ASM Comments on FDA Draft Guidance on RUO/IUO In Vitro Diagnostics

Aug. 22, 2011

Center for Biologic Evaluation and Research
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852

To Whom It May Concern:

The American Society for Microbiology (ASM) and the Pan American Society for Clinical Virology (PASCV) appreciate the opportunity to provide written comments to the FDA on their Draft Guidance for Industry and Food and Drug Administration Staff on Commercially Distributed in vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only; Frequently Asked Questions.

The ASM is the largest educational, professional and scientific society dedicated to the advancement of the microbiological sciences and their application for the common good. The Society represents more than 38,000 microbiologists professionally employed in a variety of areas, including clinical and public health microbiology and immunology, as well as biomedical, agriculture and environmental microbiology.

The PASCV is an international society, with a membership of approximately 600 professionals. Members perform laboratory testing for the detection, quantification and characterization of viral pathogens. PASCV membership includes physicians, doctoral scientists and medical technologists, representing academic medicine, clinical laboratories, commercial laboratories, the pharmaceutical industry and the in vitro diagnostics industry.

Molecular testing, as well as other novel laboratory methodologies, has revolutionized the practice of infectious diseases and medical laboratory scientists have played an essential role in the design and development of many of these novel assays. In large part, the development and implementation of laboratory developed tests (LDTs) for infectious diseases diagnosis and monitoring has grown out of necessity. This has been due to two major issues: 1) the lack of availability of needed FDA approved commercial tests over the years; and 2) conventional methods of culture and antigen detection which can often be insensitive with turnaround times that have little impact on clinical care. Molecular testing has become the standard of care for detection and quantification of many pathogens, for which there is no FDA cleared/approved test. Examples of such tests include detection of central nervous system infections due to herpes simplex virus (HSV) and varicella zoster virus (VZV), and monitoring of cytomegalovirus (CMV), BK virus, adenovirus and Epstein Barr virus levels in transplant recipients. For HCV genotype testing, which provides essential information for treatment decisions, the only available tests are RUOs. In short, these, and many other laboratory-developed molecular and non-molecular assays, are now essential for the practice of infectious disease diagnosis and monitoring, and many of these assays utilize Research Use Only (RUO) or Investigational Use Only (IUO) reagents/instruments in their performance. The proposed guidance would in effect shut down many critical tests and adversely affect patient care.

It is the responsibility of each laboratory to validate, establish and monitor the performance characteristics of their LDTs, including those that utilize RUO/IUO reagents/instruments, according to the regulatory guidelines set forth by CLIA and other agencies such as the College of American Pathologists (CAP). This process ensures the quality of testing whether the LDT utilizes Analyte Specific Reagents (ASRs), RUO or IUO reagents/instruments or neither. An additional consideration is cost; clinical laboratories have never been under greater cost constraints than they are today. Often FDA-cleared/approved tests come at a substantially higher cost than LDTs and some have performance characteristics that do not always meet or exceed that of LDTs. Testing platforms that do not have a substantial test menu may require a laboratory to have several expensive instruments, each that perform only a few assays. All of this greatly increases the cost of testing for the laboratory and, ultimately, the patient. Therefore, when an FDA approved assay is made available for an infectious agent, for which very few or no tests currently exist, the FDA should still offer clinical laboratories the flexibility to continue offering well validated and quality controlled RUO/IUO based LDTs. This should continue until such time that there are sufficient FDA approved tests to cover the clinical needs of the patient and provide optimal testing to many different types of clinical diagnostic laboratories.

If commercial companies are required to take RUO/IUO products through the regulatory process, they may decide to withdraw these products from the market. There were many examples of such outcomes when the ASR guidance was put into place and laboratories were left without access to tests for certain pathogens or with the added expense of revalidating another ASR. Many tertiary care centers with critically ill, often immunocompromised patients are highly dependent on these types of RUO/IUO based LDTs. A limitation of the use of RUO/IUO based LDTs will decrease access to testing and negatively impact clinical care.

We would like to make the following suggestions to FDA:
  • We recommend that the FDA work with appropriate clinical counterparts to provide clear and realistic guidelines for verification and validation testing for clinical laboratories that use reagents/instruments that are labeled, wholly or in-part, RUO/IUO. The ability to utilize RUO/IUO reagents/instruments is very important for diagnostic laboratories, as many critical assays currently preformed have no FDA-cleared counterparts.
  • We encourage the FDA to work with members of professional societies, such as those represented on this letter and others (e.g., ASM, PASCV, AACC, AMP, CAP, ASCP, etc.) in establishing acceptable guidelines for the use of RUO/IUO reagents/instruments for clinical diagnostic assays.This may include: 1) identifying other regulatory pathways, particularly for instruments and reagents in wide spread use, where other products/instruments do not meet the clinical needs; 2) exempting reagents/instruments where no or limited FDA cleared/approved products are available, and/or 3) exempting reagents and instruments that are currently used in LDTs that have been validated following CLIA regulations.
Although we appreciate that the FDA will use its enforcement discretion when instructing manufacturers in the appropriate marketing of RUO/IUO products, there is great concern that this current FDA guidance will have a negative impact on the potential development and utilization of clinical laboratory technology as well as be a detriment to patient care in the area of infectious diseases. The elimination of LDTs that use RUO/IUO reagents or instruments will certainly discourage the development of these important clinical assays.

ASM and PASCV support the initiative of the FDA directed towards ensuring the efficacy and safety of RUO/IUO products/reagents/instruments in the clinical diagnostic laboratory. However, a blanket implementation of this guidance will decrease access to tests that are now considered the standard of care, will limit clinicians’ access to critical results, and severely hinder the ability of the laboratory to advance testing that assists in quality patient care.

We thank you for the opportunity to comment.


Susan E. Sharp, Ph.D., Chair, Committee on Laboratory Practices
Public and Scientific Affairs Board, ASM

Angela M. Caliendo, M.D., Ph.D., President, PASCV

Christine C. Ginnochio, Ph.D., President-Elect, PASCV
Member, Committee on Laboratory Practices, ASM

Author: ASM Advocacy

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