在辞旧迎新之际，带点儿知识回家也挺充实。

许多人热衷于新药研发和创新，并不知其中酸甜苦辣咸。最近，FDA公布了22个III期临床试验失败的试验药物，其中包括辉瑞Pfizer的torcetrapib。

正巧翻阅到主管该药物研发的辉瑞前任全球研发总裁 John L. LaMattina一篇回忆文章，值得各位品味一下，什么是新药研发的经历。。。数十亿美金、十几年的辛苦、上万人的工作、甚至失去亲人的痛苦，都在所不顾。。。当临床试验因不良反应或无效被叫停下来，感觉犹如心猝死，一切戛然而止。

　　On Experiencing

　　The Failure Of A Billion-Dollar Clinical Program

　　John L. LaMattina，the former president of Pfizer Global R&D.

　　简历

I was the president of Pfizer Global Research and Development in 2007 where I managed more than 13,000 scientists and professionals in the US, Europe, and Asia. I've received numerous awards including an Honorary Doctor of Science degree from the University of New Hampshire. I am also the author of "Drug Truths: Dispelling The Myths Of R&D" and the recently published Devalued And Distrusted: Can The Pharmaceutical Industry Restore Its Broken Image?" I am also a senior partner at Pure Tech Ventures.

The FDA has published a white paper entitled “22 Case Studies Where Phase 2 and Phase 3 Trials had Divergent Results,” the purpose of which is “to illustrate the ways in which controlled trials of appropriate size and duration contribute to the scientific understanding of medical products.”

One of the 22 examples given is that of torcetrapib, a Pfizer compound that blocked cholesterol ester transferprotein (CETP). Torcetrapib at the time was unique in that, by virtue of its mechanism, it both raised HDL-cholesterol and lowered LDL-cholesterol (LDL-c)in patients in Phase 2 trials. In the white paper, the FDA went out of its way to point out the promise of torcetrapib.

　　辉瑞制药CEO Jeff Kindler 认为

that torcetrapib might be: one of the most important developments in our generation." Pfizer reportedly spent over $800 million to develop and test it.

Well, as most people indrug R&D now know, torcetrapib’s major Phase 3 trial-- which was known as ILLUMINATE and involved over 15,000 participants--failed. The results showed that torcetrapib increased mortality and cardiac events compared with placebo in patients at high cardiovascular risk. Dr. Chuck Shear was the head of Pfizer’s program and the first tolearn of the results:

I remember waking up on that crisp Saturday morning. I was looking forward to some down time as the project had been going 24/7 for a few years now. It was about 3 a.m.– my usual wake-up time–when checking through my email, there was a message from the night before that Philip Barter (chair of the torcetrapib data safety monitoring board) needed to talk to me and that it was urgent. Been there, done that, I thought.

Everything about torcetrapib was urgent, so I waited until 6 a.m. knowing that Philip was even more sleep deprived than I was.

“Are you sitting down?" Philip said. "You won’t believe this, but the DSMB recommended terminating the trial, and I agreed with them."

“What, you’re kidding!" was my reply. How could this be possible? It wasn’t even a scenario we had on our radar screen. "Are you sure?" I said." You have to see the data yourself" he replied.

With this phone call, 17 years of workon the part of hundreds of scientists evaporated. How did they feel? Chuck’s poignant comments were undoubtedly shared by others"

I know I entered an alternate reality that day–although I don’t know it to be the case–it must be something that anyone in bereavement must feel. Something was gone that would never be replaced, a hole in my heart that will remain forever. I remember onthe Metro-North train traveling down to New York City that morning–it was full of kids laughing and carrying on and going to see the tree lighting in the city later that day. I just couldn’t grasp what had happened. My wife, Deb, said it best. I was acting as though I had lost a 6-year-old child. But, even after such adevastating result, scientists pick themselves up and get back to doing their life’s work: discovering and developing new medicines to benefit people around the world. Chuck and others were no different. Soon they were hard at work on another important research project, one also designed to benefit people with heart disease. This time the project involved a novel LDL-c-lowering approach--the blockade of PCSK-9. Pfizer had discovered a PCSK-9 inhibitorcalled bococizumab, an antibody that had profound LDL-c-lowering properties when combined with statins.

However, Pfizer was not alone in the field of research. In fact, it trailed both Amgen and Sanofi/Regeneron. To compensate for lost time, Pfizer embarked on an ambitious Phase 3 program with bococizumab to demonstrate that this drug did, in fact, reduce heart attacks and strokes better than statins alone in patients with heart disease. Two key trials, known as SPIRE-1 and SPIRE-2, enrolled over 32,000 patients and development began in earnest. Chuck Shear was once again in sleep deprivation mode. But again, disaster struck. While bococizumab worked very well in Phase 2 trials, in the SPIRE studies the LDL-c-lowering effect ofthe drug waned after patients had been treated for a year. This is usually asign of a immunological response to a drug. On Nov 1, 2016, almost adecade after Pfizer stopped the torcetrapib program, it buried bococizumab.How did this one affect Dr. Shear?

This one was different. While it hurt personally just as much as my first late-stage failure–no one likes to see their years of work not providing its intended value–at least we saw no harm this time. The decision, though, was easier in the sense that it was ours to make and clear what needed to be done given the emerging clinical profile. What was tough was that we had to euthanize one of our own. Ultimately, it was the team leaders that needed to make the recommendation to management to discontinue the program and I was proud to see everyone come together on this very, very tough recommendation. What was most sobering was to watch myself and everyone go through their own "Kubler-Ross" process of grief as the profile emerged: denial, anger, bargaining, depression and acceptance. Indeed, we all lost something the day Boco died and self-inflicted an emptiness in our soul. But we’ll pick ourselves up and will be better from the experience.

When a late-stage drug candidate dies, industry pundits offer little solace. Rather, they make brief analyses of the situation and move on. Little thought is given to the efforts that hundreds of dedicated people have made to try to bring a new medicine to patients. Unfortunately, Chuck Shear’s accounts are not unique but rather the rule in drug R&D. Losses are endured far more often than wins are celebrated. Drug discovery and development is not for the faint-hearted. Thankfully, there are thousands like Chuck who do pick themselves up and move on to advance medicine.

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