Analysis of biomarkers has become an integrated part of biomarker discovery and development. The contributions bioanalytical scientists are an essential cornerstone of any biomarker campaign. In its recommendation on biomarker bioanalysis, the European Bioanalysis Forum (EBF) emphasizes to broaden the focus of the bioanalytical scientist beyond pure bioanalytical process and science considerations. The importance of connecting all stakeholders involved when developing a bioanalytical strategy for biomarkers cannot be underestimated. The resulting peer discussions will safeguard a smart integration of all scientific aspects of the biomarker with bioanalytical considerations and compliance to existing regulations.
The EBF is a nonprofit organization comprising bioanalytical scientists from EU-based R&D companies. Founded in 2006, it currently counts 49 member companies. We share, discuss and seek alignment on many bioanalytical topics including science, process and technology. Our discussions aim at recommending or influencing opinions/procedures of our members, business partners and regulators.
Biomarkers are increasingly important in drug development. Except for CLIA-managed laboratories, limited specific regulations exist. Current US FDA or European Medicines Agency guidelines do not cover biomarker assays. Different views on how to approach the bioanalysis of biomarkers have been published or are being developed. The EBF has recently published their recommendation on method establishment and bioanalysis of biomarkers.
EBF emphasizes that biomarker bioanalysis requires the integration of all scientific aspects (from analytical challenges to understanding the biology of the biomarker) before starting method establishment or sample analysis. Close interactions with the teams requesting the biomarker data are imperative to develop a robust bioanalytical strategy, which combines scientific aspects and desired compliance to regulations. The EBF developed a decision tree to guide the scientific community when developing a bioanalytical strategy for biomarkers.
Although all our discussions referred to biomarker requests entering the regulated bioanalysis laboratory, the principles of our recommendations may apply to other areas such as diagnostics, commercial kits or similar.
In summary, the EBF recommends to:
Consider four classifications when defining assay requirements:
Biomarker concentration changes;
Development phase in which the analysis is requested;
Decisions taken from the data;
Possible fit of the assay with regulated bioanalysis guidelines.
Ensure solid communication between the bioanalytical team and the investigator requesting the data.
Apply tiered approach principles when defining assay performance. In case assay performance needs to comply with regulated bioanalysis requirements, allow flexible and scientific interpretation of these guidelines.
Apply a stepwise approach when developing your assay. Ensure you understand the science of the biomarker before starting method establishment and sample analysis.
Written by Philip Timmerman et al. (European Bioanalysis Forum)
Source: Timmerman P, Herling C, Stoellner D et al. EBF Recommendation on method establishment and bioanalysis of biomarkers in support of drug development. Bioanalysis 4(15), 1883–1894 (2012).
The Japanese manufacturer, Shimadzu Corporation (Kyoto, Japan), has recently announced a collaboration with the RIKEN Innovation Center (Saitama, Japan). The company, who sponsor a laboratory at the research institution, aim to investigate the use of LC–MS/MS for microdosing in drug development.
In clinical trials, microdosing is the process of studying the pharmacokinetics of a very low administered dose of a potential therapeutic. Doses as low as one-hundredth of the usual sample volume required for a pharmacological effect are given to patients, where various analytical methods are used to assess the outcome. This process can greatly accelerate the drug-development process by discarding unsuccessful drug candidates before Phase I trials.
LC–MS/MS is often used in microdosing experiments, as it offers quantification of the analyte at very low concentrations, as well as providing detailed structural analysis. This method leads to accurate pharmacokinetic studies, where ‘cassette dosing’ is possible – a process where various candidate compounds can be compared side-by-side.
The Sugiyama laboratory at the RIKEN Innovation Center, led by bioanalytical researcher Yuichi Sugiyama (University of Tokyo, Japan), was established in April 2012. The aim of this partnership is to allow further development of Shimadzu’s MS systems that can be used for trace-drug analysis. The company envisages this leading to an improved MS system for accurate pharmacokinetic analysis on a micromolar scale.
– Written by Alice O‘Hare
Source: Shimadzu starts research with RIKEN on using LC–MS/MS to support drug discovery using microdosing; www.shimadzu.com/an/news-events/2012/riken.html
GlaxoSmithKline plc (GSK), the UK-based pharmaceutical and healthcare company, has recently announced that it is to acquire US-based biotech Human Genome Sciences (HGS). The two companies have entered into a definitive agreement under which GSK will acquire HGS for US$14.25 per share, in cash, following amendment of its initial offer of $7.17 per share made on Wednesday 18th April 2012.
The improved second proposal will value HGS at approximately $3.6 billion on an equity basis or approximately $3 billion net of cash and debt and, as part of the arrangement, GSK will obtain full ownership of Benlysta®, albiglutide and darapladib – valuable assets for which GSK has high long-term hopes. However, following the initial disappointing sales for Benlysta (a new drug for the autoimmune disease Lupus), it may be argued that the true value of the transaction lies with the procurement of albiglutide and darapladib, both experimental medicines for the treatment of Type 2 diabetes and cardiovascular diseases, respectively, with significant promise anticipated for the pair.
CEO of GSK, Sir Andrew Witty, commented, “We are pleased to have reached a mutually beneficial agreement with HGS on friendly terms and believe the combination of GSK and HGS represents clear financial and strategic logic for both companies and our respective shareholders.” He continued, “This is a natural next step in our nearly 20-year relationship with HGS.”
President and CEO of HGS, H Thomas Watkins, said, “After a thorough analysis of strategic alternatives, HGS has determined that a combination with GSK is the best course of action for our company and the best way to maximize value for our stockholders. HGS has had a long and productive working relationship with GSK and together we will be uniquely positioned to achieve the full potential of Benlysta and other products in our pipeline for the benefit of those battling serious disease around the world.”
GSK see the acquisition as an astute transaction aligned with its long-term strategy of delivering sustainable growth, enhancing R&D returns, simplifying business models and deploying capital with discipline.
– Written by Thomas Payne
Source: GSK to acquire Human Genome Sciences for US$14.25 per share in cash; www.gsk.com/media/pressreleases/2012/2012-pressrelease-1183501.htm
The Wyss Institute for Biologically Inspired Engineering at Harvard University (MA, USA) has entered into a cooperative agreement with the Defense Advanced Research Projects Agency (DARPA) to develop an automated, multiple organ-on-chip system to mimic whole-body physiology. The design will look to incorporate ten different human organ-on-a-chip, including the Wyss Institute’s ‘Human Lung-on-a-Chip’ and ‘Human Gut-on-a-Chip’ technologies.
With the ultimate aim to accelerate drug development, the deal, estimated to be worth up to US$37 million, builds upon the Wyss Institute’s previous research to engineer new microchip devices that recapitulate the microarchitecture and functions of living organs, such as the lung, heart and intestine.
With each chip being approximately the size of a computer memory stick and encapsulated in a translucent polymer, the individual organ-on-a-chip contain a hollow microfluidic channel lined by living human cells providing an insight into human physiology outside the body. By linking these individual organ-on-a-chip technologies together closely, the researchers hope to engineer a system that can control fluid flow and cell viability while permitting real-time analysis of complex biochemical functions.
US FDA Chief Scientist and Deputy Commissioner for Science and Public Health, Jesse Goodman, said that the integrated instrument being developed “has the potential to be a better model for determining human adverse responses. The FDA looks forward to working with the Wyss Institute in its development of this model that may ultimately be used in therapeutic development.”
In the future, the researchers hope that the new platform will act as an accurate alternative to traditional animal testing models and, subsequently, be used to assess drug safety and efficacy of new therapeutic candidates, as well as inform regulatory decision-making and ultimately improve patient outcomes.
Wyss Founding Director, Donald Ingber, and Wyss Core Faculty member, Kevin Kit Parker, will co-lead the 5-year project, which sees a multidisciplinary collaboration between Harvard’s Schools of Medicine, Engineering and Arts & Sciences, as well as Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University and Boston University (MA, USA).
– Written by Thomas Payne
Source: Wyss Institute to receive up to $37 million from DARPA to integrate multiple organ-on-chip systems to mimic the whole; http://tinyurl.com/bvc7qag
In a recent publication, Christian Reichel (AIT Seibersdorf Laboratories, Austria) and Mario Thevis (German Sport University of Cologne, Germany) present their research into the detection of EPO–Fc, an emerging performance-enhancing drug. The scientists offer two potential screens for this agent, which is predicted to ultimately be abused for blood doping.
EPO–Fc is a fusion protein of recombinant human EPO (rhEPO) and the Fc region of an antibody. Following pulmonary administration, this formulation has been shown to be transported by the neonatal Fc receptor across the lungs into the bloodstream. Therefore, scientists in the field predict that this formulation (such as other rhEPO) could be used in the future as a performance-enhancing agent.
The two scientists investigated whether this novel fusion protein can be detected in human serum. Out of various bioanalytical screens tested, two were found to meet the required sensitivity and specificity requirements. The first test utilized a commercial EPO ELISA kit, after concentration of the EPO–Fc in serum via protein A beads (a protein derived from Staphylococcus aureus that binds immunoglobulins). This test presented a LOD of 5 pg EPO–Fc, which was independent of the volume of serum used. In the second approved test, the scientists used an established method in anti-doping control: EPO was immunopurified and separated from the serum via either SDS-PAGE or SAR-PAGE, followed by western blotting and detection via chemiluminescence. This method resulted in an identical LOD, however it allowed additional detection of all rhEPO in the serum sample.
The research is published as an ‘early view’ research article in the journal Drug Testing and Analysis.
– Written by Alice O‘Hare
Source: Reichel C, Thevis M. Detection of EPO–Fc fusion protein in human blood: screening and confirmation protocols for sports drug testing. Drug Test Analysis doi: 10.1002/dta.1381 (2012) (Epub ahead of print).