Perhaps it has come to this. On June 1, 2011 a new guidance document draft was released for comment by the US Department of Health and Human Services, the FDA, the Center for Devices and Radiological Health, the Office of In Vitro Diagnostic Device Evaluation and Safety and the Center for Biological Evaluation and Research. The name of this document is: Commercially Distributed In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions.
The crux of this document is this: Because products labeled ‘Research Use Only’ (RUO) and ‘Investigational Use Only’ (IUO) have unproven performance characteristics and manufacturing controls that are inadequate, companies who label their products as RUO or IUO may not sell those products to any lab which they are aware uses the products for diagnostic purposes. Manufacturers also may not assist those labs in the use of their products for tests designed for diagnostic purposes. If products are to be used for diagnostic purposes they must be cleared by the FDA for use as such. “Products” may include reagents, instruments or components.
The problems with this policy are myriad and much beyond the scope of this blog, however a few points to consider:
- As written, this document’s scope is very broad and will affect areas beyond RUO and IUO reagents and molecular diagnostic testing. Many laboratories currently use tandem mass spectrometers, thermocyclers, DNA sequencers, basic HPLCs and other instruments that have not been ‘cleared’ by the FDA for use in clinical diagnosis.
- The document’s case in general revolves around the unproven performance characteristics and inadequate manufacturing controls for RUO/IUO reagents. Even in the cases where this is true, any CLIA and/or CAP certified laboratory that uses them to develop and run a Laboratory Developed Test (LDT) has conducted rigorous and appropriate validation studies and has appropriate performance controls in place to insure that no patients are put at risk. Reputable laboratories that perform LDTs routinely have extensive experience with validating and controlling reagents and instrument systems.
- Some specialty tests available only as RUO or IUO, or with component parts that are RUO or IUO, are useful in the diagnosis and management of patients with challenging or rare disorders for which there are not other options. For example, essentially all of testing for inborn errors of metabolism is performed on instruments that have not been cleared by the FDA for use in diagnostic testing, such as tandem mass spectrometers. Another example would be the development of genetic tests for the diagnosis of rare diseases. If the labs currently performing these tests cannot perform them in the future, what will we offer these patients in exchange?
- This document has the potential to have a huge impact on anatomic pathology as well, especially for immunohistochemistry. Sometimes the RUO/IUO reagent has better performance than an Analyte Specific Reagent (ASR). In our laboratory we often compare multiple immunohistochemistry antibodies for analytical performance. Although the ASR reagents fulfill regulatory requirements, in our experience with immunohistochemistry, they do not perform consistently better than RUO/IUO reagents. It is unfortunate that in a clinical laboratory environment with stringent reagent controls that the best possible reagent cannot always be used. It is also likely that ASRs will also fall by the wayside.
- In the past, use of RUO/IUO reagents in LDTs has led to and helped in the development of new diagnostic tests by manufacturers. For example, when the tacrolimus assay was initially released as FK506, it was for IUO. Studies by labs using this assay were helpful in its eventual release as an FDA approved test. This symbiotic relationship will be irreparably harmed by this guidance document.
So has it come to “don’t ask, don’t tell”? Don’t ask me what I want your reagent for and I won’t tell you how I’m using it. I cannot imagine that this mode of operation will be useful to anyone.
My thoughts and concerns are from the perspective of a laboratorian with a laboratory which performs LDTs and will be affected by this ruling. I welcome any comments from the perspective of the manufacturer/industry side, if your company will allow you to comment. In this case, be anonymous! I also welcome any and all other comments to this blog, but more than just to this blog. Read the document and send the FDA your comments. As a profession and an association, we should weigh in on this issue.