The Case for Laboratory Developed Procedures: Quality and Positive Impact on Patient Care

Kaul, Karen L.; Sabatini, Linda M.; Tsongalis, Gregory J.; Caliendo, Angela M.; Olsen, Randall J.; Ashwood, Edward R.; Bale, Sherri; Benirschke, Robert; Carlow, Dean; Funke, Birgit H.; Grody, Wayne W.; Hayden, Randall T.; Hegde, Madhuri; Lyon, Elaine; Murata, Kazunori; Pessin, Melissa; Press, Richard D.; Thomson, Richard B.

To directly support optimal therapeutic decision-making in the routine care of patients with CML, clinical laboratories have been offering accurate and sensitive PCR-based laboratory-developed procedures for BCR-ABL1 for at least the last 15 years. Recognizing that standardization of these LDP's was necessary to promote uniform therapeutic decisionmaking, the laboratory community undertook an extensive multiyear project to create a standardized "international scale" (IS) of measurement for BCR-ABL1 messenger RNA. 92 Follow-up efforts resulted in the creation of a World Health Organization-recognized panel of reference materials directly linked to the BCR-ABL1 IS 93 and the subsequent creation of secondary IS-calibrated reference materials that could be used for routine daily QC in clinical laboratories. 94, 95 Recognizing the additional need for PT, the CAP has been offering semiannual BCR-ABL1 PT surveys for at least 10 years, with a progressive increase in the number of participating laboratories (from *100 in 2009 to *190 in 2016). As proof of the nearuniversal recognition of assay standardization, approximately 90% of these accredited laboratories now report their PCR results using the standardized IS. A 2016 CAP survey confirmed excellent interlaboratory precision, with over 90% of laboratories reporting a BCR-ABL1 IS result within internationally acknowledged acceptable tolerance limits (0.5 logs) for IS reporting of a sample with an approximate 1000-to 10 000-fold reduction in pretreatment BCR-ABL1 levels 96 The primary driving force behind the remarkable increase in longevity and quality of life for patients with CML over the past 15 years has no doubt been the availability of noveltargeted TKI therapies. This has become the paradigm for personalized/precision cancer medicine programs, coupled with parallel effort of the laboratory community toward building, improving, and standardizing accurate, precise, and sensitive laboratory-developed tests for BCR-ABL1. Of note, this 15year targeted therapy program for CML occurred entirely without the availability of FDA-approved BCR-ABL diagnostic reagents, which have only become available in 2016. These FDA-approved assays were based upon those developed in clinical laboratories; they are not approved for diagnosis of CML nor do they cover the spectrum of breakpoints that occur in the disease. During those ground-breaking first 15 years of the targeted cancer therapy era, if the laboratory community had been prohibited from providing high-quality, standardized LDP-based testing under existing CLIA guidelines, the negative consequences to patient care in the past and the future would have been substantial.