The Biomarkers Consortium is an opportunity for public and private entities to join forces and pool resources in order to advance biomarkers research, an exciting and challenging mission. This novel experiment is an exciting and challenging endeavour that is presently undergoing evaluation and restructuring in some areas, to improve and optimise the identification, funding, and implementation of cross-sector biomarker projects.
Biomarkers have the potential to streamline and even revolutionise investigations of pathobiology, the conduct of clinical trials, and regulatory decision-making for drugs and therapeutics. This promise serves as the foundation and impetus for a novel public-private partnership initiated in October 2006 and known as The Biomarkers Consortium (BC). BC partners represent government, pharmaceutical and biotechnology industry, patient advocacy groups, private organisations and the public. All partners share the common interests of discovery, development and qualification of biomarkers for use across the spectrum of biomedical research and practice. The Foundation for the National Institutes of Health (FNIH), a free-standing charitable foundation with a congressionally-mandated mission to support the mission of the NIH, is the managing partner for the BC. The National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), The Pharmaceutical Research and Manufacturers of America (PhRMA) are the consortium’s founding partners. The BC is unique in its commitment to working together in a cross-sector and pre-competitive fashion.
The genesis of the Biomarkers Consortium was initially with PhRMA, the trade organisation for the pharmaceutical industry. In discussion with the NIH and FDA, the shared need for robust and meaningful biomarkers, well characterised for use and widely available to all, was self-evident.
In light of the differing missions of the parties, the value of biomarkers to each also differs somewhat, but the need is compelling for each of the partners. Furthermore, the value proposition for working in the context of a
public-private partnership provides additional motivation for each of the parties participating in the BC.
The value proposition for NIH lies within the agency’s mission to improve the public health through biomedical research. The scope of the research undertaken within the NIH’s 27 institutes and centres ranges from basic mechanistic work, to elucidate underlying biological mechanisms of health and disease all the way, to late phase clinical trials, and includes everything between those two poles. Biomarkers are indicators of biological mechanisms and also serve as probes for pathobiological processes. To the extent that biomarkers may serve as a bridge connecting animal models of disease with human signs and symptoms of disease, they provide an excellent tool for translational research. Biomarkers in the setting of clinical research allow for the detailed characterisation of patients, allow stratification of subjects in clinical trials, and can demonstrate evidence of the effect of study interventions. And finally, biomarkers will provide useful and novel tools for clinical decision-making.
Biomarkers provide metrics and indicators of both safety and toxicity for drugs and interventions. Having an available corpus of research information and consensually recognised regarding the nature, character and utility of biomarkers will facilitate the FDA’s ability to make informed and timely decisions on regulatory matters. Having biomarkers that are generally accepted and supported by a peer-reviewed literature improves the body of regulatory science on which regulatory decisions can be based. Furthermore, the availability of consensually agreed upon biomarkers used broadly by sponsors working in the same therapeutic areas provides a basis for comparison that also may ease and speed regulatory decision-making.
The industry is facing a crisis in drug development that is manifest, in part, by rapidly and steeply rising costs to drug development programmes. The cost is related, in part, to the need to do extensive clinical trials involving large numbers of subjects and with relatively distant endpoints. The availability of robust and qualified biomarkers is expected to facilitate the identification of patients for clinical trials who are likely to benefit from an intervention and are less likely to experience adverse effects as a result of the intervention. Such pre hoc stratification of potential trial participants is expected to permit the enrollment of smaller numbers of patients in trials in order to show efficacy, fewer trials discontinued as a result of toxicity, and thereby lower costs as well as potentially reduce the likelihood of post-marketing failures due to toxicity. Furthermore, biomarkers qualified to function as surrogate endpoints will allow clinical trials of shorter duration, also providing potential for significant cost savings.
Taken together, these benefits derived from the availability of robust and qualified biomarkers should serve to improve the ability to do discovery science relevant to disease and treatment, promote drug development by both speeding the process and reducing the overall development costs, and improve the ability to make timely and informed regulatory decisions, thus providing a nexus of common interest for all of the founding partners.
The value proposition, however, extends beyond the interests of the founding partners. The development of the notion of personalised medicine is dedicated to the provision of the right treatment (or intervention) for the right patient at the right time. Patient groups and clinicians can benefit from the availability of biomarkers for the assessment of risk; for diagnosis; for stratifying patients with a given risk or diagnosis into prognostic categories; for assessing status of a disease with respect to disease activity and disease-related organ damage; as well as for assessing beneficial and / or adverse effects of a therapy or intervention. In recognition of the uses and needs for biomarkers, a number of patient advocacy groups and professional organisations have also joined the BC.
The process of forming the BC was characterised by several important lessons: Key lessons related to communication, cross-cultural understanding, and negotiation. A critical element to the success of the organising process was the fact that all of the founding partners were committed to making a consortium and were therefore committed to making all reasonable efforts to come to an agreeable structure and process, even when coming to consensus was difficult or time-consuming.
An organising committee was composed of high level staff from all founding partners as well as legal counsel when needed. This group was charged with the task of defining the specific goals of the BC, suggesting a structure that would permit the accomplishment of these goals and which would be sensitive to the different practices, cultures and constraints of all of the partners. Over the space of months and many meetings, an umbrella structure was developed which was presented to the initial executive committee and ratified without significant change.
The structure of the BC rests on the premise that all activities of the BC will be pre-competitive in nature. This translates to mean that the goal and expected outcome of BC activities is not to generate new intellectual property, but rather to generate new knowledge and information that will be made available to the public (There are a number of nuances to this statement relating to human subjects protections, the use and contribution of pre-existing IP to the activities undertaken within the BC, and possible regulatory applications that may relate to BC generated work products that will be discussed further below). Working together in pre-competitive projects will, the BC expects, generate information and knowledge that will be the basis for future commercial applications such as the development of tests and diagnostics that extend and apply the information and knowledge generated in the BC.
As of November 2008, the Executive Committee of the BC has developed and implemented five biomarkers projects:
Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) for lung and lymphoma
These two studies are NIH-managed via the National Cancer Institute (NCI) and aimed at evaluating the use of FDG-PET as a potential biomarker for clinical trials conducted in cancer, specifically, non-Hodgkin’s lymphoma and non-small cell lung cancer. The goal of these projects is to improve patient management and care by validation of a tool that can measure response to treatment and accelerate drug development. Additionally, it is anticipated that these first two trials to evaluate FDG-PET in non-Hodgkin’s lymphoma and lung cancer will provide guidance to the FDA in their regulatory review process, and deliver to the Centres for Medicare & Medicaid Services (CMS) a evidence-based measure by which to inform reimbursement decisions. (This project is supported by a core investment from the NIH-NCI in conjunction with contributions from Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck & Co. Inc., Pfizer Inc., and Wyeth, in conjunction with substantial core investment by NCI).
Evaluate the utility of adiponectin as a biomarker predictive of glycemic efficacy
This project involves pooling existing clinical trial data from previously conducted studies in an effort to evaluate whether adiponectin, a soluble protein, has utility as a predictive biomarker of glycemic control in normal non-diabetic subjects and patients with type 2 diabetes following treatment with peroxisome proliferator-activated receptor (PPAR) agonists. If validated, adiponectin would be a useful biomarker in the development of new therapies for diabetes. The data for this study is being provided from Phase II clinical trials conducted by GlaxoSmithKline, Eli Lilly and Company, Merck and Co. Inc., and F. Hoffmann-La Roche. The statistical analysis for this study is being provided (in-kind) by the National Institute of Diabetes and Digestive and Kidney Diseases and Quintiles Transnational Corp.
Carotid Magnetic Resonance Imaging (MRI) reproducibility study
This study is being conducted in conjunction with the National Heart, Lung and Blood Institute (NHLBI) AIM-HIGH Study—Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-cholesterol / High Triglyceride and Impact on Global Health Outcomes. This AIM-HIGH substudy is aimed at improving patient management by validating a tool that can help identify therapeutic response and facilitate drug development. Specifically, this AIM-HIGH substudy involves an 80-patient reproducibility study, being conducted at 15 established clinical sites, to determine the reproducibility of the non-invasive technique of carotid MRI, a well-known imaging biomarker. This project is supported by a core investment from the NIH-NHBLI in conjunction with contributions from Abbott, Merck & Co. Inc., and Pfizer Inc.
Plasma-based biomarkers in Alzheimer’s disease
This study is an extension of a large five year longitudinal natural history study known as the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which was conducted as a partnership among the National Institute of Aging, private entities and pharmaceutical companies in an effort to identify imaging and biochemical biomarkers for disease state and disease progression. The goal of the add-on biomarker project is designed to use targeted approaches and whole proteome profiling approaches to identify and validate plasma-based biomarkers of Alzheimer’s Disease. Results from this studies aid in the idenfication of biomarker candidates to study disease state and/or disease progression in Alzheimer’s Disease, and serve as tools for clinical drug development and assessment of disease in Alzheimer’s Disease patients.
The BC’s mission to serve as a means for public and private entities to join forces and pool resources to advance biomarkers research is exciting and challenging. And as with any exciting and challenging endeavour, some aspects work well as originally designed and other aspects require rethinking. The BC, like any experiment, is no different and is presently undergoing evaluation and restructuring in some areas. In January 2008, the BC Executive Committee adopted a proactive effort to identify new “High Impact Biomarker Initiatives” (HIBOs), which will be rapidly feasible and provide highly focussed utility.
The BC recently adopted a new proactive approach for the identification of HIBOs in an effort to identify biomarker projects that are cross-cutting and overarch multiple therapeutic areas. The previous “bottom-up” approach, whereby projects were sought exclusively from the public applications, is now supplemented with a “top-down” approach, which involves project identification within the BC (specifically the steering committees). The impetus for this change is to identify biomarker projects that all sectors (industry, government, private organisations and academia) can champion and support. Biomarkers projects addressing big questions or issues of interest to multiple sectors and overarch therapeutic areas are most likely to find broad support and resources for implementation and dissemination. In an effort to assist in the identification of HIBOs has developed a number of key criteria for defining what a HIBO would look like, including the following:
Important – Projects should address a significant unmet medical or scientific need in biomarkers with a potentially considerable impact on public health;
Translational – Projects should result in significant improvement in the development, approval, or delivery of care to patients (i.e. diagnostics, therapeutics, clinical practice);
Transformational – Projects should address critical gaps in the biomarkers qualification / validation process and/or may otherwise transform the process of how biomarkers are developed, approved, and applied in the future;
Feasible – Projects should convey an idea or programme whose end goals can likely be achieved in a specific timeframe, and that has a reasonable prospect of producing the expected outcomes; ideal programmes are those which could result in regulatory qualification of a biomarker in three years;
Practical – Projects should leverage pre-existing resources (e.g. intellectual capital, personnel, facilities, specimens, reagents, data) wherever possible;
Fundable – Projects should be capable of generating the required funding and stakeholder support needed for implementation; and
Collaborative – Projects should uniquely benefit from the multi-stakeholder composition and approach of The Biomarkers Consortium, and feasibly executed under its policies.
The HIBOs identified as “wave one” projects are those most critical to move forward: those which the Executive Committee believes to have the greatest and most proximal impact on future diagnosis and treatment of patients and drug development, helping the medical community realise the promise of personalised medicine. By selecting high profile, cutting-edge projects for development in the BC, the expectation is that all sectors will unite to support these HIBO projects.
The Biomarkers Consortium anticipates launching four to five new “high-impact” biomarker projects this year, while a second wave of HIBOs is being developed concurrently to commence during 2009. The candidates for a 2009 launch include:
Evaluation and validation of Circulating Tumour Cells (CTC) as biomarkers of castration-resistant metastatic prostate cancer
This project is aimed at predicting response and survival to an investigational agent to treat men afflicted with progressive castration-resistant prostate cancer. The goal of this research is to validate CTC number as a biomarker for survival, which could ultimately guide treatment and accelerate drug development. The project proposes to conduct CTC analyses on blood samples from men already participating in a phase III randomised registration trial in order to evaluate the association between post-treatment change in CTC number and survival.
Comparison of two PET radioligands labelled with 11C or 18F to quantify the peripheral benzodiazepine receptor, a potential biomarker of inflammation
The goal of this project will be to assess the utility of two newly developed PET radioligands to image and quantify inflammation in periphery and brain. These newly developed PET radioligands will be tested in Alzheimer’s disease and atherosclerosis, which were selected because both result in significant disability and often death. Also, these two diseases are representative of inflammation in the brain or periphery, respectively. An ultimate application of the results of this study might extend to neurodegenerative and psychiatric diseases, as well as serve as a tool for developing new drug delivery systems and brain cancer treatment regimens.
It is the ability to step back and evaluate the structures and methods being used to implement projects that characterises an important strength of the BC. The promise of biomarkers to streamline and even revolutionise investigations of pathobiology, the conduct of clinical trials and regulatory decision-making for drugs and therapeutics, needs to be realised in an efficient, rapid and effective manner—and it is the hope of the BC that the identification of HIBOs will help make this happen!
The BC is presently in the process of developing project plans for five proposed second wave HIBOs:
• I-SPY TRIAL-2 (Investigation of serial studies to predict your therapeutic response with imaging and molecular analysis): An adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy
• Detection and characterisation of CTCs in prospective cancer treatment trials
• DCE-MRI technique optimisation study using prostate cancer as a model system
• Use of targeted multiplex proteomic strategies to identify CSF-based biomarkers in Alzheimer’s disease
• Biomarkers for immunosuppression
Through the development and approval of these high impact biomarkers opportunities, the BC is moving into a new phase of growth, initiating new, highly focussed, projects; and collecting and synthesising data from ongoing projects. The promise of biomarkers to streamline and even revolutionise investigations of pathobiology, the conduct of clinical trials and regulatory decision-making for drugs and therapeutics, needs to be realised in an efficient, rapid and effective manner—and it is the hope of the BC that the identification of HIBOs will help make this happen!
The BC has provided a new direction to healthcare research and medical product development. It brings together leaders from the biotechnology and pharmaceutical industries, government, academia, and non-profit organisations. This unified effort to accelerate the identification, development, and regulatory acceptance of biomarkers in four key areas: cancer, inflammation and immunity, metabolic disorders, and neuroscience is transforming biomarkers research. The BC is evidence of a new culture of cross-sector collaboration and partnership in order to rapidly, economically, and collaboratively accomplishing the partners’ shared goals to increase the availability and utility of biomarkers in all areas of biomedical science.
Biomarkers Definitions Working Group. (2001). Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clinical Pharmacology & Therapeutics, 69(3), 89-95.