Clinical Research Now: One Foot in the 21st Century, the Other in Ancient Greece

We do 21st century biology in our laboratories and then do clinical trials that Hippocrates would have been quite comfortable with.  – Roger Perlmutter, executive vice president of Merck and president of Merck Research Laboratories, in a panel discussion at the Forbes Healthcare Summit in October.

Perlmutter’s characterization of current clinical trials rings true.  Much of biopharma still prefers doing things the old-fashioned way. The latest evidence appears in an article by Ken Getz of Tufts in the November issue of Applied Clinical Trials. Getz reports that the industry has been adopting sophisticated adaptive methods at a rate of around 10%. To borrow a phrase, that’s a rate that Aesop’s tortoise would have been quite comfortable with.

Getz’s article not only shows that many in the industry continue to spurn more innovative and efficient methods, but also that they are doing so based on a misunderstanding:

Senior pharmaceutical company executives perceive that regulatory affairs functions are risk averse to adopting sophisticated adaptive design approaches due to their belief that more clarity from regulatory agencies is needed.

And yet, Getz states,

Regulatory agencies, in contrast, appear highly receptive to exploratory phase adaptive trial designs to challenge and inform clinical teams prior to committing to pivotal late-phase studies.

Whether accurate or exaggerated, regulatory concerns aren’t the only reason for the industry’s slow adoption of adaptive methods. Incongruous as it seems in scientific research, resistance may spring from determination to remain ignorant.  For example, sometimes development executives don’t want early stopping rules in a protocol because they want to delay learning about failure, not accelerate it. One biotech CEO told me a few months ago that he wouldn’t want a trial design to include an interim review because unfavorable data might interfere with fund-raising. The program and the company would plunge ahead in ignorance.

Traditional methods may not produce data as rapidly as sophisticated adaptive designs, but even paper-based trials ultimately produce data.  Of course, receiving outcomes data doesn’t mean accepting it. Rationalization is a powerful antidote to bad news and in clinical research, it’s easy – there are so many failure modes to choose from.  Frustrated researchers can blame trial design, the formulation, the delivery method, the dosing level, the inclusion/exclusion criteria, regulatory restrictions, changes in the standard of care, poor site performance and on and on. As long as the molecule itself escapes blame, the program remains viable. Developers who have worked years to advance a new therapeutic agent can keep the faith and carry on.

Delaying knowledge acquisition and marginalizing utilization of adaptive methods contribute to the high costs, long timelines and low success rates that we continually read about on the business pages and in industry publications. The biotech CEO who opposed an interim review of trial data for his molecule was not alone in preferring to defer learning its fate – he embodies a trend. A recent Nature Reviews Drug Discovery article from Michael Ringel, Peter Tollman and Greg Hersch of The Boston Consulting Group discusses “… the likelihood that many low-viability compounds are knowingly being progressed to advanced phases of development.” They attribute this seemingly irrational state of affairs to “… a strong bias in most R&D organizations to engage in what we call ‘progression-seeking’ behaviour.” Progression-seeking behavior includes valuing continuation of a program above learning and facing the truth.

The authors report seeing some companies make organizational changes that make truth-seeking rather than progression-seeking behavior the rational choice for R&D teams. In the same vein, a recent post in this blog discussed the need for amnesty for early stoppers in clinical development to alleviate fears that an early look at data could terminate a program and associated jobs along with a novel molecule. Somehow, the industry must find ways to prevent executive self-interest and self-delusion from trumping the interests of corporations and investors. Because wasting funds on futile projects does nothing to address the public’s unmet medical needs, progression-seeking behavior is as bad for patients as it is for the industry.

This blog has often discussed the value of adaptive design and the importance of access to timely data from the field to support operational and strategic decision-making and reduce risk. However, the most advanced adaptive methods, trial-management techniques and operational processes will make little difference if executives prefer to learn the truth about a molecule later rather than sooner.

It would be nice to close with Aesop’s fable about how the truth-seeking researcher who used adaptive methods to learn the facts sooner got the better of the progression-seeking researcher who delayed learning and rationalized failure. Aesop never got around to writing that fable so the rest of the story is up to us. If the progression-seeking researcher has a successful career prolonging programs for unsuccessful drugs and the truth-seeking researcher is out with the next wave of layoffs, the fable won’t end well for biopharma.

 

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