Guest Column | June 6, 2018

3 Good Reasons To Never Fall In Love With A Molecule

By Roger Mills, M.D.

3 Good Reasons To Never Fall In Love With A Molecule

In my 2016 book about drug development, Nesiritide,1 I used the admonishment, “Never fall in love with a molecule,” as a chapter heading. A few weeks ago, the editors of Clinical Leader asked me to expand a bit on that aphorism. That explains why I’m sitting at my desk channeling my inner Ann Landers and writing an advice column for the pharmaceutical industry. To be entirely fair, the phrase is not originally from me. In 2005, I heard it from Randall Kaye, M.D., my first boss in the industry. But it made a real impact.

So, I will offer readers three good reasons not to fall in love with a molecule.

1: The odds are really poor.

Individual development path data from over 1,100 companies from 2006 to 2015 reported an overall likelihood of approval for all developmental candidates from Phase 1 of 9.6 percent.

That data comes from a report that also looks at successful phase transitions, defined by movement out of a clinical phase – for example, advancing from Phase 1 to Phase 2. Looking at 9,985 transitions over the decade of data, your odds are best in Phase 1 if you’re looking for a short-term relationship; just over 60 percent of Phase 1 compounds made it to Phase 2. Once in Phase 2, the attrition becomes fierce. Only about 30 percent of Phase 2 development programs transitioned to Phase 3. After the bloody march through Phase 2, almost 60 percent of Phase 3 programs moved on to a new drug application or biologics license application and about 85 percent of the applications were eventually successful.

So, the data support the contention that Phase 2 is the critical phase of the process, where our critical skills and decision making are really put to the test.

2: Falling in love involves (perhaps requires?) a certain loss of objectivity.

And that loss of objectivity can lead to bad decisions.

Nobel Prize winner Daniel Kahneman addresses how this happens in his New York Times bestseller, Thinking, Fast and Slow.3 Tucked into 400 pages worth of ways to make errors in judgment, in Chapter 5 Kahneman describes something called “cognitive ease.” In the clinical development process, we make every effort to get to know our compound. As we repeatedly present progress reports on which our jobs and those of our teammates depend, we make every effort to sharpen and focus our presentations to make our ideas clear. The system seems to want us to project our enthusiasm for this exciting, challenging project. That’s developing cognitive ease, falling in love, and it’s not our job.

Our job is to be uncomfortable. Our job is to look critically at data, to plan make-or-break tests, and to know where every wart and wen hides from the first inquiring glances. And a sound corporate culture is the first-line defense against cognitive ease.

3: Falling in love can erode corporate culture.

This, of course, depends on just who falls in love. Leaders beware. Let’s look again at Thinking, Fast and Slow, at Chapter 7, titled “A Machine for Jumping to Conclusions.” Kahneman shows us multiple examples of how intuitive bias works and concludes with an acronym for a common error, WYSIATI, or “What You See Is All There Is.”

Kahneman reminds us that what we see is not all there is. Falling in love makes us happy and confident. This is not OK in drug development. We need to delve into the quantity and quality of the evidence and to acknowledge there may be missing evidence. We need to be wary about framing effects. “90 percent one-month survival” sounds a lot better than “10 percent of subjects died within a month.” And we need to pay attention to base rates; what do the controls tell us?

This represents a much more sophisticated version of my favorite (apocryphal, I know) Sergeant Friday line, “Just the facts, Ma’am.” A corporate culture that encourages tough questions, insists on good evidence, and looks at alternative ways to frame questions will not support a love affair with a molecule. But beware of the problems that come when the lovebug bites the leader setting the norms of corporate culture. If those norms are no longer accepted, morale erodes rapidly. For a chilling example, I recommend John Carreyrou’s terrific new book, Bad Blood, which details the rise and fall of Theranos, the blood testing company.

There you have it, my three good reasons to never fall in love with a molecule.

Thanks, Randall.


  1. Nesiritide: The Rise and Fall of Scios. True Directions. 2016
  3. Farrar, Strauss, and Giroux. New York. 2011

About The Author:

Roger Mills, M.D., is an academic cardiologist who recently retired from Janssen Research & Development, LLC. He has worked as a site investigator or study-responsible physician in all phases of clinical research, from first-in-human trials to post-approval registries. He remains active as a peer reviewer, consultant, and writer. His book Nesiritide: The Rise and Fall of Scios won the Foreword INDIES 2016 Bronze Winner for science. Watch for his new book, 240 Beats per Minute: Life with an Unruly Heart, co-authored with Bernard Witholt,  next month.