ICCS Portland Plenary Session I: Regulatory Issues.
Chair: Teri Oldaker

Regulatory issues: sounds pretty tedious, doesn’t it? But Teri Oldaker put together a terrific panel of speakers who each addressed different facets of this very timely topic.

First to speak was Bruce Davis (Trillium Diagnostics), longtime member of and stalwart contributor to the society. Bruce’s commitment to ICCS’s mission is once again apparent in this lecture, “Development and Validation of Laboratory-Fluorescent Cell-Based Developed Tests”.

Bruce started with some background information about the history of laboratory-developed tests (LDTs) and a recent push by the CAP to increase oversight of “homebrew” testing. According to the CAP’s proposed model, almost all testing done in clinical flow cytometry labs in the US would fall under the heading of “high risk”, and the lab would therefore be required to “submit the test to the FDA for review prior to offering it clinically”. Between the inherent complexities of cell-based fluorescent assays, the lack of practice-wide standards or predicate devices, and FDA-specific issues, Bruce illustrated one possible scenario for laboratory-developed tests with a Prohibition-era photo depicting bottles of liquor being poured down a drain. Bleak times indeed, and the FDA’s draft guidance documents for RUO diagnostic products and in vitro companion diagnostic devices do little to allay our concern.

But instead of just sitting quietly and worrying about the situation, Bruce has been busy, and the next point of discussion was the formation of the ICSH (International Council for Standardization in Hematology)/ICCS Working Group charged with drafting “guidelines for validation of cell-based fluorescence IVD assays”. The participants met in Dedham, ME in March, 2011. The internationally diverse group of 36 experts and 8-10 observers was divided into subgroups dealing with pre-analytical, analytical, performance criteria, and post-analytical issues. The project is well under way, and Bruce reported that working drafts from all four groups had been completed in September, and that an edited draft would circulate in November, with a final draft projected by the end of November.

Bruce’s final remarks were a call to action: under the issues, question authority when it seems to be at odds with common sense, and get involved in consensus-driven guidelines and accreditation processes. As he put it, “If you do not write the rules, they will be written for you.”

Next up was Harry Solomon (GE Healthcare). Unlike Bruce, Harry is new to flow cytometry, and in fact has yet to ever lay hands on a cytometer or look at a dot plot with a view to rendering a diagnosis. He is, however, intimately familiar with many of the challenges facing those of us engaged in the practice of clinical flow cytometry. In his lecture entitled “Interoperability and Standards – Toward an Integrated Pathology Workflow” he began by introducing himself and describing his day job: “interoperability architect.” That’s right, interoperability architect, and GE Healthcare actually pays him to do it. So unlike the rest of us who have to consider issues like interoperability and standards in our spare time, he understands these concepts in detail and has hands-on experience with implementation.

Having introduced himself, he then introduced the topic of interoperability in the context of a clinical flow cytometry lab, with the lab depicted as a number of separate desert islands (i.e. order entry, cytometer, listmode analysis, electronic medical record, etc.) and asking the question: “Can they exchange and use information?” He then showed us a great example of something that used to be non-standard and is now so standard that we don’t even think about it: screw base light bulbs. He described the process whereby the standard was developed and adopted, and emphasized the advantages that accrue to both consumers and vendors when standards are followed. To quote him: “Standards make a market.” He continued by describing a healthcare scenario in which standards had been successfully adopted and interoperability achieved: radiology. Decades ago radiology was in pretty much the same situation as flow cytometry (and the rest of pathology, by the way) is now. Much work and discussion later, radiology is now a paragon of interoperability, with digital images being easily portable and workflow streamlined.

Harry finished up by describing many of the ongoing efforts to standardize pathology workflow, including DICOM and HL7, as well as ISAC’s work to date on the data file standard, and concluded with a call to action (hmm, recognize a theme here?): “Multi-specialty collaboration, care coordination, and patient engagement all require interoperable systems, and a standards-based approach across all of pathology is the only economically feasible way to achieve it. Step up to the plate!”

The session’s final speaker was Gerald Marti (Food and Drug Administration), another longstanding member of ICCS and one with a somewhat unique perspective on regulatory issues due to his position with the FDA. His lecture, “An Introduction to the 510(k) Clearance Process for IVD Clearance”, was an excellent review of current FDA processes as regards both IVDs (in vitro diagnostics) and LDTs.

Again, this topic was introduced from the historical perspective, beginning with the original Federal Food Drug and Cosmetic Act of 1938, the Medical Device Amendments in 1976, and subsequent Modernization acts in 1997, 2002, and 2007. Gerry then moved on to the topic of IVDs, their risk-based classification, and the different types of regulation that apply to each of the three categories, with special emphasis on 510(k), the premarket notification required of Class II IVDs.

Once he’d finished with IVDs, he addressed LDTs. The discussion again began with the history: once primarily comprised of low volume tests performed locally in a non-commercial setting, this category of testing has now grown enormously in volume, type, and complexity, and it’s increasingly offered in a highly commercial, extensively advertised setting. The FDA is therefore understandably concerned about the potential for abuse, and the inadequacy of the current piecemeal approach of analyte specific reagents (ASRs) and in vitro diagnostic multivariate index assays (IVDMIA). In order to address these concerns the FDA has embarked on drafting a framework for oversight of LDTs that incorporates stakeholder comments. After listing various on-line resources and encouraging the audience to come forth as stakeholders in the process, Gerry summed things up with an interesting vignette about the ASR category and how it first came about.

As Gerry describes it, a meeting among “homebrew” stakeholders and the FDA that had originally been planned to take place at the FDA had to be moved to a less formal venue at the last minute. The resulting discussions were so productive that the parties were able to come to a very rapid consensus on the level of oversight that would be sufficient and necessary to address the FDA’s concerns about LDTs at that time without bringing homebrew testing to a halt. The result of that meeting was an entirely new category of reagents, ASRs, and the intervening years have seen remarkable progress in high complexity testing that use ASRs that would otherwise have been unlikely. By getting involved in the process, Gerry says, we can hopefully arrive at another similarly productive result.

In summary, this was an interesting and engaging set of speakers who all ended their talks with calls to action. Kudos to Teri Oldaker for inviting them, and don’t be shy participating in ICCS’s ongoing efforts in this arena.

Jeannine T. Holden, MD
Emory University School of Medicine, Atlanta, GA.