Derek Lowe is scandalized by the fact that 9 out of 10 drugs that get to a first-in-human trial don’t get approval or, to use some jargon, a clinical failure rate (CFR) of 91% per year. He quotes a recent paper which followed CFR over the last six decades [Note: Just to make things confusing, the paper itself calls this percentage “clinical attrition” but Lowe rebrands it to a CFR. Let’s for the sake of consistency stick with the latter, although a pedant may question whether that statistic truly is a rate. ] and noted that it was improved somewhat in the 1970s and 1980s — down to about 80% — but was consistently at or above 88% in every other decade analyzed.
Both the paper and Lowe present this as a Bad Thing. Here is a direct quote from Lowe:
But let’s think about that 91% failure rate for a moment. When I bring this up in presentations, I invite the audience to consider what the auto industry would look like if 91% of new car designs proved unable to roll out of the factory, or if 91% of new airliner models were unable to leave the ground - and if you only found that out after spending all the R&D money to build them at full size and trying to fly them. No cutting-edge restaurant could survive if 91% of its innovative dishes proved inedible or outright poisonous. What other industries operate under these bizarre conditions?
Sounds scary! The paper has a different and a somewhat less alarming spin: see how bad our preclinical testing is if so many of the drug candidates don’t make it to approval for reasons of biology. If there are bad side effects, or the drug doesn’t make it to the targeted tissue, or the liver destroys it too quickly, should we not have picked that up in cell culture or animal testing? Should we not focus our resources on developing more human-relevant preclinical tools, and maybe call them New Approach Methodologies (NAMs)?
At this point in the story I should mention that the paper in question, titled “Need for NAMs: A systematic evidence synthesis revealing over half a century of drug development failure”, was published in NAM Journal. Holy motivated reasoning, Batman.
So now let’s look at the counterfactual: what if the increased CFRs from 1980s to today came by design, from the realization by drug developers that preclinical testing isn’t the greatest at predicting toxicity and is completely useless when it comes to efficacy, so why not just get drugs to clinical as quickly as possible and be as quick in cutting them? My go-to paper outlining this philosophy is one from 2010 which a team from Eli Lilly — as successful at developing drugs as they come — published in Nature Reviews Drug Discovery. To pick out two key points from their above-the-paywall outline:
Reducing late-stage (Phase II and III) attrition rates and cycle times during drug development are among the key requirements for improving R&D productivity.
To achieve the necessary increase in R&D productivity, R&D investments, both financial and intellectual, must be focused on the ‘sweet spot’ of drug discovery and early clinical development, from target selection to clinical proof-of-concept.
Which is to say: since Phase II and especially Phase III trials are an order of magnitude more expensive than Phase Is, let’s quickly do what we must to get drugs into clinic, gather early human data, then make an informed decision. If that makes an arbitrary number go up, so be it.
You can see why the de-emphasis of preclinical efficacy data could have made some lab people unhappy, which I guess is why we now have a journal called NAM. Or was it ‘Nam?
Of course, there are tradeoffs everywhere, and the big tradeoff in the “fail fast” school of drug development is that you are tying your faith, financial and otherwise, to the health care system and contributing to the health care ouroboros. The one where Americans pay so much for health care because drugs are so expensive to develop, and drugs are so expensive to develop because health care in America is generally so expensive. But of course, no one is obligated to run their early-stage trials in the US.