Clinical development: Overengineered, underengineered, just right?

Print 15 April 2016
Cormac Sheridan / BioWorld

HAMBURG – The blame game is a favored industry pastime, and drug regulators were set up to get it in the neck on the final day of the DIA Europe meeting, in an Oxford-style debate on the motion: This house believes that overengineered clinical development has inhibited innovation.

Lined up in favor of the motion were Sam Wadsworth, chief scientific officer at Cambridge, Mass.-based gene therapy firm Dimension Therapeutics Inc., and Mike Ryan, vice president, strategic accounts, at Medidata Solutions Inc., a New York-based developer of cloud-based clinical trials management systems. Opposing were Martin Landray, professor of medicine and epidemiology, at the University of Oxford, in the U.K., and Bettina Ryll, the Uppsala, Sweden-based founder of Melanoma Patient Network Europe. Not a single regulator was present on the platform, although several contributed from the floor to a lively and entertaining debate.

A live poll taken at the start demonstrated considerable support in the room for the proposition – 63 percent agreed, just 18 percent disagreed, and 20 percent abstained (n=42).

Wadsworth held regulators responsible for holding back innovation because of their inclination to “do it the old way” or else to engage in lengthy discussions about how to do clinical trials. “All of this, to companies, translates into increased costs and increased time,” he told attendees. The complexity of the problem increases because of the multiplicity of regulators, all of which have different views on clinical development. In Europe the problem is further compounded by the multiplicity of regulators and health technology assessment (HTA) agencies – some countries have more than one HTA agency. “And even within the EMA, there are many countries that have different opinions,” he said.

Ryan said that one-fifth of all phase II protocols and one-third of all phase III protocols collect non-core data – information that does not influence primary or secondary endpoints. Protocol violations are a further drag on the process. “Companies have to recruit more patients to weed out the errors that are being generated by non-compliance,” he said. The high level of non-compliance and protocol violations in clinical trials is costing the industry billions of dollars every year, money which could otherwise be spent on product development. Trials have grown in their complexity.

“Patients and doctors are finding it impossible to run clinical trials, because too much is being asked of them,” he said. But the development process remains wired to the past. “We’re managing processes that are out of date.”

Landray countered that the current problems arise from an absence of or inadequate engineering. He cast poor interpretation and misapplication of regulations and an overly cautious approach to technology as the “enemies of innovation.” He argued for a quality-by-design approach to clinical development, which builds on a culture of critical thinking, focusing efforts on essential activities and focus on errors that matter, while building broad stakeholder engagement. All of these are principles of engineering design, he said. “Our failure has been to apply those principles closely,” he said. “It’s not overengineering is the problem – it’s forgetting to engineer is the problem.”

He defended regulators, who have made valuable inputs into new development approaches, such as quality by design, risk-based management and risk-proportionate studies “All these things come out of working with regulators,” he said. Ryan questioned how much traction they have gained in industry.

Ryll warned her opponents not to confuse the symptoms with the cause of the problem. She also criticized pharmaceutical companies for poor clinical trial designs that offered patients no benefits, while using shareholder returns as a metric of innovation. Extending the patent life of an old drug by tweaking its chemistry does not constitute innovation, she argued.

Some common ground did emerge toward the end of the session.

“Trials must become simpler and more accessible,” Ryan said. “We agree that trials are too expensive, too slow, highly wasteful and do not address the questions we want,” Landray said. “That’s not overengineering – that’s insanity.”

By the close of the debate, Landray and Ryll had managed to shift the audience significantly. In the final vote, support for the motion dropped to 38 percent, while opposition to it climbed to 59 percent, with 3 percent staying on the fence (N=37). Polished Oxfordian rhetoric (plus deep experience of large-scale academic trials in cardiovascular disease) allied with powerful patient advocacy trumped cutting-edge medical innovation and smart technology. (The five attendees who skipped the final poll appear to have voted for an early lunch.)

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