The resulting Two-Temperature LATE-PCR method significantly reduces the quantitative endpoint uncertainties inherent to symmetric PCR and does not require an external reference sequence for normalization.
Predicting full behavioral change after the intervention period ends, and thus substituting a missing endpoint, may increase uncertainty compared to using an observed outcome parameter like, in this case, smoking cessation.
Like the many studies included in the Cochrane review, both of these REDUCE trials use endoscopic ulcer prevention as a primary endpoint; there is some uncertainty as to how this translates to clinical outcomes such as serious GI complications, although there was also significantly less dyspepsia noted with combination therapy compared with ibuprofen alone.
Rate of lung function decline (RLFD) (as FEV1percentt predicted/yr) is a robust measure of CF therapeutic efficacy rarely used as a study endpoint, in part due to uncertainty of sample size requirements.
The lack of a precise date of initiation of the disease process, the uncertainty of which endpoint to measure for each stage of the disease, a proper reference standard, and optimal cutoff values among different laboratories are significant matters of debate.
The costs of eradication, managerial impediments to executing national control programmes, and scientific uncertainty about transmission endpoints, are challenges to the success of this effort, especially in areas of high endemicity where financial resources are limited.
Finally, with uncertainty in clinical endpoints and trial design, the interaction between a wide range of stakeholders is extremely important to explore ways to optimize development pathways.
It has been suggested that clinical significance, clinical and economic uncertainty, relevance of endpoints, indication (specifically, drugs for life-threatening conditions), and cost to government (in terms of financial impact) can affect the likelihood of acceptance of PBAC submissions, in addition to cost-effectiveness criteria, 23, 25– 27 which may influence the decision-making process.
This includes transparency in the model, clarity in its intended endpoint, applicability domain, predictions and associated uncertainty, and above all, information that directly addresses the regulatory demands.
Neither the lower number of endpoints of interest, nor the potential uncertainty of the results, is critical, because the goal is to determine which chemicals require higher scrutiny.
HTA reviewers could be willing to accept the unavoidable clinical uncertainty associated with surrogate endpoints given the limitations of clinical trial design.
