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A forward march for adaptive designs

From new methodology to IND submission priority to portfolio impact, adaptive trial design continues to make headway in the US and Europe

A report this year by Tufts Center for the Study of Drug Development (Tufts CSDD) indicates adoption of adaptive trials should increase significantly in the next few years, particularly for exploratory phase trials. This echoes strong positive signals this year from regulatory agencies, which included potential priority review status for IND applications whose clinical studies employ adaptive design.

Efficiency or Productivity?
The Tufts CSDD report found that simple adaptive designs, such as futility stops and sample size re-estimation, could save sponsor organisations $100m to $200m annually. In a session previewing the findings with forty executives from large pharmaceutical companies, the majority agreed that futility analysis should become standard practice in all phase II and phase III studies.

In earlier stages, more sophisticated adaptive designs serve to acquire clearer, more valuable information that improves decision-making. For example, poor dose selection in phase II is frequently cited as one of the top causes of late-stage clinical trial failure. While the observed relationship between dose and efficacy for many drugs is often non-linear, the majority of phase II trials reported on ClinicalTrials.gov in the ten years between 2002 and 2011 involved only two or three doses. Acquiring information about additional doses refines understanding of what are often complex dose–response relationships, helping ensure the dose carried forward to phase III trials has the best chance of success. Adaptive designs allow the inclusion of many additional doses, in some cases six or more, without the untenable expansion of the number of patients as would be required in a traditional trial. The strategic application of adaptive design to not just reduce costs, but also fundamentally increase the likelihood of success in later clinical development is essential for both large pharmaceutical companies struggling with portfolio productivity as well as biotechs that need to secure either new investment or a commercial deal to be able to grow. 

Regulatory Support
The Tufts CSDD report also addresses the positive supportive position adopted by regulatory agencies that recognise the use of adaptive design in exploratory phase development is a key step in addressing late phase product attrition. Getting the dose right at phase II has become a rallying cry across the industry from both regulators and pharma/biotech leaders and the past year has seen greater clarity on the use of adaptive designs from regulatory agencies. 

Very recently the European Medicines Agency (EMA) issued a qualification opinion on a novel statistical methodology for dose finding trials which employs adaptive modelling to optimise the analysis of dose-response relationships in exploratory development. The application of this methodology has the potential to improve dose selection and help pharma/biotech make better investment decisions in early phase clinical development. 

In addition this year, the FDA added another major incentive for drug companies to consider the use of adaptive methodology. Companies submitting an IND application can now potentially benefit from priority review status if their phase II and phase III trials deploy adaptive design. The decision by the FDA to encourage the use of adaptive trials is explained in the manual of policies and procedures (MAPP) aimed at IND applicants. 

Why the emphasis on adaptive trials? The Center for Drug Evaluation and Research (CDER) acknowledges that it simply does not have the current resources required to satisfy the timelines either put in place by the FDA or established by federal regulations. As such, it has prioritised phase II/III adaptive trial designs as well as other types of study. The changes to the IND MAPP should attract significant attention from drug companies planning their clinical strategies for new products.

Also late last year, the Center for Devices and Radiological Health (CDRH) published data showing that the agency had now approved over 120 adaptive design trials indicating that the use of adaptive design is not limited to drug development, and also has application in the medical device sector.

Adaptive trial design continues to make headway with both the FDA and EMA recognising the benefits that this methodology can bring to drug and medical device development.

The Author
Phil Birch is senior vice president, global strategic marketing at Aptiv Solutions. He can be contacted at phil.birch@aptivsolutions.com

19th December 2013

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