I was in tears laughing as I read the investigator's brochure for fospropofol on a flight to Baltimore. Fospropofol was a water-soluble prodrug of propofol, rapidly metabolized into phosphate and propofol. Fospropofol was being developed, in part, to eliminate propofol pain on injection. Unfortunately, phosphate makes your genitals burn, as every anesthesiologist who has given a bolus of I.V. dexamethasone phosphate or codeine phosphate to an awake patient knows (no anesthesiologist ever does this twice). It struck me as an uneven trade. What, exactly, is one supposed to tell the patient before inducing with fospropofol?
During the presentation I had been asked to give, I explained that the perceived benefits (slower onset and offset) were not benefits at all. I also shared my view that genital burning was a showstopper. To my amazement, and against both the available evidence and scientific first principles, the company leadership was convinced that fospropofol was magically more “predictable” than propofol. Someone had convinced them that the lipid formulation of propofol made it unpredictable (whatever that means). Unswayed by my presentation, they pursued the mirage of “predictable propofol” until they went bankrupt.
Fospropofol provides a cautionary tale about the importance of failing early. Time and capital are limited resources. Everyone thinks the project outlined on a coffee-stained napkin in Palo Alto is going to be the next big thing. It is a godsend when your next big thing proves to be a flop before you have sunk your heart, soul, and family savings into a hopeless project. Every innovation is a long shot. As a result, companies that relentlessly innovate necessarily fail often.
Few remember the Microsoft Assistant (it was a pop-up paper-clip) or Apple Newton. There is an entire website devoted to projects launched and killed by Google (see killedbygoogle.com). Quoting Jeff Bezos: “I've made billions of dollars of failures at Amazon.com. Literally billions of dollars of failures. You might remember Pets.com or Kosmo.com. It was like getting a root canal with no anesthesia. None of those things are fun. But they also don't matter. What really matters is, companies that don't continue to experiment, companies that don't embrace failure, they eventually get in a desperate position where the only thing they can do is a Hail Mary bet at the very end of their corporate existence. Whereas companies that are making bets all along, even big bets, but not bet-the-company bets, prevail,” (asamonitor.pub/33dnuZs).
“Failing often” is an area of personal expertise. I have founded, or cofounded, four companies over the past four decades, burning through years of my life and several hundred million dollars of invested capital in the process. The first was “Soft-Pack,” a computer software company that I started in 1976 to develop business software for Wang minicomputers. Wang Laboratories acquired a license and sold our software as the “Wang Manufacturing Management System” throughout the United States and Canada. Clueless, I ran the company from my dorm for my last two years at Princeton and my first three years at Stanford Medical School. Soft-Pack died when the PC revolution in the early 1980s sent minicomputers into trash dumps. My second company, Aesculapius Systems, created software to simplify writing “history and physical” admission reports using pre-populated templates. This was decades before Epic popularized the templated H&P. My computer-printed H&P made a splash whenever I clipped one into the medical record binder. However, Aesculapius was written in C for the Osborne computer. Oops...
In the 1990s, I was one of the Stanford and UCSF academic founders of Pharsight Corporation. I took a leave of absence from Stanford to serve as Vice President of Product Development shortly before the company went public. When the Internet bubble burst in 2001, I laid off most of my team, placing myself at the top of the list. Two years after returning to Stanford with my tail between my legs, the opioid crisis started heating up. I cofounded PharmacoFore to developed opioid prodrugs to reduce the risk of diversion. PharmacoFore patented dozens of opioid prodrugs that could not be diverted to parenteral administration. Along the way, we also invented a novel propofol analog, an opioid antagonist, a non-opioid analgesic, and a drug for ADHD. Shortly after changing the name to “Signature Therapeutics,” we ran out of runway, defaulted on our debt, and our patents were acquired by another company. However, at least we did good science. Francis Collins still presents my opioid prodrug slides when talking about novel technologies that the NIH supported to address the opioid epidemic.
But not always
“Fail early, fail often, but not always.” That is the magic formula of the innovators who shape our future. I nailed the first two, but the third has proven elusive. However, one need not look hard to know what success looks like. Despite many failures, Amazon, Apple, Google, and Microsoft enjoy staggering success. The reason is that they combined willingness to fail early and often with the vision, technical brilliance, executive competence, and sheer determination necessary to succeed.
Our surgical colleagues have been busy innovating the past decade. In this issue of the ASA Monitor, Drs. Dabo-Trubelja and Gottumukkala review procedural innovations outside of the OR, including transbronchial cryobiopsy, arrythmia ablation without fluoroscopy, and transarterial chemo-embolization. Drs. Lee, Vora, Shyn, and Sundararaman look at irreversible electroporation, which destroys tissue (typically solid tumors) using electrical fields to create permanent lethal nanopores in cell membranes. The anesthesiologist needs to prepare the patient for the large electrical currents required for the technique. Drs. Khanna and Schumann review an entire spectrum of devices that can help monitor patients at home after surgery, thus reducing postoperative morbidity and mortality. In the near future, we may see biosensors for glucose and hemoglobin, chest patches that record and transmit heart rate, heart rate variability, and respiratory rate, necklaces that measure bioimpedance and fluid status, and watches that measure heart rhythm, oxygen saturation, and blood pressure.
Much of the current innovation is perioperative medicine driven by software. Drs. Feng, Kang, and Sundararaman review new mobile phone technologies that improve the experience of perioperative patients: the general patient education app Krames (Staywell), the pre-procedure educational app Emmi (Wolters Kluwer Health), the post-op monitoring app HealthLoop (GetWellNetwork), and two electronic messaging apps, Medumo (Philips) and Twistle. Drs. Kovacheva, Cohen, Scoon, and Bates look at innovations in artificial intelligence that augment perioperative care. This includes AI approaches that predict heart failure and risk of postoperative mortality.
Swimming with Sharks
Ted Stanley, the anesthesiologist/entrepreneur who brought us oral transmucosal fentanyl citrate, strongly encouraged ASA to provide mentorship to physician entrepreneurs. At Dr. Stanley's encouragement, in 2017 the Foundation for Anesthesia Education and Research launched “Swimming with Sharks” at the annual meeting. Swimming with Sharks paired aspiring physician entrepreneurs with successful innovators (except for me) or biomedical investors. This year's Swimming with Sharks will be conducted in collaboration with AngelMD.
There will be two Swimming with Sharks sessions. The first will feature four early-stage entrepreneurs, with an initial proof-of-concept prototype or experimental data, who are looking for seed funding to launch their business. The second session will feature four physician entrepreneurs who have launched their businesses and are seeking early-stage funding. In each case, the presenter will be paired with a successful innovator or investor who while help him or her hone the “elevator pitch.” All applicants must have filed preliminary patent applications, permitting them to freely “pitch” their ideas to potential investors and, of course, the ASA audience. Physician–entrepreneurs interested in participating in the 2021 Swimming with Sharks program should complete the application at faer.org/sharks.