Posted: 29 Mar 2019 01:36 AM PDT On March 25, 2019, FDA issued a draft guidance, “Rare Diseases: Natural History Studies for Drug Development,” to help inform the design and implementation of natural history studies that can be used to support the development of drugs and biological products for rare diseases (hereinafter “Rare Disease Natural History guidance”). This is the latest in a number of draft rare disease-focused guidance documents released by FDA (e.g., on common issues in drug development in February 2019 here and human gene therapies in July 2018 here). The existence of a stand-alone guidance document on this topic demonstrates FDA’s recognition of the important role natural history studies play in rare disease drug development, which is understandable given that natural history has been underutilized as well as underappreciated when used. In addition, when natural history has played a key role its use has often not been thoroughly described or explained so that its use as a precedent was muted. Informing Drug Development The Rare Disease Natural History guidance endorses use of information from these studies as primarily helpful informing the design and conduct of adequate and well-controlled clinical trials of investigational drugs that can support review and eventual approval decisions. This includes identifying the appropriate patient population to study. The guidance notes that a natural history study may uncover important, detectable physiologic changes that are important predictors of disease progression or are clinically important in their own right. In addition, a natural history study can be useful in understanding patient subgroups and identifying which may benefit from a particular clinical trial. These things together can inform decisions on inclusions/exclusion criteria, the stage of the disease to treat, the duration of the trial, the frequency of data collection, and endpoints. Specifically related to endpoints, FDA endorses natural history studies as a way to identify and develop two types: (1) clinical outcome assessments (COAs) and (2) biomarkers. COAs are measures of how a patient feels, functions or survives. The guidance states that a natural history study can help evaluate the ability of a new or existing COA to detect change in a particular disease, including in the pattern of the progression of the disease or its symptoms. FDA notes that natural history studies can be important vehicles for testing COAs to establish their performance and reproducibility for use in clinical trials. Meanwhile, biomarkers are objectively measured indicators of biological processes, pathologic processes, or biological responses to therapeutic intervention, such as physiologic measurements, blood tests, and imaging. The guidance states that a natural history study can help identify or develop biomarkers that can be useful in guiding patient selection and dose selection in drug development programs and can also be predictive of treatment response. Evidence of a biomarker being predictive of treatment response is important to establishing the potential surrogacy of that biomarker, such as for use as an accelerated approval endpoint. Use of Natural History Data as an External Control The Rare Disease Natural History guidance also explores the use of natural history study data to serve as an adequate control group for a clinical trial to support marketing approval. While FDA previously explicitly recognized the use of historical controls (as described in its guidance on control groups here), and has approved drugs based on studies using historical controls, this guidance provides additional insights into when historical controls are most appropriate in the rare disease context. Considerations in Selecting or Designing Historical Controls The Rare Disease Natural History Guidance provides considerations for deciding whether to utilize such a control, given its inherent limitations (e.g., inability to control for certain biases), as well as ways to maximize the utility of these controls when planning for their use. FDA provides the following considerations:
The Rare Disease Natural History guidance also sets forth scenarios when natural history controls are most interpretable. These include when the treatment effect:
Using Historical Controls to Supplement Concurrent Control Arms In one noteworthy expansion from previous FDA guidance, the Rare Disease Natural History guidance takes a more wholistic approach (or as the guidance states “a hybrid approach), that endorses the use of external control data to add to a concurrent randomized control arm in a clinical trial. While not explicitly stated in the guidance, the co-authors of this post view this as an opening to use the historical control to expand an existing placebo control arm to increase its size and, therefore, increase its ability for the trial’s ability to detect a between-group difference when testing its hypotheses. We propose that sponsors of clinical trials plan their studies to include a small placebo-control arm – one that is minimally sized in order to power the maximum possible treatment effect expected, therefore so that it is still ethical to include such a placebo control. The sponsor would also collect natural history data in a way that minimizes bias and other weaknesses of historical controls as discussed as FDA lays out in its guidance (and as we outlined above). Upon completion of the trial, the sponsor would then compare the results of the placebo cohort with that of the natural history cohort and, if sufficiently similar, would use the natural history cohort to “add” to the placebo cohort. Combining the two cohorts would be permissible if predefined correlations or other assessments of similarity are achieved, providing comfort that that there is less bias in the natural history cohort from known or unknown factors that is not present in the randomized placebo arm. The average numeric baseline and post-treatment values in the natural history cohort need not be the same as the placebo control cohort, since different patient populations will be expected to be different at baseline, but as long as the magnitude of the change from baseline is similar between the two cohorts, then the two can be deemed similar. Essentially anchoring the natural history data with the placebo arm data will give regulators an opportunity to assess and, in turn, feel more comfortable with the historical control, which may facilitate greater acceptance of historically-controlled trials. Practical Considerations for Natural History Study Design The Rare Disease Natural History guidance also includes discussions of different types of natural history studies (e.g., retrospective vs. prospective, cross-sectional vs. longitudinal), as well as an overview of natural history study design elements, which will help orient those not familiar with study design more generally. Of note, FDA recommends:
|
No hay comentarios:
Publicar un comentario