Quote:The primary, and secondary, and tertiary
endpoints efficacy endpoints will be reviewed. They should be considered
within the context of a closed testing procedure, and in the order of the
stated efficacy hypotheses, specifically the primary endpoint
(progression-free survival) first, followed by the secondary endpoint
(all-cause mortality) followed by the tertiary endpoint.).
Quote:The primary objective of this study is to compare overall survival (OS) between patients randomized to DCVax-L and control patients from comparable, contemporaneous trials who received standard of care therapy only, in patients with newly diagnosed glioblastoma. This endpoint will be assessed using 3 different analyses
Quote:The first secondary objective is to compare overall survival (OS) between patients randomized to placebo who received DCVax-L treatment following disease recurrence and control patients from comparable, contemporaneous clinical trials, in patients with recurrent GBM.
Quote:The second secondary endpoint, confirmed progression-free survival (cPFS), is confirmed disease progression (cPD) compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
Quote:The third secondary endpoint, PFS, is progression-free survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
Quote:The fourth secondary objective, OS, is overall survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
Quote:The fifth secondary objective is tumor response compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
Quote:The finding of substantial evidence of effectiveness is necessary but not sufficient for FDA approval. The approval decision also requires a determination that the drug is safe for the intended use. As all drugs have adverse effects, evaluating whether a drug is “safe” involves weighing whether the benefits of the drug outweigh its risks under the conditions of use defined in labeling.Uncertainties regarding benefits and risks are considered when making an approval determination; a drug with greater risks may require a greater magnitude and certainty of benefit to support approval.
Quote:Although randomized double-blinded, concurrently controlled superiority trials are usually regarded as the most rigorous design, as discussed further below, five types of controls are described in section 314.126:10 placebo concurrent control, dose-comparison concurrent control, no treatment concurrent control, active treatment concurrent control, and historical control (a type of external control).11 Of note, when the first version of the rule was published in 1970, historical controls and active treatment controls were included.12 Thus, from its earliest description of adequate and well-controlled trials, FDA included trial designs (as discussed below) that may be more difficult to interpret, which reflected FDA’s recognition that different trial designs (including choice of control) may be appropriate in different disease settings.
Quote:11 The regulation uses the term “historical control,” which is a subset of “external control.” FDA also accepts other types of external controls. An externally controlled trial compares a group of subjects receiving the test treatment with a group of patients external to the trial, rather than to an internal control group consisting of patients from the same trial population assigned to a different treatment. The external control can be a group of patients, treated or untreated, at an earlier time (historical control) or a group, treated or untreated, during the same time period but in another setting. An important subset of externally controlled trials are “baseline controlled trials,” where there is not a specific external control group but assurance, based on experience, that no change could occur (e.g., tumors are known not to shrink spontaneously or patients not given general anesthetic remain awake). See International Conference on Harmonisation E10 guidance on Choice of Control Group and Related Issues in Clinical Trials (ICH E10). This guidance uses the term “external control,” except when referring to section 314.126.
Quote:Externally controlled trials differ in several important ways from the other trial designs identified in 21 CFR 314.126. Most notably, random assignment is not a feature of external control designs. As a result, there may be differences in patient characteristics or concomitant treatments in the trial population compared to the external control population that lead to differences in outcomes that are unrelated to the investigational treatment. In addition, the lack of blinding could introduce bias. For these reasons, external control designs are usually reserved for specific circumstances, such as trials of diseases with high and predictable mortality or progressive morbidity (e.g., certain malignancies or certain rare diseases) and trials in which the effect of the drug is self-evident(e.g., general anesthetics).
Quoteespite the limitations of externally controlled trials compared with concurrently controlled trials, strong support for effectiveness can emerge from externally controlled trials, especially when
(1) the natural history of a disease is well defined,
(2) the external control population is very similar to that of the treatment group,
(3) concomitant treatments that affect the primary endpoint are not substantially different between the external control population and the trial population, and
(4) the results provide compelling evidence of a change in the established progression of disease.
Such results could include partial or complete response in a disease where spontaneous regression is not observed, or stabilization or improvement in function in a disease where progressive functional decline is well documented to occur over the duration of the treatment period in the trial. Another example of where there is strong evidence of drug effectiveness is reversal of clinical signs and symptoms following a toxic exposure or overdose after administration of a drug antidote. In all such circumstances, a detailed understanding of the full range of possible clinical outcomes, with a well-documented natural history of the disease in the absence of treatment, is essential to interpreting trial results and, therefore, drawing a conclusion about the effectiveness of the drug.
Quote:For example, compelling results may overcome challenges associated with less rigorous trial designs, such as those with an external control. As discussed above, a small externally controlled trial with an outcome markedly superior to the well-established natural history of a disease may provide a compelling case for drug effectiveness.