Seattle, WA, May, 2005

Q: What if you were eighteen years old today, but knowing what you know. What course of study and what kind of career do you think you would pursue?

A: When I was eighteen I was planning an undergraduate degree in chemistry, which I thought would be a really good scientific background, and then planned to go to medical school. I didn’t have highly refined long-range plans. The biotech industry didn’t exist. The pharmaceutical industry was basically a New Jersey phenomenon, very classically based mostly natural microbe or plant based drugs. The most exciting field was biochemistry. Biological degrees were mostly not molecular biology, but were focused on the study of flora and fauna.

What I learned at the UW was how to be a scientist and how to do interesting things. My advice would be, instead of having a plan, I’d say what interests you? And be flexible. I’d seek the best education I could get with as much practical experience as possible. For instance, when I was an undergraduate I did a lot of research with Alvin Kwiram, which was equivalent to a graduate student’s lab for a year and a half. It was incredibly valuable, and 30 years later we’re still good friends.

So I would say go for a quality type of experience. I wouldn’t pick a field. Even if you’re an M.D./Ph.D. candidate, you do your Ph.D. and then spend 4 to 6 years doing your MD and then your residency. The half-life of knowledge of a Ph.D. now is about 3 to 4 years. So even if you got a Ph.D. and then an M.D., the Ph.D. would be somewhat obsolete. It’s the skills you learn of discovery, analysis and leadership; those are timeless. I would encourage someone not to pick a field, but to do something that gives them those skills

With what I know now, I’d make exactly the same choices. I can’t say that about other things in my life.

Q: As you look back from here on what you’ve been involved with, what one accomplishment stands out as particularly fulfilling?

A: In 1983 I left Seattle to go to San Francisco to do a fellowship in pulmonary medicine. Prior, I had spent a year in clinical research at Harborview that led to great publication. I showed up with more advanced skills than they anticipated. I was at ground zero of the AIDS epidemic at San Francisco General Hospital. At the time the survival of AIDS patients was 6 weeks. There were two competing theories back in 1983 and one was we should provide hospice treatment and there was a second which was we should do research. The amount of federal investment in AIDS research - it wasn’t called HIV AIDS; the virus wasn’t known - was zero. I decided that I would join the faction conducting research. We focused on treating and preventing PCP, a form of pneumonia very common in AIDS patients. We did the first animal studies, human studies, and by 1989 we got FDA approval of the second AIDS drug. I started that work in 1984/85; I was barely 36 years old and had my first drug approved. Within months, tens of thousands if not a hundred thousand people were on aerosolized pentamidine, which substantially prevented pneumocystis carinii pneumonia. This kept many people alive until the development of the antiviral drug cocktails. More importantly, we established by trial design much of the methodology for later AIDS trials and we also showed that this was a market. Before 1984-85, pharmaceutical companies weren’t interested in AIDS because they thought the people were going to die in six weeks and there were only 2000 people diagnosed. By 1990 Big Pharma was involved full scale in research.

Q: Could you please tell a bit more about how the methodology of trials affected subsequent research?

A: One of the problems was what are the end points in an HIV trial. Is it death, progression to disease, pneumonia? What are the rates of progression? If you knew all this events, one could easily design a trial. The second trial is a lot easier to do because you can determine what the sample size needs to be.

When we decided to do a Phase III we had $25,000. Phase III programs can cost a hundred million. So how did we do it? We put together a consortium of hospitals. We did a dose response study and enrolled over 500 patients. It was a simple large study with the end points being death or progression to disease. This was published in the New England Journal of Medicine. The typical protocol in my company now is 64 pages. This protocol was only four pages but it was a very elegant design that clearly proved the higher dose worked better than a lower dose. Ergo the drug must work. With that we understood the incidence of events -time to progression and the end points, which allowed other future studies to be based on these models. The biostatistician, David Fiegel who worked with me later became head of the anti-viral division of the FDA. He led the efforts to speed up approvals of AIDS drugs.

After this, I left academic medicine, which puts very little value on developing therapies. They want scientific discoveries and NIH grants, not a drug that actually works. It became pretty obvious to me that I was an industry person, not an academic person because what I was trying to do wasn’t aligned with the reward system in academia. It’s not good or bad; it’s just different.

Q: Of the people you have known and worked with, who stands out as particularly deserving of your admiration?

A: I’d say two people. Alvin Kwiram. He was a tough professor, one of the toughest one could face. He did a phenomenal job as chair of chemistry, building the department, then as research provost, and is just a great person. The other is Len Hudson, Professor of Pulmonary Clinical Care at the UW. In a very competitive area he managed to always find interest in what other people were doing and always used his influence to help people build their careers. He was never a 'me-me' type. He made the University highly competitive but never brought out competition among the people he worked with. That’s a leadership style which is in the long term very successful.

Q: Let’s talk more about the kind of leadership that’s necessary to succeed in your field.

A: The problem with leadership is we work in a society that values its leaders but finds them wanting. People want a leader who can take input, separate the wheat from the chaff, take the organization where it needs to go and is relatively nurturing and supporting rather than screaming and shouting. The problem is very few people in our industry, myself included, have all the requirements for the perfect CEO. The perfect CEO knows bench research, understands clinical trial design, has FDA relationships, knows marketing, knows how to do an IPO, can handle interpersonal conflicts among a staff, is successful with investors. The list of what they want from a CEO is impossible. No one can fulfill the list and the job is very difficult, so what you have to do is you’ve just got to do your best. Most importantly, you can’t play for yourself in this business, because if you do you’ll lose your partners - your colleagues, employees, investigators, the FDA, and more importantly, your patients, which is who we’re trying to help. But if you take care of everyone else, things will work out ok for you. If you start putting yourself as number one, you’re going to get yourself into a lot of trouble.

Q: What’s the right leadership style to succeed in an arena which requires very substantial interdisciplinary collaboration?

A: In order to get a drug approved, you need many disciplines. Big Pharma has done this by having a huge organization with someone on top. The problem is when organizations get so large the top people aren’t making decisions, they’re making policies and procedures on how decisions should be made. You have your smartest people trying to write down rules. In a small organization, you can have your brightest people making the decisions. At Big Pharma you’ve got the smartest people in the world but the organization is so big they can’t help people down in the organization where their help would be important. You need a critical mass from start to finish in drug development which is probably 100 to 200 people. If you’ve got 40,000 people, how do you manage them effectively? What you’re doing is you’re just laying processes out, you’re not effectively managing. And since a lot of this is gut call based on early data, making decisions, pushing programs forward, that takes a diverse skill base. There’s probably hundreds of good ideas at Big Pharma that probably aren’t getting to the top because of the noise that’s blocking them out.

Q: Imagine you have become Secretary of the Department of Health and Human Services. What one adjustment to national policy would be the top of your list?

A: We haven’t dealt with the issue of whether medicine is a right or an option. We have a society in which a quarter to a third of the people don’t have any health insurance, but they really do, because they can show up and get it for free when they’re sick. That strategy of not sharing the risk is basically bankrupting the system. If people can get a free ride or think they can dodge the bullet often they’d rather invest in a new pickup truck. We don’t mandate that people pay into a health care system yet society is not going to allow people to go without any health care.

We need a national debate about what we really want. Is it a single payer system that everybody’s a member of and then you can option some enhancements? There are so many vested interests it’s difficult to even start the debate without goring people’s oxes.

The FDA does a fabulous job, they have great employees but the most important thing I’d do is build a campus where they can come together, interact and learn from each other and not repeat each other’s mistakes. We should build a a pentagon-type complex where everyone could be together. The other problem is that the FDA is woefully under funded in terms of IT and tools that would allow them to pick up drug interactions. Other essential things are being ignored. We’re not investing in drug safety. Many drugs that are unsafe are off patent; they’re generic; they’re made by bulk manufacturers who have no incentive to insure drug safety.

We’re the only advanced country in the world without a national healthcare system. Things could be done that would simplify the system. You could mandate one form for all insurance claims - this would save hundreds of millions of dollars, just by having one form for all insurance claims. There are a lot of economies in the system that we could capture, but we’re not chasing them out. We spend far more on administration than Canada does. Also, there are huge pay disparities historically between different medical specialties. People who do procedures get paid more than general care specialties. This discourages people from going into primary care. We’ve got to decide whether every heart surgeon deserves to be paid three times the President of the United States when 70% of the money comes from the government. The problem is physicians work for the government but they don’t know it.

Q: What scientific advancement in the past five years have you found personally most exciting?

A: Since I’m a development guy, I like to see the late stage. You can see years and years of molecular biology research and understanding different enzymes and how things work, how cells work and so forth, then someone puts it all together and takes a compound that affects one particular enzyme and says, "aha, I’ve applied it." The example in the past five years for me would be Gleevec, the drug that came out of Novartis, which is a treatment for chronic myeloid leukemia. They actually figured out the cause, tyrosine kinese enzyme gone astray. They developed a specific inhibitor, and many patients are cured. That’s impressive. This took 25 to 40 years of understanding leukemia, synthesizing all that information to come down to a pill that works. And it shows that with more understanding in the future, one can expect more drugs with results like this. It’s the same thing as Fleming’s discovery of penicillin. Wahoo! Salk’s vaccine. Wahoo! Gelvac is the latest wahoo moment. But was Salk given the Nobel prize? No, because it was derivative research, based on people who figured out the cell cultures. All that work that allowed the development of a vaccine. So I’m impressed with the late stage findings. But they are standing on the shoulders of giants.

Q: When did you first detect within yourself the impulse toward science?

A: Like every other chemist, I built rockets in my garage and blew things up and thought this was scientific experimentation. You gravitate to the things you’re good at, and I was good at it in school. I saw a lot of fun in it. My father was a rocket scientist, so that was a hot place to be but by the 70’s that seemed to be petering out. I was drawn to an area where there was a lot of excitement.

Q: Which comes back to the first part of the interview, about how to prepare for a career in the life sciences.

A: The quote I have on my computer is one from Louis Pasteur. “Chance favors the prepared mind.” You just have to have a prepared mind.

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