FDA Marketing Application Issues
Using banked specimens can yield significant savings in time and money. Nevertheless, they can also present FDA pitfalls. The crux of the problem is that the applicant has no control over how the specimens were collected. Because the proposed intended use must be consistent with the specimens’ clinical history, this can severely circumscribe the intended uses that may be claimed (See “Adroit Crafting of Intended Use Critical,” GEN, November 15, 2008). Furthermore, it may be impossible to fill in data gaps in the clinical records. In its remnant specimen policy FDA cautions that sponsors “accept the risk that they may not be able to provide sufficient information to satisfy FDA’s premarket review needs.”
The applicant also needs to be sure that the specimen-collection process did not introduce a biasing effect. The doctors must have collected the specimens while treating their patients, and not while conducting a study. This could introduce some bias, or render the data set nonrepresentative of how the test would actually be used. Are potential confounding variables accounted for, such as the heterogeneous use of treatments in an oncology patient set?
Companies also need to be certain that if the study endpoint is clinical truth, the patient files adequately document and verify the clinical outcome. For instance, if the IVD is intended to give prognostic information regarding the likelihood of cancer recurrence, do the patient records demonstrate whether the cancer recurred? How was recurrence—or its absence—determined? FDA routinely audits study sites for premarket approvals. Will these sites holding the clinical data pass an FDA bioresearch monitoring inspection?
FDA may be skeptical of certain kinds of claims supported by retrospective data. There seems to be some indication that FDA is more likely to allow a retrospective prognostic claim than a predictive one relating to selection of a treatment.
The complexities of using banked specimens to support a companion diagnostic were illustrated by the December 2008 FDA panel to consider K-Ras testing before certain drugs could be prescribed. FDA speakers raised a number of concerns such as possible data dredging and the criteria that should be applied to these studies. A senior official from the Office of In Vitro Diagnostics commented, “The extent to which revision of the drug’s use and clinical validation of the diagnostic test can be based on retrospective analyses of retained specimens requires scrutiny.”
While less costly than a new prospective study, retrospective studies can represent a significant investment of time and money. The cost of doing the study can be substantial. The cost in time and money will be even greater if FDA finds the study results unacceptable, denies the application, and the company essentially must start all over again. Therefore, before initiating a large-scale or novel study using banked specimens, the applicant should hold a pre-IDE meeting with FDA (See “Make the Most of Pre-IDE Meetings,” GEN, March 1, 2009). While this meeting cannot ensure FDA acceptance of the study data, this can help minimize the chances of conducting a study that won’t pass FDA muster.
The use of banked specimens can offer dramatic savings in time and money. These studies, however, are not risk free. IVD companies should be sure that they can gain access to an appropriate set of specimens that are backed by adequate data, present no informed consent or related legal issues, comply with applicable regulatory requirements, are consistent with the applicant’s proposed intended use, and are backed by adequate clinical records.