European Biopharmaceutical Review
The challenges facing the pharmaceutical and biopharmaceutical sectors are well known. While spending on R&D has approximately doubled over the past decade, the number of new drugs reaching the market each year has fallen. However, these challenges are not new, and there have been numerous attempts in the past to address issues with R&D efficiency and the late-stage attrition of compounds in development. Concurrently, much has been made of the potential of personalised medicine to deliver more targeted therapies. The corollary of this is that such therapies have a smaller patient population, and so the price of such treatments necessarily rises, making them tall poppies in a cost-constrained marketplace.
There is hope that translational approaches in pharmaceutical and biopharmaceutical development will address these issues. It is still too early to say whether these approaches will help solve the ills of the pharmaceutical sector, or will better address patient needs, but it seems that some themes are starting to emerge:
Translational research is, in reality, a return to the time before the discovery of a therapy and its application in humans were temporally separated by regulations
the sector has embraced the concept, and a move towards smaller, project-focused translational medicine (TM) means that decision-making will have to be devolved back towards scientists
governments and other public bodies have responded with a proliferation of initiatives, creating confusion but also opportunity, as the supply of partners potentially exceeds demand.
The question remains of how best to unlock the value of European patient data and clinical science in order to address the growing time, cost and failure rate of pharmaceutical R&D. At the core of this is how best to ensure the industry interacts effectively with translational research ‘hubs’ to improve their understanding of disease progression in patients.
Is Translational Medicine a new discipline?
Translational medicine has been defined in many ways, but in essence seeks to integrate real patient data at a much earlier stage of development than has previously been the case, allowing the early identification of factors that may prove problematic later in development. It uses many of the post-genomic technologies that have become familiar over recent years, including biomarker identification and validation, expression analysis, pharmacogenomics and toxicogenomics.
To facilitate the required level of interaction between the respective parties, clinicians, scientists, patients, funding bodies, charities and industries need to be co-located in order to collaborate together, with access to IT and infrastructure such as tissue banks and imaging facilities. This should encourage an understanding of the different issues facing the different levels within, to borrow a phrase from Steven Jay Gould, non-overlapping magisteria. However, while the term itself became common currency from the mid-1990s, there is nothing new or unusual about it. Anyone without experience of pharmaceutical development might be forgiven for thinking that it is the way drugs have always been developed. Certainly, when Howard Florey treated Albert Alexander with the first human dose of penicillin in 1941, he was adopting a translational approach. Indeed, one author has recently suggested the term ‘translational science’ rather than the more common ‘translational medicine’, as medicine is, by its very nature, translational (1).
Either way, the years of testing mandated by regulatory authorities have had the effects of separating the tools, techniques and, most importantly, people, both in time and often geographically. The difference is that the explosion of new analytical techniques means that it is extremely rare for any one individual to be able to cover all of the necessary disciplines, which means effective collaboration is key.
How has the Pharmeceutical Sector embraced the concept?
To address some of the issues identified above, the pharmaceutical sector has increasingly embraced new approaches. Originally, many approaches were internally focused, maximising the use of existing resources, and often only looked externally when required. Most companies have adopted further measures to facilitate this process, such as:
Project support for existing functions, where a dedicated TM function supports the transition from research to proof-of-concept (PoC)
embedded resources, where there is no separate function, but where translational thinking is disseminated across the organisation
re-engineering of R&D, so that early development runs from discovery to PoC, prior to handing over to late-stage clinical development .
Historically, pharmaceutical companies have followed a relatively closed approach to innovation, with a strong internal R&D focus, but with limited external liaisons in key areas and the use of contract research and testing resources as appropriate. In the area of translational medicine specifically, the sector has seen some large initiatives designed to allow embedding of the data and learning from patients. These are often top-down, long-term strategic collaborations, covering multiple therapeutic areas, often with a geographical focus. Such examples include:
In 2010, Roche established a public private partnership with Singapore’s scientific and medical institutions, including A*Star, The National University of Singapore, The National University Hospital and others – including healthcare providers – to establish a hub for translational medicine
also in 2010, sanofi-aventis signed a research partnership with Aviesan, the French National Alliance for Life Sciences and Healthcare, to develop projects in research areas such as ageing, immunoinflammation, infection and regenerative medicine. Membership of Aviesan includes CEA, CNRS, INRA, INRIA, Inserm, Institut Pasteur, IRD, the conference of university presidents and the conference of regional and university hospital CEOs
in 2006, Wyeth (now Pfizer) entered into a £50 million partnership with TMRI to create the world’s first translational medicine research collaboration in Scotland. TMRI is a private company commercialising Scottish biomedical research with industry leading partners to produce valuable commercial outputs. The company is owned by Scottish Enterprise, the Universities of Aberdeen, Dundee, Edinburgh and Glasgow and their associated NHS Health Boards.
At the same time, companies are seeking to embed translational learning through all levels of their organisations, while opening up innovation across the company. This is pushing the decision-making to lower and lower levels of the organisation, and means that the types of translational assets are changing. Done well, it is also an opportunity to truly put value-creating decisions back in the hands of scientists.
This suggests that the model for effective translational research may evolve. Rather than a small number of broad collaborations, success may be determined by multiple, pre-competitive, ongoing initiatives. This will require interaction with organisations across the world to access patient samples and data to reflect pharmacogenomic differences, especially in emerging markets, although genetic variation may only be part of the problem. The recent EVEREST study demonstrated that there were differences in the outcomes of over 4,000 patients from three continents and two regions in Europe (2). While some of this may be due to genetic variation, other factors include differences in local medical practice, different healthcare systems, aetiology, or the use of different treatment regimens (3).
A surfeit of government initiatives?
Translational research requires product developers to be able to access patients, their samples and their data at a much earlier stage of development than in the past. This means that data must flow from the patient bedside to the development bench; that feedback flows the other way; and that the contribution of each component is recognised, both in kudos and remuneration. This is a challenge for all parties, but governments have recognised the opportunity to monetise the investment they have made in biomedical research and infrastructure. This has led to an explosion of translational research initiatives and a culture where, for clinical academics, research often needs to be translational in nature, or at least in name, to maximise its potential to obtain grant funding. The US has invested significantly in initiatives to facilitate translational research, and is significantly ahead of Europe and other traditional centres of global drug development, both in terms of investment and time.
The UK alone has recently seen the establishment of five academic health science centres (AHSCs), five comprehensive biomedical research centres (cBRCs), numerous specialist biomedical research centres (sBRCs) and biomedical research units (BRUs), 17 experimental cancer medicine centres (ECMCs) and various other initiatives. A new approach based on therapeutic capability clusters (TCCs) has been announced to facilitate the interaction of partners with these national assets. Other European states have their own initiatives, and the European Commission has a number of programmes. Specific examples include:
In 2008, the German Ministry of Education and Research (BMBF) invested €20 million in Max Planck Innovation’s Drug Discovery and Development Center (DDC), that comprises a Lead Discovery Center (LDC) and a Development Company (DevCo)
Molecular Medicine Ireland (formerly the Dublin Molecular Medicine Centre) was founded in 2002 by University College Dublin, NUI Galway, the Royal College of Surgeons in Ireland, Trinity College Dublin and University College Cork to accelerate the translation of scientific research into better quality outcomes for patients and position Ireland as a centre of excellence in molecular medicine
CREATE Health is the Strategic Centre for Translational Cancer research in Lund, Sweden, funded by the Swedish Foundation for Strategic Research, and is based around Lund University Hospital with researchers from the Faculties of Medicine, Natural Sciences and Engineering.
From the government side, there is a real risk in Europe of a ‘tragedy of the commons’, where available resources are labelled ‘world-class’ and packaged into propositions that are designed to attract a smaller number of large partners, in the face of alternative partnerships being developed in the US and emerging territories.
Do translational initiatives create wealth?
Many of these initiatives are being driven by the public sector to integrate academic and clinical research into an attractive package to maximise the potential for commercial collaboration. Some commentators take the view that the more the government funds precompetitive R&D, the less industry does, in part because state funding encourages a culture in which companies expect to be able to access the results from such investment, and in part because increasing government on R&D means higher tax, and there is less cash for companies to spend on R&D or for individuals to donate to biomedical charities. This seems to be especially true for many translational initiatives; there appears to be a misalignment of the expectations of both parties.
Much government funding is predicated on the fact that global pharmaceutical companies will partner with national assets for the benefit of both parties.
However, the supply of potential clinical academic centres is in danger of exceeding the demand from the industry. We expect this to be exacerbated as pharmaceutical companies increasingly shrink their internal R&D and shift their focus to the emerging global powerhouses.
Certainly the dual imperatives in Europe of attracting partners to exploit clinical research in a commercial collaboration, while seeking to reduce the cost or availability of next-generation medicines (especially of biopharmaceutical products), would appear to be conflicted, potentially reducing the attractiveness of Europe as a preferred location.
Creating value in translational research
The traditional blocks to translational research have been detailed by others, and include the challenges in translation from basic biomedical science into human studies, and then the translation of the learning from clinical studies into the treatment of patients. Key issues historically have included a lack of qualified investigators, the availability of patients’ samples and information in a coherent form and concerns about confidentiality. To these may be added certain additional issues of relevance to commercial partnerships between the pharmaceutical sector and external industries including:
As populations become more stratified, geographical differences are growing increasingly important. As such there will be an increasing desire for PoC studies in representative patient groups. This will lead to a further refinement of requirements
many of the initiatives described above have been driven from the top down. Increasingly, as translational initiatives are embedded within organisations, the level of interaction is expected to be driven not by senior executives, but by the project teams themselves. As such, the number of collaborations may increase, and the ability to establish such relationships will be key
many existing initiatives are described as precompetitive. However, what constitutes precompetitive is contingent upon the utility of any results to a participant. Similarly, the value of a single biomarker, for example, may be highly contingent upon how it is put to use, and new business models are emerging to facilitate this process
the power of translational research is to achieve attrition of development candidates earlier within the development process. However, project teams may not have the incentive to kill projects early, as the benefit to the individual and the organisation are not aligned. Existing portfolio management tools may not recognise the new value inflection points this approach brings
many public sector translational initiatives are designed to give access to samples, patients and services, in return for some participation in the commercial returns. However, in early stage PoC studies, the commercial partners may actually be interested in a more restricted offering of access to patient samples and data, and be reticent to transfer assays back into the public sector, and if they do, to rely on the quality of the data
initiatives to share data in open fora seem doomed to failure. Academic partners may be loath to publish negative studies, and equally, pharmaceutical companies may not wish to commit the resources needed to format data from failed or back-up compounds in an accessible format
the informatics and infrastructure support are not yet coherent to allow seamless integration of teams. These will increase in importance as the interaction moves from a small number of broad collaborations to a more ad hoc access to patient samples and data.
Translational research is a new term for an old approach that has again become relevant to contemporary issues. However, its true value lies in the seamless integration of the parties, although various factors may complicate this, including commercial issues. The public sector has recognised the value of this, but is addressing it with a confusing level of initiatives that allow the commercial sector to be more selective in accessing resources on a global scale. However, a coherent approach to infrastructure and informatics may benefit both parties, and minimise the risk of Europe becoming a translational backwater.
About the authors
Bob Damms is an expert in technology healthcare, and in the assessment and commercialisation of new products and technologies. He has over 25 years’ experience of developing and commercialising new technologies in the life science sector, in consulting, venture capital and equities research roles. He has worked across most healthcare subsectors, including drug discovery and development, medical devices, orthopaedics and biomaterials, and from university start-ups,though established entities, global corporations and governments. His particular interests include the convergence of technologies in the healthcare sector, translational research, and novel funding models.
1. Martin Wehling, Principles of Translational Medicine, Cambridge University Press, 2010
2. Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan, EVEREST programme
3. Feldman AM, Multinational Trials: Lost in Translation?, Clinical and Translational Science 2 (2):p91, 2009
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