises a debate about the methodological criteria adopted by global regulatory agencies for approving the marketing of drugs, specifically in the rare disease scenario, and orphan drugs, at extremely high costs. Critical points related to the methods for planning and conducting the clinical studies that supported the regulatory process for drugs must be identified and revised.
Patient or healthcare consumer involvement: it is essential that patients, managers and health decision makers understand the process of drug regulation in their country, as well as know the uncertainties related to the findings of pivotal studies used to support approvals.
References:
1. Moher 1998
2. Schulz 1995
3. Catalogue of Bias Collaboration. Catalogue Of Bias. [Internet]. Catalogue Of Bias. 2019. Available from: https://catalogofbias.org/biases/attrition-bias.