Making the vital connection

NGP talks to GSK's Paul Matthews about the unique challenges posed by the combination of imaging and drug development.

“By communicating the results of trials and the rationale leading up to them in an open public forum, we can increase the quality of the science”
-Paul Matthews

Being the Vice President for Imaging at GSK is not just a job for Paul Matthews. Speaking to him, it is immediately clear that he is passionate about the opportunity to bring chemical imaging to the heart of drug development. As he explains, this is not because it is just another test, but because it creates greater confidence in drug development, particularly at the early stage.

He notes the current challenges of a high attrition rate in the industry - when attrition is late in the drug pipeline it's both extremely expensive and time-consuming, and is not doing either the patients or the industry itself any good as a result. "We'd like to bring confidence in decision-making early and we can do this by trying to study pharmacology in humans in the same ways that we've become accustomed to and with the same detail of information we've been accustomed to getting in pre-clinical species. In order to do this, we need to have powerful non-invasive approaches to quantitative physiology and pharmacology. This is what imaging is really all about," explains Matthews.

"While I speak of imaging in the context of drug development, it's not about developing pretty pictures, although that's a side benefit. It's about providing quantitative information related to where a molecule might move in the body in a biodistribution study, molecular interactions of a putative drug with its target, or about physiological responses of the human tissue. This is what imaging can bring to us and its confidence in decision-making is the impact."

He describes the current relationship between drug development and imagining as an "interesting period of marriage". Matthews adds that the technology connecting the two has been missing for some time, at least in principle, but what has really been missing is the connection of drug development in the hands of people who understand how to use the information that's derived from investigation and those with an expertise in imaging.

"Bringing imaging to drug development isn't just about going down a checklist," he says. "It's about developing powerful questions and then finding the technology that answers those questions and not different ones. Previously, the limits placed on the ability of the imaging to have an impact on drug development happened through parties who were not engaged with the same agenda. A company would go to an academic site or an external CRO, who had a limited understanding either of the problems of drug development or the specific problems of a molecular series.

"Here, what we've been able to do is actually merge clinical teams developing drugs with teams delivering this high-level pharmacological and physiological data, so the two have a common language. The questions can be translated across. The tools can be suited to the problem. And that's what is beginning to make these studies have impact rapidly. To give you a flavor for this, in the last seven months we've done as many studies with the opening of the imaging center and bringing it up to full speed, as GSK did in a similar area over the previous couple of years, and that's because we can make things move much faster, do studies that count and bring value to the company and, ultimately, to patients."

Communication

R&D is one of the key functions in which science and the business of pharma are merged, and ensuring communication between the two is essential. However, this is no easy task. Matthews explains that communication is the number one challenge facing any large organisation; there being three issues that each organisation must face. "One is a communication across R&D itself to help this very broad organisation learn to optimise its ability to work together, so that we don't have individual drug units pursuing similar problems without knowing about each other.

"The second area of communication is perhaps even more critical if we're to transform the industry, and that's to communicate the needs of late-phase development into early phase and to merge the problems that late phase will encounter in the clinic into the early development decision-making. And, in turn, to use the science from early development to translate out to late phase, to help define the populations that are targeted for a new treatment, the way studies are designed and also the way in which the potential benefits are communicated.

"That leads to the third communication problem. Making drugs is fundamentally a very complex scientific effort. We need to get away from the notion that every drug hitting the same target is equivalent and communicate the potential differentiation of our molecules, which we're working towards from the very beginning of discovery way out past the stage at which it's marketed.

"We need to help physicians and patients understand the differences between drugs within the pharmacopoeia, but also the differences between the way drugs may act in different kinds of people. This is a new type of agenda that we're going to have to grasp. I've mentioned three: communicating with R&D, communicating between early and late-stage pipeline and communicating the science of drug development to the user population. But they're all wrapped up together. It's about making science the core of drug development and being transparent about how the information is used in the process," he says.

Matthews explains that actively promoting this course of communication throughout the organisation is something that the senior executives within GSK's R&D department are attempting to do. He notes that one key element that has been taken into account is to create working teams that are small enough to speak together, are co-located and have a limited agenda, which allows issues to be fully aired and done so openly amongst larger segments of the group.

These groups have been named development performance units, or DPU.

Matthews explains that the major drug development units, either the larger units or the former Centers for Excellence in Drug Discovery (CEDDs, have been divided up into these DPUs. The size of each unit ranges between 40 and 70 people, all of whom are located on single sites, and this allows for face-to-face communication on a regular basis. However, although this brings many advantages to the communication process, by dividing up a big organisation into smaller units the risk remains of failure to communicate between each DPU.

"To some extent, this is helped by organising clusters of DPUs together as CEDDs, or units in oncology," says Matthews. "For our pharmaceuticals, where the leadership regularly meets together with a leader of the CEDD or unit in order to develop coordinated strategies and provide a communication strategy that, again, is limited to a relatively manageable number of players who can meet regularly, face to face.

"You can understand that I'm a great fan of trying to get human-to-human contact to make those communications. Now, finally, what we're trying to also do is create structures that move across DPUs and CEDDs and begin to share what is learned from one with the others. These take a variety of forms; they're suited to the problems that they're trying to address."

Challenges

Matthews provides an example of GSK's peer review forum - a group of senior clinical scientists who meet on a weekly basis to review new protocols coming through drug discovery. The review is voluntary, although it is taken up by almost every unit moving protocols forward, and provides feedback on the science and attempts to help create the strongest protocols possible. In doing so, the hope is that expertise is brought across from one unit to bear on the problems of another.

Another challenge that continues to increase is the identification of disease areas that are being pursued across DPUs or CEDDS. Matthews notes that discussion groups are coming together to look at the strategy for the company in terms of the science and the relatively autonomous units that lie beyond that.

He also notes that there are a number of higher-level mechanisms that are set up to provide scientific feedback in the form of scientific advisory boards that sit above the CEDDS and DPUs, in which learnings are shared so the best science can be produced, as well as to allow a good accountability for safe clinical practice and trials. "It's not a solved problem. It has to be addressed at multiple levels using different approaches. One of the things that we're trying to grasp is making person-to-person contact t the foundation of this, because that's ultimately what's so much effective," says Matthews.

Internal communication is essential for better science and employs an equally critical role for the wider public - more information communicated on the same level of efficacy and depth of R&D has the potential to cut down on health scares. Matthews explains that some recent examples of this have been generated by the pharmaceutical industry itself - by failing to communicate the science well to the news media who misunderstand as a result.

So how is this to be remedied? Matthews believes that it will be a slow process, but one in which GSK can be confident and successful. "First, we've got to create an open, transparent industry. We have to be able to communicate why we're pursuing the areas that we are. We have to communicate the importance of science and objective thinking being at the basis of our decision-making. And, finally, we have to be able to communicate this science, the results of clinical trials for example, in a fully open and transparent fashion.

"At the same time, we have to be willing to engage our scientific community and even the public in very open feedback. We have to get away from KOL meetings that are stacked with people who we think are going to provide us the right answers. We have to go out and find the people who are going to be able comment the most robustly and provide the strongest opinions on what we're trying to do. That's GSK's commitment now. By having open science, by communicating the results of trials and the rationale leading up to them in an open public forum, we can increase the quality of the science, because now it's being tested against the best the scientific community has to offer.

"We can also help the public have more confidence that decisions aren't being made behind the backs of everyone, that things aren't being hidden. Finally, we have to continue to address the issues of scientific ethics and business ethics throughout the process. We have to make sure that the motivations of the people we have involved, both within the company and outside, are transparent and appropriate.

"We have to appreciate the tremendous responsibility that has been vested in the pharmaceutical industry to be the primary bringers of new therapies to the public. We have to recognise that we have a pact with the public who depends on our drugs, with the shareholders who are supporting the company, to be ethical in everything we do. If we begin to stray from that, we're only going to hurt ourselves.

"GSK has taken these values very strongly to heart; they're a core of what we're all about. An example of this is our peer review group that vets every early stage protocol going through, trying to provide good scientific input. This group includes not just GSK staff but also external scientific advisers, who are independent of the drug pipeline of progression and who can openly look at our science and provide us with the clearest documented feedback that we can get from them," he says.

Technology

GSK has a track record of turning such findings into powerful and marketable drugs; Matthews explains that drug development must not only have strong communication to be successful but also be collaborative. "We're in a very special place; we're at the interface between pre-clinical science and clinical science, trying to translate the findings from our pre-clinical colleagues into pharmacology in humans to help provide confident decisions moving forward.

"We see that as our space. Again, we try to be firm, open scientific critics of the development program; we try to ensure that we're asking powerful questions that will either help a molecule move forward, if it's appropriate, or kill a molecule if there is good reason to stop the development."

To take on this challenge, GSK has a range of scientists participating in development; this range is varied and they do not all share the same scientific agendas. This allows the project to be objective rather than being carried away by the need to move a molecule on to the next stage. Bringing together scientists from different backgrounds is vital so as they don't carry the same biases to the problem. GSK's aim is to create an independent development unit, contributing to drug efforts in multiple CEDDs, DPUs and units.

GSK's overall strategy is divided into three priorities - to grow, deliver and simplify each specific role in each area of responsibility. Matthews explains the importance of simplicity: "When companies grow, there is an effort to address many problems - communications, governance, coordination - but what they inevitably do is create more and more rules, so it becomes increasingly byzantine.

"Our goal, as a group within GSK that is trying not just to conceive clinical trials, but to execute them, and not just ordinary clinical trials, but trials that put a premium on speed and efficiency, our job is to try to identify the hairballs that we can throw out of the mix to try to help us move more quickly. So simplification is something that becomes critical to our business case.

"We depend on being able to move rapidly from solutions to one problem to the challenge of solving another. If we're mired by bureaucracy and unnecessary complexity, our mission is going to be severely limited. So simplification is something we're taking to heart. We're continuously re‑examining all of our processes and the way we relate to our partners; we're trying to bring out unnecessary elements to do all the simple things like cutting meetings, making meetings more focused, but also to try to make all of our processes as simple, transparent and needs based as possible."

Growing the company is also important - translating value into growth is the company's strategy. By growing in quality rather than quantity, GSK can bring greater value to the market. Matthews explains that the focus is on making more rational, early-phase decision-making, which will drive better drugs for patients.

He envisions delivery as having a sense of urgency, which permeates throughout the organisation. Interactions between DPUs and CEDDs are fast-paced, making the drug development timeline significantly shorter. "We're trying to bring more patients into the organisation in regular discussions about what the patient needs, so that we can show the bench scientists what it is like to have the disease that we're trying to work on.

"We're also trying to bring an intelligent plan to drug development so that we don't repeat things that don't need to be repeated. So urgency, and bringing science and a considered development approach to the problem, is how we're trying to bring delivery.

"Our belief is that with a rational development process, with a science-based development process and with a very open and transparent approach to that science, we're going to ensure that the molecules that we're moving forward deserve to be moved forward, and that we address efficacy and safety issues that need to be highlighted at the earliest stages possible. This limits the amount of resources, ultimately, that we may waste. And in the end, it is going to deliver products of real value to the market."

Paul Matthews is Vice President for Imaging at GlaxoSmithKline and Head of the GSK Clinical Imaging Centre.

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GSK Imaging Centre

In partnership with Imperial College and the UK Medical Research Council, GSK has built a Clinical Imaging Centre (CIC) at Hammersmith Hospital in London, UK. The CIC houses leading imaging scientists and state-of-the-art PET and MRI equipment. The imaging centre partnership is one of the largest industry-university collaborations.

The goals of the CIC include to:

• Accelerate effective drug discovery and development in GSK
• Establish a centre of excellence with a critical mass of imaging expertise
• Develop and utilise imaging methods for novel molecular targets from the GSK portfolio
• Characterise the distribution and pharmacokinetics of novel drug candidates in man
• Characterise key human diseases represented by the GSK portfolio
• Develop and implement novel methodologies for the above