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- Mendell (2016) Longitudinal Effect of Eteplirsen versus Historical Control on Ambulation in Duchenne Muscular Dystrophy. ANN NEUROL
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- 2016 Meeting Materials, Peripheral and Central Nervous System Drugs Advisory Committee
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During the FDA advisory committee meeting, Dr Temple gave a presentation about "Historically Controlled Trials": see FDA's presentation slides (Dr Temple's presentation started from page 20).
Historical Control Cohort
The comparison of eteplirsen with historical controls was not part of an adequate and wellcontrolled study. The applicant obtained historical data after observations were made for the eteplirsen patients. Historical data were obtained from 2 DMD patient registries (Italian DMD Registry and the Leuven Neuromuscular Reference Center – NMRC) for comparison to eteplirsen-treated patients
According to the ICH E10 guidance on Control Group and Related Issues in Clinical Trials, the major and well-recognized limitation of externally controlled (including historical control) trials is inability to control bias. The best group and control group can be dissimilar with respect to a wide range of observable and unobservable factors that could affect outcome. It may be possible to match the historical control group to the test group in observed factors but there is no assurance for any unobserved factors. “The lack of randomization and blinding, and the resultant problems with lack of assurance of comparability of test group and control group, make the possibility of substantial bias inherent in this design and impossible to quantitate.”
Because of the serious concern about the inability to control bias, the use of the external control design is restricted only to unusual circumstances.
Moreover, the historical control group was identified post-hoc in this NDA, leading to potential selection bias that cannot be quantified. If a historical control is to be utilized, selection of the control group and matching on selection criteria should be prospectively planned without knowing the outcome of the drug group and control group.
- ICH E10 states that “an externally controlled trial should generally be considered only when prior belief in the superiority of the test therapy to all available alternatives is so strong that alternative designs appear unacceptable…” However, such prior belief does not exist for eteplirsen.
- ICH E10 states that “use of external controls should be limited to cases in which the endpoints are objective…” however, performance on the 5-minute walk test can be influenced by motivation. Patients may not achieve maximal 6MWT due to concerns of falling or injury, or patients could try harder with encouragement and with the expectation that the drug might be effective.
- Pocock’s criteria for acceptability of a historical control group require that “the methods of treatment evaluation must be the same,” and “the previous study must have been performed in the same organization with largely the same clinical investigators.” This is especially important when assessing endpoints such as 6MWT, in contrast to hard endpoints such as mortality. For this NDA, these requirements are not met.
Based on ICH E10, “a consequence of the recognized inability to control bias is that the potential persuasiveness of findings from externally controlled trials depends on obtaining much more extreme levels of statistical significance and much larger estimated differences between treatments than would be considered necessary in concurrently controlled trials.” The success criteria for this historical control study were not discussed or pre-specified in the protocol.
Given all these concerns, including issues of comparability of eteplirsen-treated patients and historical control cohort patients, the fact that 6MWT is not a “hard” efficacy endpoint, the potential of selection bias due to the post-hoc identification of the control cohort by the applicant, and all the known pitfalls with the use of historical controls, the comparison of the eteplirsen with historical control is not statistically interpretable.
- If the proposed historical control cohort is a priori or post hoc. It is encouraged to collect historical control information from natural history studies.
- if the patient population from historical control is comparable
- If the outcome measurement is comparable
- if the outcome measurement is a hard endpoint (such as death) or soft endpoint (such as 6MWD)
- If the endpoint measure is easily affected by other factors
- if the endpoint is a soft endpoint (such as objective response rate ORR), whether or not any approach is implemented to avoid the bias (such as using central reader)