Clinical trials face more hurdles than ever, not least protracted timelines and soaring costs But with study design constrained by outdated regulations, rising to these challenges is proving difficult. We talk to the FDA and Mats Sundgren of AstraZeneca to discover how the clinical trials framework is being modernised.
In April 2012, the FDA held a public consultation, ‘Modernising the regulation of clinical trials and approaches to good clinical practice’. With its broad range of speakers, drawn from the full spectrum of stakeholders, the hearing provided rich grounds for debate. All had their own ideas about how the clinical trials framework could best be overhauled.
One aspect, however, was unequivocal: with current regulations dating back to the 1970s, there is little case for maintaining the status quo. Tailored towards a hugely different environment, existing strictures are poorly suited to trials in 2012.
“There have been dramatic changes in the clinical trials enterprise,” remarks the FDA’s Michelle Bolek. “These include increased size and complexity of trials, increases in the number of trials performed globally, greater use of CROs, participation of vulnerable populations, and numerous scientific and technological advances.”
Faced with this cultural sea change, the industry cannot be content with minor tweaks. With costs continuing to rise –average expenditure has tripled over the past 12 years – healthcare systems running trials are creaking under the strain. Furthermore, outmoded policies make it hard to integrate new technologies. It is clear that purging the inefficiencies from the system will amount to all-out reform.
This, of course, is not the first time these issues have been raised. The Critical Path Initiative, aimed at improving clinical trial practice and policy, was introduced as early as 2004. Similarly, the Clinical Trials Transformation Initiative (2007) came about in response to sky-high prices and stifled innovation.
Unfortunately, such initiatives have come under flak for not being transformational enough. Speaking at the FDA hearing, Doug Peddicord from the Association of Clinical Research Organisations (ACRO) alleged that their “research on research” approach was unlikely to “facilitate any significant change to current practices, let alone transformation of the enterprise”.
He went on to lay out suggestions for how the FDA might progress. The Clinical Trials Transformation Initiative, he said, should perform comparator studies that pit old approaches against new. Their goal should be to demonstrate “actual savings in development time and cost for a given product.” And patient needs should always be given precedence over the whims of corporations or institutions.
Since the hearing took place, the FDA has been busy assessing the points that were raised. “We will consider the suggestions received at the April hearing, as well as our stakeholders’ suggestions for improving the regulations,” affirms Bolek. “Input from the public will help identify issues that may inform additional harmonisation efforts.”
For now, though, the challenges posed by drug development show few signs of abating. And as such problems become entrenched, a number of bodies outside the FDA are urgently seeking solutions of their own.
Narrow the field
For Dr Mats Sundgren of AstraZeneca, the situation requires some truly radical thinking. Principal scientist in clinical development, he is also one of 33 partners of the Innovative Medicines Initiative’s Electronic Health Records for Clinical Research (EHR4CR) project, and the coordinator on behalf of AstraZeneca. A four-year undertaking with EU backing, the project endorses a full-scale paradigm shift.
“The pharma industry has been unable to develop innovative products for the last two decades or so,” laments Sundgren. “The attrition rate is a big problem, with only around 2–5% of projects actually hitting the market. So there’s huge pressure on the industry, and that’s reflected in clinical trials.”
Sundgren is emphatic that the next few years will see important changes in the healthcare industry. As older drugs lose their patents and advances in genomics make themselves felt, healthcare is moving towards an arena of personalised medication.
“Personalised healthcare is the approach now taken by the industry,” he explains. “We are no longer trying to produce drug products that treat the majority of the population of the planet. This means we need to target and understand the right patients. So to test if our inclusion/exclusion criteria make sense, we need to have much more external health information and patient data.”
The trend is towards a culture in which each disease management model is adapted to a patient’s genetic profile. Often described as ‘translating bench science to bedside clinical practice’, this movement into personalised healthcare holds great promise for treatment and diagnostics. The industry, however, will need to push beyond its limitations before any significant changes can take place.
Under the present framework, personalised medicine is difficult to accommodate in clinical trials, and patient recruitment is a case in point. Even with present levels of selectivity, late-stage clinical trials can take up to a year to locate their subjects. Narrowing down the criteria to certain genotypes is hardly poised to simplify matters.
This issue is one of the key dilemmas being addressed by EHR4CR. In essence, the project’s aim is to find ways of reusing existing electronic health records (EHRs) of hospital patients in clinical research. A rich seam of data, previously untapped by pharma companies, EHRs could greatly accelerate patient recruitment and shrink the development timeline for new medicines.
“We have identified the top-ranking services that the pharmaceutical industry is asking for in order to enhance the efficiency of clinical trials, and one of these is finding the right patients,” says Sundgren. “We are aiming to develop a new business model in order to ensure we can reuse electronic health records to support clinical trials.”
The advantages are obvious. With more information required than ever before, sourcing such data in isolation is likely to prove both time-consuming and costly. Reusing EHRs represents nothing less than a breakthrough opportunity for the industry.
Of course, this undertaking is not without its pitfalls, legal and ethical in nature as well as technical. For the pharma industry to connect its internal health information domain with external records, it will need to take an unprecedentedly collaborative approach.
“We need to connect more closely to healthcare, not only because healthcare institutions are the original owners of information sources like EHRs, but also because developing new biomarkers will bring us into close collaboration with many partners simultaneously,” says Sundgren. “So there is an opportunity for pharma companies to work not just with hospitals but also with other pharma companies in precompetitive arenas.”
Sundgren does not believe that pooling information will come about through sheer goodwill. Rather, those involved will be offered a financial incentive, along with an element of accreditation.
“The new business models will need to govern and regulate the financial implications of reusing data in a trustworthy way,” he says. “So this is a very sensitive area in which all stakeholders need to be transparent. We also need to find a sustainable and scalable solution. Pharma companies should be able to choose the hospitals that are preferred for a certain drug or patient category, and one of the levers will be platforms that allow virtual integration of data from different sources.”
Looking back several decades, we can see an analogous situation within the banking sector. Faced with their own dilemma – how best to leverage information technology to make trustworthy financial transactions – banks worked together to create the standardised messaging network SWIFT. While this analogy is imprecise, it usefully illustrates how competitors can join forces.
In our financially beleaguered times, the real question to ask is whether pharma companies can afford not to collaborate. The EHR4CR project, after all, does not just stand to benefit patient recruitment. It is relevant to protocol feasibility, clinical trial execution and drug surveillance reporting. All these areas will reap rewards from a more data-intensive and multidisciplinary approach.
“Over the next ten years, I think the industry will conduct smaller but more data-rich trials, with exactly the right patients,” forecasts Sundgren. “Clinical studies will be conducted in closer collaboration with hospitals, in which observational studies and data from EHRs inform both the pre-design of studies and the way they’re conducted. I also foresee that they will involve considerably fewer patients, which will help address the extremely high economic price that studies face today.”
This emphasis on data is not confined to static hospital records. It also extends to real-time patient monitoring, using sensors connected to mobile devices. This should provide a much clearer tool for understanding how the drug is working and help steer its passage to the clinic.
“Everyone has to win in this situation,” says Sundgren. “We can probably improve the attrition rate and heighten our success in taking drugs to market, although what will change is that each drug will have a very limited and specified indication.”
The EHR4CR project still has over two years left to run. As it edges closer to developing a robust and scalable business model, its points of focus are indicative of a broader shift within the industry. No longer are pharma companies content to stick within outdated frameworks. They are united in their search for building blocks that will help a drug move more effectively towards its launch.
Encouragingly, top-down change is happening in tandem with bottom-up. If the FDA has been slow to evolve, a more welcoming approach to innovation is on the cards. “We are evaluating our regulatory approach to clinical trial oversight, to ensure it meets our objectives without being unnecessarily burdensome or unduly impeding implantation of innovative approaches,” says Bolek.
As these approaches take shape, the stage is set for a new type of clinical trial – one in which the design is better suited to a field undergoing constant shake-ups. For the industry, this is a cost and time-saver. For the patients, it’s a genuine revolution.
Case study: a clinical trial of the future
The goal of this trial is to develop a set diagnostic tool and biomarker for diabetes. This involves a large amount of data – internal and external. While the project is primarily driven by a pharmaceutical company, the R&D stage takes place as a collaborative venture with the healthcare industry. During this phase, the tool is supported by sophisticated reuse and data mining of health information including electronic health records (EHRs).
Its success in the phase I and II trials depends on the outcomes of a finely tuned group of patients, who, in turn, have been selected through EHRs. These studies are carried out using devices and sensors, handled by the patients themselves, which monitor glucose levels in real time. An interactive patient evaluation, the studies provide far more information than is usually captured in clinical trials.
Mats Sundgren is a principal scientist in global medicine development, biometrics and information sciences, AstraZeneca R&D. He has more than 26 years of experience in the pharmaceutical industry (discovery, development, IT, marketing and patents). He is currently working within the area of R&D strategy focusing on implementing strategies for bridging health information technology with clinical research.
This article appears in the Autumn 2012 edition of World Pharmaceutical Frontiers