Raymond D. Aller, MD, and Hal Weiner
First premarket clearance for next-gen sequencing system
Illumina in November received premarket clearance from the FDA for the MiSeqDx system, the first high-throughput DNA sequencing analyzer to receive FDA clearance. Illumina also received FDA premarket clearance for the MiSeqDx Cystic Fibrosis 139-Variant Assay, MiSeqDx Cystic Fibrosis Clinical Sequencing Assay, and MiSeqDx Universal Kit.
“It’s a great day for medicine,” Greg Heath, senior VP and general manager of Illumina’s diagnostics business, told CAP TODAY. “We’re getting the endorsement of the entire community to move forward with this technology, a versatile tool that all laboratories will use in the not-too-distant future.” A number of companies want to develop assays for Illumina’s NGS platform, he says. The technology’s only limitation, in his view: “The brilliance of those in the community who come up with these tests.”
The MiSeqDx benchtop sequencer offers users the ability to run diagnostic or research applications on a single system designed and validated for the clinical market.
The MiSeqDx Cystic Fibrosis 139-Variant Assay is designed for simultaneous detection of 139 clinically relevant disease-causing mutations and variants within the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The assay includes all cystic fibrosis-causing variants recommended for carrier screening purposes by the American College of Medical Genetics and Genomics and American Congress of Obstetricians and Gynecologists.
The MiSeqDx Cystic Fibrosis Clinical Sequencing Assay leverages Illumina’s targeted resequencing chemistry to provide highly accurate sequencing data for the protein coding regions and intron/exon boundaries of the CFTR gene.
With the MiSeqDx Universal Kit, clinical laboratories can develop their own diagnostic tests. The kit includes library preparation reagents, sample index primers, and sequencing consumables needed for laboratories to develop amplicon assays on the in vitro diagnostic platform.
Francis Collins, MD, PhD, of the NIH, and Margaret Hamburg, MD, of the FDA, in the Nov. 21 New England Journal of Medicine, write that the FDA, along with authorizing the Illumina technology for marketing, recognized the need for reference materials and methods. “As a result,” they write, “the FDA collaborated with the National Institute for Standards and Technology…to develop reference materials consisting of whole human genome DNA, together with the best possible sequence interpretation of such genomes. The first human genome reference materials are expected to be available for public use in the next 12 months.”
The FDA marketing authorization “of a non–disease-specific platform will allow any lab to test any sequence for any purpose,” they write. “Thus, putting in place an appropriate risk-based regulatory framework is now critical to ensure the validation and quality of tests…developed in-house by clinical laboratories.”
Drs. Collins and Hamburg call the arrival of NGS “at this regulatory landmark” only the start: “We need to work together to ensure that research progresses, that regulatory policies are developed, that patients’ rights and needs are addressed, and that clinical use of genomic information is based on rigorous evidence.”
Right test or wrong? Study parses test utilization
Low-volume tests are ordered inappropriately at a higher rate than medium- or high-volume tests, and underutilization in lab testing may be an “underappreciated” problem, according to a study reported Nov. 15 in PLOS ONE (8[11]:e78962.doi: 10.1371/journal.pone.0078962).
The study, led by investigators at Beth Israel Deaconess Medical Center and titled “The landscape of inappropriate laboratory testing: a 15-year meta-analysis,” also found that, on average, initial testing (during a patient’s initial exam) has a higher overuse rate than repeat testing (same tests repeated during hospital stay).
According to the analysis, the overall mean rate of overuse is 20.6 percent, and the underuse rate is 44.8 percent (but based on fewer total study measures). Overuse during initial testing, at 43.9 percent, was higher than during repeat testing, 7.4 percent.
Overuse of low-volume tests, at 32.2 percent, was three times that of high-volume tests, 10.2 percent. “This may result from a relative lack of familiarity with low- vs. high-volume tests among physicians,” write the authors. “However, when taking into account the total number of inappropriate tests, on a per-order (as opposed to per-analyte) basis, high-volume tests likely represent the bigger target for improvement.”
A multi-database systematic review was performed on published studies from 1997 through January 2012. Initially, the authors cast a wide net and came up with 34,000 papers, but after a filtering and refining process, they examined 42 papers covering 1.6 million orders of 46 of the 50 most commonly ordered lab tests. The authors acknowledge one could argue that the number of studies and study measures reviewed is small relative to the total number of tests and clinical scenarios encountered in practice. “In part this arises from our decision to include studies of utilization only if they explicitly addressed the appropriateness of the tests. This restriction was necessary to avoid confusing the number of tests being ordered (utilization) with the appropriateness of those tests (e.g. to distinguish low overutilization from high underutilization).”
Xalkori granted regular FDA approval
The FDA has granted Pfizer’s Xalkori (crizotinib) regular approval for the treatment of patients with metastatic ALK-positive non-small cell lung cancer as detected by an FDA-approved test. Xalkori was previously granted accelerated approval in August 2011.
The FDA’s action is based on data from the phase three PROFILE 1007 confirmatory trial comparing Xalkori to standard chemotherapy in previously treated patients. The results of this study were published in the June 20, 2013 issue of the New England Journal of Medicine. Median progression-free survival was 7.7 months in the crizotinib group and three months in the standard chemotherapy group. Response rates were 65 percent with crizotinib, 20 percent with chemotherapy.
New use for Siemens Tissue Preparation Solution
The Siemens Tissue Preparation Solution now makes it possible for molecular pathology laboratories to extract high-quality nucleic acids from fresh frozen tissue as well as from formalin-fixed, paraffin-embedded tissue.
Sample input is flexible and includes resected or biopsy FFPE tissue, pulverized or homogenized fresh frozen tissue, tissue microarray cores, and laser capture microdissected cells. “All of these tissue types can be consolidated into a single run,” says Ellen Sampson, senior global product manager, molecular diagnostics, Siemens Healthcare Diagnostics. Sampson says the fully automated process and universal reagents kit can co-purify RNA and DNA from a single tissue sample.
Microarray to optimize antimicrobial therapy
A study that evaluated the effect of rapid organism identification and resistance detection by the Verigene Gram-Positive Blood Culture microarray assay on outcomes for patients with enterococcal bacteremia found a 21.7-day mean per patient reduction in hospital length of stay. The mean per patient savings in hospital costs was $60,729.
Published in the Journal of Clinical Microbiology (2013;51[12]:4008–4011), the study took place at the University of Florida Health Jacksonville. A pre-post quasi-experiment compared inpatients with enterococcal bacteremia from February to September 2012 (pre-intervention) and September 2012 through February 2013 (post-intervention). An infectious diseases and/or critical care pharmacist was contacted with microarray assay results, and antibiotics were recommended. Clinical and economic outcomes were assessed for 74 patients.
The authors write: “Mean time-to-appropriate antimicrobial therapy was 23.4 hours less for patients in the post-BC-GP group, compared with patients in the pre-BC-GP group (48.5 vs 25.1 hours; P= 0.005). There was a non-significant decrease in the time-to-appropriate antimicrobial therapy for patients with VSE [vancomycin-susceptible Enterococcus] bacteremia (40.2 vs 18.6 hours; P=0.115). For patients with VRE [vancomycin-resistant Enterococcus] bacteremia, a 31.1-hour decrease in mean time-to-appropriate antimicrobial therapy was appreciated between the pre- and post-BC-GP groups….”
The authors acknowledge the small sample size—46 and 28 patients in the pre- and post-BC-GP groups, respectively. In addition, they say the data were extracted retrospectively in a non-blinded manner from the electronic health record, and accurate documentation was assumed.