Guidance Document Mania!

Friday, September 09, 2011

All I can say is someone back at CDRH has been eating their Wheaties! The last several weeks there has been a flurry of guidance documents. Our next several blogs will be devoted to analyzing and discussing these documents.

On August 15th CDRH issued the Draft Guidance for Industry, Clinical Investigations, and Food and Drug Administration Staff – Design Considerations for Pivotal Clinical Investigations for Medical Devices.

This document, hands down, is one of the best ever produced by the Agency and speaks directly to issues related to clinical trials for IVDs.

This guidance does a very nice job of laying out the considerations that go into the design of any pivotal trial including the importance of:

  • early exploratory studies (for IVDs this includes analytical studies and studies to develop appropriate algorithms on actual human samples),
  • design of studies (often not clinical outcome studies for IVDs but rather comparisons against references methods or evaluation of disease), and
  • considering bias and variability of device performance including concerns about subject selection, stratification of subjects and site identification.

In Section 8 of this document “Diagnostic Clinical Performance Studies” FDA reminds us that our intended use must guide the design of the trial and goes on to acknowledge the importance of establishing the accuracy of results reported by diagnostic devices: “The safety and effectiveness of a diagnostic device are often not separable. Both are linked to the ability of device to accurately diagnose or quantify the clinical condition of interest. When the result reported by a diagnostic device is incorrect (e.g. the result is either misclassified as false positive or false negative) or misinterpreted, subjects can be harmed by subsequent inappropriate management or by psychological trauma.”

The best part of the document is a pithy list of considerations about a diagnostic device that need to be evaluated when designing a clinical study for a diagnostic.

  • what the device measures or detects;
  • what the device reports (this can be difficult question particularly for complex multivariate products)
  • cell, tissue, organ, part, or system examined,
  • specimen sources, specimen types and specimen matrix,
  • how the device is used (per instructions for use)
  • when the device of use (conditions of use)
  • by whom the device is used (operator or target user)
  • or what (target condition)
  • on whom (target population) device is used.

Finally the document takes on the difficult issue of use of retrospective specimens and how to do performance comparison studies. A quick thank you to the Agency for this as use of retrospective specimens is one of the most common and challenging discussions in the IVD industry and having something to refer to is very helpful

This document is definitely worth the time to read and re-read. I’ve downloaded on my Kindle and will be referring to it frequently.


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Dylan Reinhardt
Dave Kern
Steve Gutman
Jo-Ann Gonzales

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