Failure as a Necessary Step in Drug Development (Tip of My Hat to David Kroll)

The Forbes magazine has an impressive line-up of columnists; I follow many of those who write on the sciences and healthcare-related topics. One of them is Dr. David Kroll, a pharmacologist by profession and passionate, long-time science communicator. His column yesterday had especial interest for me; in it, David took the example of Dr. Derek Lowe—a pharmaceutical industry scientist who’s also a prolific and erudite blogger—who was apparently his inspiration for starting his own blog, and mentioned an intriguing thing Dr. Lowe had said during a Question and Answer session with Karen Weintraub for STAT News (quoting from David’s column including original links, below):

Over the weekend, Karen Weintraub at STAT News brought us a Q&A with Derek Lowe, PhD, the first pharma industry insider to start a blog—and under his real name as well. […]

What caught my eye this weekend was one of Lowe’s quotes from the STAT article that got a bit of traction on social media:

I’ve been doing this for 27 years, and I have never once put a drug into a pharmacy. I tell people: “If you want to know why your prescriptions cost so much, it’s me.” I’ve done nothing but spend money the entire time.

I certainly understand Lowe’s intent to show how much failure goes into drug development. But what might be lost in this quote is that his “failures” have made indirect contributions to drugs that have made it to market.

David went on to explain in detail why he considers that such failures are important eventually to drugs that were successfully marketed. Do read his impassioned defence of failures as necessary steps in science. His words made much sense to me, because I have been through that experience.

I have, at one point in my career, worked in the pharmaceutical industry for about two years, during which I got to see the drug development process from up close, especially the long drawn-out path of new drug discovery. I was working to develop novel azole antifungals, something which would perform better and with a wider spectrum than then-existing azole drugs in the market. In this process, our productive medicinal chemists synthesized hundreds upon hundreds of chemical entities—novel molecules and their chemical variations—and I was required to perform various microbiological tests, using at first several levels of in vitro techniques and finally, in vivo in established mouse models of the fungal infections.

What was most interesting, intriguing, and significant to me was the observation that, at every such level of testing, the number of candidate drugs would get drastically reduced. Eventually, after completion of these preclinical tests, there would be barely a handful of candidates of interest, and those would be taken into higher mammalian models for toxicity and pharmacokinetics/pharmacodynamics (PK/PD) studies—where, invariably, there would be still further decrease in potential candidates. For instance, ECG assessment in a canine model (the preferred model for cardiac electrophysiology studies because of its amazing correlation with human results) showed that one candidate was prolonging the QT interval, an indication of its toxicity towards the heart, leading to its prompt rejection from consideration. This inverted pyramidal, funnel-type model is essential to bring the safest and most efficacious drug to the market. Not for nothing it takes easily 12-15 years of research and trials for a drug to successfully make it to the market.

Pharmaceutical Research
Credit: AFP Photo by Philippe Huguen, used under CC-BY-SA4.0

As David has pointed out in his column, failure of a drug candidate at any level of the discovery process brings clarity, sequentially, as to what not to do, how not to proceed, and what steps to avoid the next time. This experience represents valuable data that needs to be properly logged and retained—NOT discarded or disregarded, and considered in the overall analysis. This is why, I believe, transparency in preclinical and clinical trial data for drug candidates is so very important for evidence-based medicine. I feel that if the needless aura of mystery surrounding this entire process is dispensed with, it would bode well for development of better and more efficacious drugs (as well as repurposing of older, even discarded, drugs for novel indications) towards more effective patient care and disease management. [This is the principal reason why I wholeheartedly support the AllTrials campaign.]

This is also why I strongly feel that Dr. Lowe’s words MUST be read within their specific context – a context which, without a doubt, many will miss (thereby misconstruing the import of those words). I am not sure if, within the interview, he was exaggerating a bit for effect; it was just one paragraph in the Weintraub Q&A piece. Regardless, I do believe that David is absolutely right, that those so-called failures, encountered during drug discovery research, ARE most certainly major contributions to our overall knowledge—even if not directly to the therapeutic armamentarium.

2 Comments

  1. I did pre-clinical studies to identify hits for antimalarial drugs during my PhD and agree completely with your sentiments, especially the need to publish negative data surrounding drug development. It is especially important for evaluating the success rates of different development approaches, in my case structure-based drug design, in silico screening, and targeting protein-protein interactions.

    • Kausik Datta

      March 14, 2016 at 4:32 pm

      Thank you for your comment, Dr. Hain. Did you find some exciting chemical entities with good potential? For our antifungal, we had an excellent lead to begin with, but somehow eventually it didn’t pan out.

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