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May 20th, 2015 – by Nuala Moran

Real world evidence holds the potential to both increase efficiency in R&D and to bridge the gap between the proof of efficacy required to pass regulatory scrutiny and the demonstration of likely effectiveness needed to satisfy health technology assessment bodies, says Professor Sarah Garner, Associate Director for Science Policy and Research at NICE.

The first report by the National Institute for Health and Care Excellence (NICE) in March 2000, ‘Guidance on the Extraction of Wisdom Teeth’, seems innocuous enough, but it was not long before the UK health technology assessment (HTA) body – and the movement it spawned – was being blamed for blocking patient access to drugs and stifling innovation in the pharmaceutical industry.

“HTA is perceived as hurdle. But I struggle with that, because what HTA is doing is answering the most important question for health care systems and patients, which is not whether a product met its primary endpoint, but whether it will be clinically effective compared to alternatives,” says Professor Sarah Garner, Associate Director for Science Policy and Research at NICE.

Professor Garner’s view draws on an academic research project in which she interviewed stakeholders ranging from venture capital investors to physicians and patients. “This reinforced for me that HTA was not responsible for the industry’s productivity issues,” she says. “The fact is that HTA is the last in a long chain of events and because it works transparently, ends up taking the flak.”

The research pointed to a need to conduct a systematic assessment to uncover where the fundamental shortcomings lie. “You can fiddle with HTA methodology, cost thresholds, and so on, but this would not solve the problem – that the drugs coming through have not got the evidence they need and that the increases in costs are unsustainable.”

Based on this analysis, it is important for NICE to be part of the solution. “We should be working with all stakeholders to address these issues and make sure that the incentives are in place to find solutions in areas of high unmet need,” Professor Garner says.

Of course, NICE was not alone in recognising a different approach was required, and various projects and pilots are in train to develop new methodologies and tools, under the Medicines Adaptive Pathways to Patients (MAPPs) banner.

NICE is involved in a number of these initiatives, including the European Medicines Agency’s (EMA) Adaptive Pathways pilot, the Innovative Medicines Initiative (IMI) GetReal project and the Massachusetts Institute of Technology’s New Drug Development Paradigms (NEWDIGS) programme.

Pathway engineering

The aim of the EMA’s Adaptive Pathways pilot is to engineer a switch from the traditional approach of staging large and expensive phase III trials and granting approval in broad patient groups, to granting early approvals in areas of high unmet need and allowing the label to be expanded in line with the evidence.

The EMA cites several imperatives. In addition to patient demand for access and the fact that constrained budgets call for targeted drugs with increased therapeutic value, the Agency notes that segmentation is happening in any case, as a result of increased understanding of disease biology and the identification of subgroups of patients.

To help companies plot adaptive pathways, the EMA has held safe harbour discussions in which sponsors are able to have without-prejudice exchanges with regulatory and HTA experts, of whom Professor Garner is one. “I think this has proved very useful and there have been some fascinating discussions. It is helpful for small companies that have not considered the need for real world evidence or where a drug would fit into a care pathway and the value proposition of their product,” she notes.

Although the EMA has announced that nine products have been accepted into the Adaptive Pathways pilot, other details remain confidential for now. However, Professor Garner believes the pilot is prompting a more thoughtful approach at an early stage in development when it can make a real difference. This includes suggestions of new reimbursement models and more pragmatic trial designs. “For example, proposed trials are more ‘real world’ in terms of inclusion/exclusion criteria, and there is a blurring of phase III and phase IV,” she says.

“If you put

[a subgroup with] high unmet need as the first of a number of possible indications, you need to think about the evidence differently, particularly if randomisation is not ethically possible,” says Professor Garner. “That’s why it is important the HTA contributes to trial design and work to develop new tools and technologies for MAPPs.”

Post-approval monitoring

In this spirit, in November 2014, NICE announced it was formalising its relationship with MIT NEWDIGS. While the initial focus of the MIT NEWDIGS programme was on adaptive licensing to allow for early approval and coverage of a new drug for a limited population, the concept has evolved to take in access, post-approval monitoring and use in clinical practice.

Such a whole life cycle view can drive efficiencies and help to ensure the evidence is available to feed into HTA decision-making. “That’s why NICE wants to be in place to help shape this redesign process,” Professor Garner says.

With this same objective in mind, NICE is also taking part in the IMI’s €16.3 million GetReal project, a concerted effort to develop ways of capturing and incorporating real life data into drug discovery and development.

It is hoped the outputs of the project give companies the means to put effectiveness at the heart of drug development, making it possible to generate data that assists decision making to reduce attrition and supports HTA to speed up patient access following regulatory approval.

Bridging the gap from efficacy to effectiveness

Factoring real world evidence into clinical development should give an indication of how effective a drug will be in practice, in the face of preferences of physicians, the guidelines of different health care systems and when subject to the vagaries of patient adherence.

Half-way through the three-year GetReal project, Professor Garner says, “The biggest success for me is that this is about co-design. HTA bodies and EFPIA members have moved from a culture where they were on different sides of the fence, to sitting round the table discussing shared objectives.”

The work package led by Professor Garner has examined case studies of drugs that – although eventually successful – had a hard time passing HTA scrutiny. The aim is to identify the shortcomings in the evidence and translate this back through development to pinpoint where trial designs should be reshaped to gather data for HTA decision-making.

“The methodology requires more work to bridge from efficacy to effectiveness. It is a very complex area, but GetReal is providing the opportunity for dialogue to identify the potential and lay foundations for real world evidence to contribute to drug development and HTA decision-making,” Garner says.

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