Dr Ann Hunter, Red Sky House, Fairclough Hall, Halls Green, Weston, Hertfordshire SG4 7DP, UK. E-mail: firstname.lastname@example.org
Integration of clinical and preclinical pharmacology in pharmaceutical companies could be improved by several key recommendations:
Companies should ensure that there is an adequate pool of trained clinical pharmacologists and preclinical pharmacologists. Training should include topics that allow clinical pharmacologists to be cognizant of the methods, issues and challenges faced by the preclinical pharmacologists and vice versa.
Companies should incentivize such integration internally by aligning objectives and metrics/incentives.
In academic medicine and the NHS there should be support for involvement of clinical pharmacologists in basic academic research and industrial R & D and new ways of facilitating and incentivizing preclinical pharmacologists and clinical pharmacologists to move between these various environments should be sought.
In recent years, several drivers have motivated a switch in pharmaceutical companies to ensure that preclinical and clinical pharmacology organizations are better connected internally. These have included the increased costs of research and development (R&D), coupled with high attrition rates at all phases of development. The costs of bringing a new medicine to market have continued to escalate and are now estimated to be US$ 1.78 billion , but success rates in terms of launched products have remained relatively static (Figure 1).
Of greater concern has been the prediction that new chemical entities produced by pharmaceutical companies will account for only 10% of the prescription drugs filled by 2015, raising the question of how the estimated US$ 150–200 billion that is collectively spent on (R&D) annually can be sustained, especially in the current global economic context . These R&D costs include the cost of failure and have driven the wave of consolidation that has occurred in companies over the past 20 years, in an effort to gain cost savings through increased efficiencies and rationalization of infrastructures. Unfortunately, once a company decides to work on a target, it will spend at least US$ 10–20 million before achieving proof of concept (PoC) with a compound that is active against that target in humans. Recent data have shown that the major cause of failure in the clinical PoC phase is lack of efficacy , and this phase is recognized as a critical milestone by industry leaders (Figures 2 and 3). It was perceived by large companies that a biotech model in which pharmacology and clinical pharmacology are very closely aligned might be a way to solve this productivity gap. The aim of such a model would be to increase understanding of how a target was relevant to the disease in question, to demonstrate target engagement by compounds early in development, and hence to reduce the risk of failure at PoC.
Centres of Excellence of Drug Discovery
Most pharmaceutical companies in the 1980s and 1990s were organized by line disciplines, and there was a very sharp divide between the ‘R’ and ‘D’ arms of the organizations; a radical shift was therefore needed. In 2001 the newly created GlaxoSmithKline (GSK) organization made such a change and formed Centres of Excellence of Drug Discovery (CEDDs), which were accountable from chemical lead through to PoC and which brought discovery biologists (including pharmacologists) and clinicians with the same objectives into the same organization. Subsequently, variations on this model have been formed in other companies such as Astra Zeneca and Pfizer. It was hoped that such interdisciplinary groups would be able to effect better translation of pharmacodynamic (PD) actions seen in animals to outcomes in humans, potentially gaining an early indication of clinical proof of mechanism (PoM), as well as having the time and resources to develop experimental medicine models in phase I and surrogate markers of efficacy.
How successful was this CEDD model in integrating basic preclinical pharmacology expertise with the relevant clinical pharmacology? The answer is somewhat mixed, as might be expected. In terms of increased understanding of the relationship of the target to disease, the CEDD model did not always have the hoped for benefits. This was partly because, although many industry-based clinical pharmacologists have some therapeutic focus, they are not usually experts in a particular disease area, since they often have to move between therapeutic areas as priorities within the company change. Therefore, they could not always bring deep understanding of diseases or mechanisms to a particular target. Even within a particular CEDD, their focus was very much on clinical studies (and their performance assessed using clinical metrics), with little or no emphasis on their contributions to early discovery
This led to a lack of real reverse translation from humans back to preclinical studies, which could have been highly beneficial, since significant clinical input into basic translational biology could have made a positive impact in terms of improved predictive validity.
However, some areas were really able to benefit from having basic pharmacologists and clinicians in the same small organization. One such area was that of establishing target engagement. In central nervous system (CNS) pharmacology, it is critical to show that a compound reaches the CNS over the right time frame and with the right exposure. One way in which this can be demonstrated is by the use of radioactive tracers and ligands for imaging, for example using positron emission tomography (PET). In the Neurology CEDD, the basic scientists, PK modellers and clinical pharmacologists worked together to discover and validate new PET ligands and used them to demonstrate target engagement and to select doses for phase II studies . They were also able to establish PD assays for many programmes, which were translated, when possible, into phase I studies, so that PoM could be demonstrated in humans.
Another area in which the integration of clinical and preclinical pharmacologists worked extremely well was the development of experimental medicine models. The groups were able to pool their knowledge and resources in a particular area, for example pain, to establish a range of human models based on mechanisms, for example hyperalgesia . Of course, no one company has the resources to establish such models with all the reference compounds required, and this is therefore an emerging area for pre-competitive collaboration. In the areas of pain and other CNS disorders such initiatives have already begun, most notably through the Innovative Medicines Initiative . Similar collaborations will also be required for establishing surrogate markers of efficacy in phase II studies and will involve not just industry participants but other key stakeholders, such as academia, patient groups and regulators.
So the CEDD organization demonstrated some of the benefits that can result from better integration of preclinical and clinical pharmacology in an industrial setting. However, if clinical and non-clinical pharmacologists were to work even closer together they would create many opportunities for further benefits to be gained. There are challenges to this, some of which are internal to companies and some of which are external factors.
Integrating clinical and preclinical scientists
As mentioned above, many clinical pharmacologists feel that they do not have sufficient knowledge of preclinical biology for them to be able to contribute usefully to discussions about studies and target pharmacology in the discovery phase. Moreover, in many cases industrial clinical pharmacologists are not recognized or rewarded for spending time on non-clinical science. Even within the CEDD system, the clinicians in the CEDD had to work in line with processes and structures that were part of the central, non-CEDD clinical organization. Many of these processes were geared more towards late phase and post-launch studies and did not have the flexibility and agility that is often required in early clinical development. Although in the CEDDs, preclinical scientists were involved in clinical study design, the level of this type of engagement across companies is very variable. This is partly because many preclinical scientists are not rewarded for their input to clinical studies in the same way as they are for their contribution to the discovery phase. If the benefits of integrating preclinical and clinical pharmacology are to be fully realized, it is important that both objectives and incentives should be aligned to make sure that integration occurs optimally.
Major advances are occurring in genetics and our understanding of disease that should radically change the way new medicines are developed. Although many of these scientific advances are currently having the most impact in immunology and oncology, there are other therapeutic areas, such as infectious diseases and CNS disorders, in which the disease burden is already high and is increasing. These two latter areas are also ones in which the UK has great research strengths, and it will be important to make sure that training in clinical pharmacology maintains both a breadth and a depth of therapeutic expertise to support the translation of basic research into therapeutic opportunities. As well as small molecule development, there has been a large increase in biopharmaceutical R&D, in both large pharmaceutical companies and biotech companies, and this requires both clinical and non-clinical pharmacologists who have the specialized expertise required for the development of biological agents. For both small molecules and biologics, PK–PD modelling and simulation remains critical and can form a pivotal point for integration of data from animals and man.
One of the biggest changes in the future will be the increasing importance of stratification of patients for clinical trials. This has received impetus not just from a technological standpoint, in terms of increased technical feasibility, but also from economic and policy drivers. Such stratification is seen as one way to cut the costs of failure and increase the chances of success, and it is strongly supported by funders such as the Medical Research Council and The Technology Strategy Board. Successful stratification depends on integration of knowledge of the mechanism and the system being targeted, as well an understanding of the role that that mechanism plays in the subset(s) of the patient population to be treated. Close collaboration between preclinical and clinical scientists will be essential for the success of this approach.
Externalization and more open ways of collaboration may mean that many of these studies will be designed and executed outside of large pharmaceutical companies, in collaboration with academia and/or biotech companies and through different funding mechanisms. Some drug companies have already announced such initiatives, including Johnson and Johnson, Pfizer and GSK. However, while there has been a closing of the preclinical and clinical pharmacology divide within the industry, there is still a strong division between these disciplines in many academic institutions. It will be important to address how better integration can be achieved in academia if collaborative projects are to be developed successfully.
Ultimately, any system can be made to work if you have the right people and the right incentives, which is why, although integration can and must happen, having the right ‘human capital’ to start with is vitally important. Making pharmaceutical and biotech companies attractive places for pharmacologists, especially clinical pharmacologists, to work will involve not only companies but also the NHS and academic medicine. Currently, jobs in pharmaceutical companies are often seen as a one-way street, with no possibility of returning to the NHS or academia, where the metrics for career progression are different from those in industry. This is a critical problem for the UK to fix in order to ensure that companies have a vibrant pool of clinical pharmacology talent from which to draw.
AJH has shares in GlaxoSmithKline Pharmaceuticals and is a non-executive director of Proximagen Group plc.