Labceutics and Asuragen announced this week that that they will conduct an international, multi-center quality assurance study to track standardization across labs conducting BCR-ABL1 testing on the International Scale.
According to Labceutics, the study will measure how variable testing is among labs in Europe for monitoring BCR-ABL transcript levels to ensure that chronic myeloid leukemia patients have the disease and that they aren't relapsing while being treated with Novartis' Gleevec (imatinib) or newer tyrosine kinase inhibitors. "The study will be a quality assurance scheme modeled on existing External Quality Assessment programs to evaluate the inter-laboratory variability of BCR-ABL1 RT-qPCR results using different standardization modalities," Labceutics said in a statement.
Although Gleevec has been on the market for more than a decade, there is a lack of standardized procedures and reference materials in leukemia monitoring, which can make it difficult to compare results obtained from different labs.
Under the terms of the agreement, Labceutics will conduct the study, analyze the data, and report the results. Asuragen will provide analytical reference materials that are calibrated to the primary international reference standards of the World Health Organization. Published by the European LeukemiaNet consortium, the International Scale was developed with numerous stakeholders at the National Institutes of Health to serve as a global standard for detecting and reporting BCR-ABL transcript levels.
Labceutics has recruited labs in five countries in Europe to participate in the study. Labs participating in the study will be blinded to other labs that are involved in the trial, and will have to use their own protocols to conduct BCR-ABL testing and then compare this against testing using the calibrators from Asuragen. Labceutics will provide the participating labs with a report on inter-lab variability and plans to work with them through a series of "consensus and integration forums" to establish BCR-ABL testing standards.
"Our approach here is not merely to report variability as previous studies have done, but to collaborate as required with our laboratory network to improve the overall quality of BCR-ABL testing and reporting," Maria Fe Paz, Labceutics managing director, told PGx Reporter over email. "Assuming this very 'hands on' approach works, we hope to illustrate it as the model for future companion diagnostic rollouts and to illustrate the problem solving power of involving laboratories much, much earlier in the commercialization of testing."
CML is a cancer of the white blood cells caused by unregulated growth of myeloid cells. A translocation of chromosomes 9 and 22 results in the BCR-ABL fusion gene that drives proliferation of myeloid cells in the bone marrow and in the blood. Typically, testing for the BCR-ABL1 fusion gene is conducted by RT-qPCR to further track the treatment response of CML patients who have already achieved cytogenetic response. As such, standardized testing methods could help doctors more reliably manage patients receiving tyrosine kinase inhibitors such as Gleevec, Novartis' Tasignia, and Bristol-Myers Squibb's Sprycel, and compare results across labs and patients.
"The aim is more reliable and accurate test results that ultimately will improve the management of patients with CML," Emmanuel Labourier, Asuragen's director of clinical development, said in a statement. "The use of stable and commutable ARQ IS Calibrator Panels, based on our well-characterized and clinically validated Armored RNA technology, will give laboratories the ability to directly generate IS compatible results without the lengthy and complex process of sample exchange."
Labceutics, a subsidiary of personalized medicine-focused consultancy Diaceutics, aims to drive adoption of personalized medicine by facilitating the broad availability of companion tests across the 14,000 labs in the EU that operate in a decentralized fashion. The company polled 31 labs in Spain, Italy, Germany, France, and the UK between September and December of 2011 in an effort to identify the barriers the industry faces when adopting new companion tests for personalized medicine products.
The survey, conducted by Delphi, revealed that "pharma has forgotten laboratories are a critical stakeholder" in commercializing their personalized drugs, Labceutics said (PGx Reporter 3/14/2012). According to the survey, 64.5 percent of labs said that the most frequent way they find out about a new test is that the lab manager reads about it in a publication; 16.1 percent hear about new tests most readily from doctors; and 12.9 percent said they learn of new tests in some other way. Only 6.5 percent of labs polled said they were contacted directly by a drug company about a new companion test.
"One of the main reasons Labceutics was created is to help ensure that pharmaceutical and diagnostic companies have access to well-organized quality assurance laboratory testing services across Europe, where the laboratory market is very fragmented," Fe Paz said in a statement. "Demand for companion diagnostic testing is increasing rapidly across Europe and greater involvement of the laboratory community is essential if we are to ensure physicians have the right test at the right time. This study is an example of laboratory collaboration on a pan-European scale."
In deciding to conduct the current quality assurance study, Labceutics felt that inter-laboratory variability in BCR-ABL testing would be "the classic companion diagnostic challenge."
"On the surface, this is a diagnostic area which has all the component parts for success — the marker is quantitative and has high clinical utility to guide imatinib treatment response," Fe Paz said. "In fact, you could say that imatinib was a posterchild in personalized medicine transforming the management of CML."
Two years ago, Cepheid and Novartis announced they were collaborating on the development of a test for monitoring BCR-ABL gene transcripts to help doctors more reliably manage Philadelphia chromosome-positive CML patients treated with Gleevec and other TK inhibitors (PGx Reporter 10/13/2010). The companies have said they plan to file for regulatory approval for the test through the US Food and Drug Administration.
"Novartis has invested heavily to ensure there are numerous guidelines recommending [BCR-ABL testing], both IVD kits and [lab developed tests] are available, and finally there have been previous external quality assessment studies looking at inter-laboratory variability," Fe Paz noted. "In spite of this, the twin problems of low levels of laboratory conformity to a published standard and limited diffusion of the test across European laboratories have impacted clinical management of CML."
Launching a drug/test combination product in Europe is already challenged by the country specific regulations and reimbursement requirements. Adding to this, Fe Paz has observed that when launching companion tests for drugs, pharmaceutical companies tend to focus on educating opinion leaders in the physician community and on delivering the test in a quality-assured manner through a limited number of laboratories. "And where testing has migrated slowly beyond this initial core laboratory grouping, they have defaulted to use of LDTs and their own samples/references as is the norm in an unmanaged laboratory rollout," she noted.
Labceutics is hoping to publish the results from this quality assurance study in a peer-reviewed journal and at medical conferences, in order to demonstrate that a more integrated and standardized system of molecular testing across labs can facilitate a more stable market for personalized medicine products.
"We want to use this [study] as a benchmark for all of us at the frontier of personalized medicine, illustrating that it is insufficient just to launch new tests or publish guidelines or assume that laboratories and or diagnostic companies will solve these problems without rolling up your sleeves and working with the stakeholder who has to integrate all of this," Fe Paz said.