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Enabling Clinical and Translational Research

Biomarker Network


Molecular Medicine Ireland has been asked to facilitate the establishement of an Irish Biomarker Network and with this in mind will hosted the Irish Biomarker Inaugral Workshop ‘Improved Translation of Biomarkers to the Clinic’ on Thursday November 4th Croke Park Conference Centre in Dublin which was a great success and a tribute to the active engagement and contribution of the speakers, chairs and audience alike.
 
 
The Workshop was well attended with over 100 academics, clinicians and industry representatives united in their interest in biomarkers. Dr Ruth Barrington CEO of MMI opened the Workshop and welcomed the attendees from all corners of the island of Ireland, the UK and most especially the keynote speaker Dr Francis Kalush, Network Leader for the Diagnostics (In vivo and In Vitro) and Personalised Medicine Network from the FDA and the guest Chair Mr Don Black, Director of MHICC/Trialynx Inc. and the International Partnership for Critical Markers of Disease, both having travelled from the USA for this Workshop. Dr Barrington mentioned that MMI had been approached by principal investigators in the partner institutions to assist in the establishment of a Biomarker Network and emphasised that this event was the first public manifestation of work that has been underway for a number of months. The representatives from the MMI partner institutions engaged to date include Prof. Dolores Cahill, UCD, Prof. Louise Kenny UCC, Prof. Mark Lawler TCD, Dr. Nicola Miller, NUIG and Prof. Alice Stanton, RCSI.

Dr Barrington presented the key objectives of the Workshop which were as follows:

  • To address some of the key hurdles in translating biomarkers to the clinic, in particular the European and FDA regulatory requirements
  • To share the expertise and insights of those who have successfully developed or are currently developing and validating biomarkers for clinical use
  • To explore the interest in the establishment of an Irish Biomarker Network and to define the objectives and values of such a Network and how it could best assist in biomarker discovery, validation and translation to the clinic.
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Workshop Programme and Presentations

Workshop Proceedings

 Improved Translation of Biomarkers to the Clinic

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Programme and Presentations


MMI hosted the inaugural Irish Biomarker Network Workshop on Thursday 4 November 4th 2010 at the Cusack Stand Conference Centre, Croke Park in Dublin.

The key objectives of this Workshop were to bring together clinicians and scientists working in biomarker research in Ireland with a focus on;

  • Addressing some of the key issues in translating biomarkers to the clinic.
  • Exploring the value and key objectives of an Irish Biomarker Network.

Opening of the Irish Biomarker Network Workshop

The Irish Biomarker Network Workshop was opened by Dr Ruth Barrington, CEO of MMI.

Session I : Overview of the background to the establishment of an Irish Biomarker Network.

Professor Dolores Cahill, Professor of Translational Science, School of Medicine & Medical Science, UCD.

Please click here to download presentation.

 

Session II : The FDA and European perspectives on the regulatory requirements for the validation of biomarkers in clinical trails.
Chair: Dr Donald Black , formerly of Merck and GE Healthcare and now Director of MHICC/Trialynx Inc. and the International Partnership for Critical Markers of Disease (CMOD), USA.
The FDA perspective.

Keynote Speaker: Dr Francis Kalush, Network Leader for the Diagnostics (in vivo and in vitro) and Personalised Medicine Network.

Please click here to download presentation.
The Irish and European perspective.

Dr Sarah O'Meara, Pre-Clinical Assessor, Irish Medicines Board.

Please click here to download this presentation.

  

Session III : Shared experiences in the evaluation and clinical validation pathway for biomarker discovery and development.

Chair: Dr Tom Lillie, Executive Director, Hematology-Oncology Therapeutic Area, Amgen, Uxbridge, UK.

Biobanking for Biomarker Discovery in Obstetrics and Paediatrics - Lessons learned from the SCOPE and BASELINE studies.

Professor Louise Kenny, Professor of Obstetrics and Consultant Obstetrician and Gynaecologist. The Anu Research Centre, Cork University Hospital and UCC.

Please click here to download presentation.

uPA as a biomarker for breast cancer: from pilot studies to recommendation for clinical use

Professor Joe Duffy, Professor of Pathology and Laboratory Medicine, St, Vincent's University Hospital and UCD.

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Molecular Diagnostics Research Group Commercialisation Activities

Dr Thomas Barry, Molecular Diagnostics Research Group, NUI Galway.

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Widespread Dysregulation of miRNAs in Neuroblastoma: Association of miRNA Expression with Survival.

Dr Isabella Bray, Cancer Genetics Group, RCSI.

Please click here to download presentation.

Developing Microarray Based Diagnostics

Professor Paul Harkin, Professor in Molecular Oncology Queen's University Hospital and President & Managing Director, Almac Diagnostics.

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Speakers Biography- Please click here to view the speakers biographies.

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Workshop Proceedings

Overview of the background to the establishment of an Irish Biomarker Network

Prof. Dolores Cahill, UCD set the scene by describing discussions that PIs have around biomarker discovery, validation and commercialisation and the issues encountered. The idea of establishing a biomarker forum to address some of these issues was conceived and MMI was approached as the vehicle to facilitate a Network. Prof Cahill acknowledged the support of the Board of MMI which approved the establishment of a Biomarker Network as one of its initiatives and sought representation from each of the MMI partner institutions to progress this agenda. Prof. Cahill presented the proposed objectives of a Biomarker Network that were discussed by the MMI partner institutions which include; coordinating expertise across the biomarker discovery, development and clinical validation spectrum that could support PIs; sharing of biomarker proposals across a secure website; lobbying of funding and enterprise agencies to fund strategic developments in biomarker commercialisation; information on the practical aspects of regulatory compliance; alignment with the national biobanking initiative; building links with international biomarker and biobanking networks; alignment with the clinical trial cooperatives, in particular for the opportunity to procure pre-treatment samples; exploring the potential for a demonstration project as a flagship for the Network; building a biorepository of patient and healthy control samples that could be shared for national and international collaborations.

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The FDA and European perspective on the regulatory requirements for the validation of biomarkers in clinical trials

Dr Black opened the regulatory session by discussing his long standing interest in biomarkers and introduced the work of Critical Markers of Disease (CMOD) Consortium, which brings together academics, industry and regulatory representatives to advance the development of biomarkers. He announced that the next CMOD international biomarker conference will be held in Dublin Castle on June 26-27 2011 in concert with IMB, EMA, FDA, Health Canada and MMI.

Dr. Francis Kalush – The FDA perspective
Dr. Francis Kalush, in her comprehensive presentation provided a detailed overview of the FDA activities and initiatives for personalised medicine; the regulatory framework developed by the FDA to accommodate companion drug/diagnostics; the streamlining of the co-development process and details of the different centres in the FDA that provide consultative opportunities for early phase development of a biomarker and a drug. Dr. Kalush emphasised that in the drug-diagnostic development pathway, when a diagnostic test is used for patient stratification, the efficacy and safety of the drug becomes inextricably linked to the effectiveness and safety of the diagnostic and therefore the diagnostic test needs to be approved with the drug and its use included in the drug labelling.

Dr Sarah O’Meara – the IMB and European perspective
Dr. Sarah O ‘Meara presented the current IMB and European perspective on biomarkers and outlined the regulatory considerations and guidance that have been adopted by the EU and globally to assist stakeholders in validating and qualifying new biomarkers. Dr O’Meara provided an overview of the EMA supports for researchers of biomarkers in drug development, including the EMA Pharmacogenomics Working Party informal briefing meetings, the scientific advice offered by the Scientific Advice Working Party on protocol assistance for biomarker qualification, market authorisation evaluation and guidance documents on biomarkers. Dr O’Meara advised that there are a number of guidance documents published and adopted by the EMA in this area which are available at http://www.ema.europa.eu. Dr O’Meara also provided an overview of the qualification procedure for biomarkers and indicated that the EMA and FDA have concluded the first joint qualification process for biomarkers which included the qualification of seven biomarkers of drug-induced renal toxicity in the context of non-clinical drug development. It was noted that the use of biomarkers in clinical trials is considered interventional according to the Clinical Trial Directive 2001/20/EC and comes within the scope of the legislation thereby requiring Competent Authority approval. Dr. O’Meara acknowledged the lack of harmonization in Europe with regard to the application of the clinical trial legislation for biomarkers which is recognised by the EU Commission and Member States. Dr O’Meara indicated that clarification will be sought on clinical trials involving biomarkers at the next amendment to the Clinical Trial Directive 2001/20/EC.

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Case studies of biomarker discovery, development and clinical validation

Dr. Tom Lille from Amgen set the scene for the case study session by outlining how biomarkers underpin personalised medicine through improved efficacy and safety for patients, increased cost effectiveness and improved clinical trial design and outcomes.

Prof. Louise Kenny - Biobanking for Biomarker Discovery in Obstetrics and Paediatrics
Prof. Louise Kenny from Cork University Maternity Hospital and UCC presented a comprehensive overview of the need for biomarkers in obstetrics and paediatrics and specifically diseases of late pregnancy. Prof Kenny discussed the specific challenges for biomarker discovery in obstetrics and paediatrics and the strategies her group has adopted to overcome these, in particular for metabolomic biomarkers. Prof. Kenny described SCOPE, a global consortium which has developed a unique international pregnancy biobank of samples from 7,500 women with detailed clinical phenotypes, known and novel clinical risk factors, well characterised disease phenotypes and a comprehensive bank of quality specimens for biomarker discovery and evaluation. SCOPE has achieved harmonisation globally through the implementation of standardised procedures across centres which have been pre-approved by the FDA for biomarker discovery.

Prof. Joe Duffy - uPA as a biomarker for breast cancer: from pilot studies to clinical use
Prof. Joe Duffy from St Vincent’s University Hospital and UCD presented an important clinical dilemma for clinicians which is treatment of lymph node negative breast cancer patients and how to differentiate those with aggressive from those with indolent cancer. Prof Duffy’s early research demonstrated that uPA and its inhibitor PAI-1 provided additional data for breast cancer patient management to that of conventional prognostic factors, including ER status and lymph node status, a key requirement for the use of biomarkers in clinical decision making. The validation of uPA and PAI-1 as an independent prognostic factor in lymph node negative breast cancer was confirmed by greater than 20 independent groups. Prof Duffy detailed the clinical validation of uPA and PAI-1 in breast cancer internationally in two independent level one studies, both in a randomised prospective multi-centre clinical trial and in a pooled meta analysis (with both published and unpublished studies) in over 8,000 patients. The American Society for Clinical Oncology (ASCO) recognised these results for uPA and PAI-1 and recommended their use for the determination of prognosis in patients with newly diagnosed node negative breast cancer.

Dr Thomas Barry - Commercialisation of diagnostic markers for infectious diseases
Dr Thomas Barry presented the expertise of the Molecular Diagnostics Research Group (MDRG) at NUI Galway which is focused on discovery and development of unique diagnostic markers for infectious disease caused by bacteria and fungi, food pathogens and environmental water contamination pathogens. Dr Barry discussed the strategy adopted by the MDRG in bringing diagnostic markers to the clinic. In the absence of a large clinical sample population, the Group focussed on the generation of a significant intellectual property portfolio around the biomarkers they have discovered, in the region of 30-40 infectious disease agents. This required the Group to become industry compliant and to implement good laboratory practice in order to validate the diagnostic markers to a level that was acceptable to industry. This focus on commercialisation has resulted in the technologies developed being associated with three of the top six in-vitro diagnostic multinational companies in the world. Dr Barry highlighted that one of the significant personal challenges in this approach to biomarker discovery and generation of IP was the lack of freedom to publish the research. However, once IP was protected the Group published 25 peer reviewed publications in the area of molecular diagnostics for infectious diseases.

Dr Isabella Bray - microRNA as biomarkers in cancer
Dr Isabella Bray, of the Cancer Genetics Group at the RCSI discussed microRNA as biomarkers in cancer and highlighted that several independent studies across different cancers have demonstrated significant differential expression of miRNA associated with this disease, for example upregulation of miR-21 associated with multiple cancers. Dr. Bray highlighted the association of the miRNA signature with poor survival in neuroblastoma. Dr. Bray concluded with the potential for the miRNA expression signature, combined with analysis of segmental imbalances, to provide greater prediction of survival outcome in patients with neuroblastoma than current markers used which in turn should improve patient treatment stratification.

Prof. Paul Harkin - the DSATM multigene assays for cancer
Prof. Paul Harkin, from Queen’s University Hospital and Almac Diagnostics provided a comprehensive overview of some of the critical factors in discovering multigene assays, discussed the DSATM and Xcel Array technology platform developed by Almac Diagnostics for use with formalin fixed paraffin embedded material and discussed Almac’s Col-Dx assay which predicts for relapse in stage II colon cancer. Prof. Harkin highlighted a key point which is not always appreciated in the transition from development to analytical and clinical validation which requires all components of the test to be validated together in order to meet regulatory requirements including how the samples are collected, the assay itself, the instrumentation used to run the assay, reagents and integrated software. Prof Harkin focused on the study design for biomarker discovery and validation, in particular recognising two critical components, biological and technical. Prof Harkin presented Almac Diagnostic’s choice of technology platform for biomarker discovery and clinical validation which is RNA based biomarker discovery using microarray technology. Based on this technology, Almac Diagnostics has developed a number of disease specific microarrays for ovarian, breast, colorectal, lung and prostate cancer in partnership with Affymetrix, which encode 50-60,000 transcripts for these disease types for which 30-40% of this content will not be found in any other commercial microarray.

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Lessons learned and experience shared from case studies

  • The importance of appropriate study design, accurate statistical methodology and planning for biomarker discovery and validation.
  • The need for pristine phenotyped clinical data and high quality standardised samples using rigorous SOPs is essential.
  • The need for appropriate patient and/or population cohorts which are adequately powered for biomarker validation studies and verification of the clinical validation in independent studies.
  • The importance of future-proofing and harmonisation in biomarker discovery and development programmes especially with regard to samples, phenotypic data and the informed consent model.
  • The use of the correct technology platform with appropriate bioinformatics is key.
  • Effective biomarker discovery and development needs to control for biological, operator, different centre and reagent effects to distinguish signal from background.
  • Advice on IP protection should be sought before any disclosure which may involve complex multi-institution licensing and revenue sharing agreements. It is best that the licensing agreements are signed off before the work begins. One contact, preferably with the correct skill set, should be the key negotiator in this process.
  • Commercial partnerships are the most likely endpoint for biomarker development in the academia arena.
  • For biomarkers being developed for clinical use, the assay technology needs to be simple to perform.
  • Independent clinical data and sample monitoring for quality control and quality assurance is key.
  • The true measure of the value of a biomarker is that it drives patient management and influences clinical practice thereby adding value to the healthcare system.

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Facilitated discussion on the value, focus and the key objectives of an Irish Biomarker Network

Prof Dermot Kelleher led a provocative and constructive discussion on the value, focus and the key objectives of an Irish Biomarker Network which concluded with great enthusiasm and a resounding agreement for the concept of such a Network. It was agreed that the Irish Biomarker Network should be inclusive of all academics with an interest in biomarkers on the island of Ireland and should involve a relationship with industry and with the regulatory authorities. The Network should also involve key stakeholders including patient organisations and ethicists.

The following objectives were proposed for an effective, co-operative Network:

  • The importance of appropriate study design, accurate statistical methodology and planning for biomarker discovery and validation.
  • The need for pristine phenotyped clinical data and high quality standardised samples using rigorous SOPs is essential.
  • The need for appropriate patient and/or population cohorts which are adequately powered for biomarker validation studies and verification of the clinical validation in independent studies.
  • The importance of future-proofing and harmonisation in biomarker discovery and development programmes especially with regard to samples, phenotypic data and the informed consent model.
  • The use of the correct technology platform with appropriate bioinformatics is key.
  • Effective biomarker discovery and development needs to control for biological, operator, different centre and reagent effects to distinguish signal from background.
  • Advice on IP protection should be sought before any disclosure which may involve complex multi-institution licensing and revenue sharing agreements. It is best that the licensing agreements are signed off before the work begins. One contact, preferably with the correct skill set, should be the key negotiator in this process.
  • Commercial partnerships are the most likely endpoint for biomarker development in the academia arena.
  • For biomarkers being developed for clinical use, the assay technology needs to be simple to perform.
  • Independent clinical data and sample monitoring for quality control and quality assurance is key.
  • The true measure of the value of a biomarker is that it drives patient management and influences clinical practice thereby adding value to the healthcare system.

Next Steps for the Irish Biomarker Network

  • MMI to convene a meeting in January/February 2011 with those interested in engaging and participating in the Irish Biomarker Network to develop and to agree a work programme based on the key objectives as outlined above.
  • MMI to convene a meeting with EI/IDA to determine how they might like to engage with the Irish Biomarker Network and how to fulfil industry requirements in the area of biomarkers.
  • MMI to convene a meeting with the IMB to determine how they might like to engage with the Irish Biomarker Network and to ensure that the regulatory perspective is incorporated in the Network work programme.
  • The Biomarker Coordinating Group to establish working groups with responsibility for the delivery of specific areas of the work programme.
  • MMI to work with the Biomarker Coordinating Group to plan discuss the organisation of a parallel session for the Irish Biomarker Network at the Critical Markers of Disease International Conference on Biomarkers in June 2011
  • MMI to propose potential speakers for the Critical Markers of Disease International Conference on Biomarkers to be held in June 2011.

To downlaod a copy of the Proceedings for the Irish Biomarker Inaugural Workshop click here

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