Dr. Charles Knirsch: “These Are Not Ruthless Decisions”

Knirsch is Pfizer’s vice president of clinical research. He spoke to FRONTLINE about the company’s pioneering work on antibiotics, and why it’s shifting to focus on other areas. This is the edited transcript of that interview, conducted on August 29, 2013.

Did this whole process [of discovering penicillin] change Pfizer? … How?

Pfizer had been in existence well before penicillin and had been doing a number of different things, but penicillin actually was part of a public-private partnership.

The NIH [National Institutes of Health] was involved. They had issued a request for proposals, and really, because of the casualties that were occurring during World War II, battlefield injuries and deaths from infections were actually a large cause of the mortality, not just the things that go on in a war like bullets and whatnot. So being able to treat infections caused by injuries in the field is a major accomplishment by any clinician, and having penicillin to do that obviously revolutionized medicine, and Pfizer was a part of that. …

… This period of the ’50s and ’60s after World War II saw a lot of discovery, a lot of new antibiotics come on the scene. … Was there any concern about resistance at that point with so many new antibiotics? Did it seem that you could just keep inventing?

… The war on cancer came in a period when control of infectious diseases seemed to be at hand. Now, I think maybe if you’d ask the infectious disease community, they probably wouldn’t have had that amount of optimism, because we know that with therapeutics comes resistance eventually and the need for regenerative process of new therapeutics.

… Clearly in the ’60s, with the control of infections in the developed world, it did seem like we, the science, would move to be able to control other large problems like atherosclerotic heart disease, cancer, and I think all of us hope someday maybe things like Alzheimer’s disease.

And at that time, was there thought [given] to the idea that resistance was out there or not?

Some of the real luminaries in the field predicted this, and I think when you speak to them or were mentored by them, in many of our cases, they knew that difficult times would come unless there was a continuous stream of therapeutics or interventions that would prevent infections. …

We’ve talked to a lot of doctors and physicians about the use of antibiotics, and many of them say in retrospect they feel there was a lot of overuse of antibiotics, and even at their own hands as they look back on it. And I just wonder, was that evident then that this overuse was happening? Is this resistance essentially something that we’ve caused by ourselves?

I think resistance would occur even with appropriate use of antibiotics, and I think there will still need to be new therapeutics, even with appropriate use.

The bacteria have the advantage really is what it comes down to. Their doubling time is in a matter of minutes and hours, so the opportunity with every new organism that is dividing is the chance for a recombinational event or some way around the therapeutic that is designed to treat that bacteria. I think that even with appropriate use, you will see the emergence of resistance.

Clearly with overuse that would accelerate that process, but it’s really not that simple. I’m speaking as a clinician now.

Why?

If you withhold an antibiotic and you are not correct in your diagnosis and there really is an infectious disease, and you fail to treat early a skin infection with what some people refer to as a flesh-eating bacteria, you’ve failed to treat an early meningococcal meningitis. The consequences are grave, so people with a relatively inexpensive therapeutic choose to treat.

But wasn’t there also a large amount of treatment of viruses and other things that really couldn’t be resolved through the use of an antibiotic?

I think if we had a bedside diagnostic that would differentiate between a bacteria and a virus, or frankly even had therapeutics against these viruses — and we’ve tried, actually, in this area. We had a coronavirus program that does make that easier.

But you have somebody with, say, 10 to 14 days of a cough, maybe a low-grade fever, hasn’t been able to go to work for that period of time, I think the primary-care physician will at that point elect to treat with an antibiotic, and that’s particularly true if the patient might be a diabetic or have chronic obstructive pulmonary disease.

It’s not just as simple as overuse, although clearly there are prescriptions that have been written I think maybe sometimes because the physicians are under increasing demands to see more patients per day and so that’s what they elected to do.

And you’ve been there, right? There’s a certain amount of pressure that also just comes from your own sense of “Am I diagnosing this right?”

… Let’s put it this way. In the hospital environment, you have a patient with a hospital-acquired pneumonia, and you’re pretty sure of that. There are other things it could be, so with an illness that might have a 10, 15 or 20 percent mortality even when treated, and a 50 percent mortality when it’s not treated, it’s the security that you’re doing everything for your patient to use that antibiotic.

… How did we get to this point of overuse, or at least many doctors saying we may have given out too many? Who’s responsible? Why did that happen?

I’m usually trying to find the solution to things like that, and as a former hospital epidemiologist, we would look to screen patients for bacteria that in a hospital environment might be dangerous. We set up programs and publish papers on how to screen out, say, tuberculosis, from bringing that into a population that might be in there compromised either due to AIDS or organ transplant.

The way I look at this, though, is to imagine the future, and as part of the innovative industry that does try to imagine the future and things that we can make a meaningful difference in, we look at maybe preventing these infections.

For instance, there are several conditions in the hospitals that we think can be prevented with, say, a prophylactic strategy — in other words, a vaccine strategy — and we are actively working on programs that will prevent those infections.

So when you asked what penicillin — it used to be effective against Staphylococcus aureus, one of the largest causes of postsurgical infections in the hospital. We also make an antibacterial that is really, I think, the go-to antibacterial for serious Staph aureus infections.

Someday we think that we will have a vaccine, and we’re working hard on that right now to prevent Staph aureus infections in those same hospital patients.

So our job as the innovator is to think about the future, to apply our best science and technology to solving that problem.

It’s an interesting line of research, this pursuit of a vaccine, but isn’t there really a fundamental difference between a prophylactic and a therapeutic? When you get the vaccines and prophylactics, don’t you really have to think about large numbers of people being protected, whereas therapeutics are more precise and essentially go after the particular illness or disease?

I agree that’s [true in] the past and maybe even the present tense. I think the future, though, will be individual manipulation of the immune system, not just as immune suppressives but as immune adjuvants.

So I do think that vaccines will be used on individual patients both preventively but also therapeutically.

I don’t understand what you mean about a vaccine being used therapeutically. If I already have the bacteria, are you saying that you would just give me a vaccine that would work to stimulate the immune system to attack it? Is that after the fact?

Clearly in more slowly progressive infections you might look at that. Again, we’re imagining the future here. In slowly progressive infections that you would think, say, in terms of an oncology vaccine and then in treating something that’s now there, yes, I do believe that.

There are other modalities, and there are technologies that we can’t even imagine yet; for instance, antibody therapies. I think you are raising a concern that a small molecule has the advantage of being able to be used acutely, in the real time, but we also know, even with those small molecules, that it takes 24 to 48 hours to have any effect anyway. Even at that point of time when the small-molecule antibacterials that we’ve been talking about, there is a time lag for the patient to respond.

… Was there a period when you think that industry began to see the rise of resistance? … Did people begin to say, “We have something changing here; there’s a paradigm shift”? …

We don’t discover and develop drugs in isolation. We rely on our partnerships with the brightest minds in academia, on our other companies, for instance. And yes, I have been at Pfizer for just over 15 years, and we have been part of discussions and advisory boards where we were imagining a Gram-positive world and a Gram-negative world because the biology is different.

We were working on Gram-positive therapies. We’re still studying agents like Linezolid, and we were confident that that was an agent that we would move forward and would be treating patients successfully, that after that there would be a selective pressure in the hospital for Gram negatives, for instance, which we’d been seeing some trouble with in many places, and that we would then focus our imaginations, our discovery efforts, our resources on a Gram-negative pathway.

So that shift toward the Gram negatives was both a decision, shall we say a corporate strategy, but also a response to a real scientific issue that you saw, which was the rise of resistance.

We were imagining it before the rise actually occurred, because it’s when you have a selective pressure of existing therapeutics, you then know what will happen to the organisms that are not being treated.

So yes, over 10 years ago we were talking about moving our biology and chemistry programs to work on Gram-negative agents.

So maybe 1990s was really the point at which this thinking and seeing this resistance happen?

Yeah, and we also knew even before the l990s how quickly Gram-negative organisms become resistant to the existing therapeutics. They have some advantages, and biologically they’re also really difficult to design molecules to get to the targets.

Because they’ve got that shell, because they can pump them out, because they’ve got these defense mechanisms.

They’ve got that polysaccharide covering, and they have pumps as well. That’s not to say that the Gram-positive organisms are easy. They also require a lot of work, a lot of effort, a lot of resources both in terms of people and in actual dollar terms to develop Gram-positive therapeutics.

Can you reflect a little bit on the shift that took place as you began to see the rise of resistance, and how you shifted to deal with that and to get into the Gram negatives?

Our job and our métier as an innovative discovery and development organization is to imagine what the future medical need is and then to address it.

While we were in the midst of developing Gram-positive programs, agents like Linezolid that actually are really state of the art, and we did state-of-the-art clinical trials to develop the knowledge and understand the benefit-risk of those agents, we also were on the drawing board, meeting with the best minds to imagine what the organisms of the future might look like and the medical needs that would need to be solved in those cases.

And where did that take you?

We devoted enormous amounts of strategic work, project management, financial resources and people, was what it comes down to — biology teams, chemistry teams — to continue work on the Gram positives, because we do pharmacovigilance [PV], and when novel resistance mechanisms pop up in a Gram positive, we’ll bring it in-house, study it, understand it or work with a laboratory that might have more expertise than we actually have on a particular resistance mechanism.

But we were also testing and developing and doing medicinal chemistry. When I look at the medicinal chemists, there are very few of them, but they’re the Rembrandts of the industry in terms of really understanding structure activity relationships.

That’s just a start, because you’ll get a hit, a series. You’ll go into combinatorial chemistry after that to refine the different properties and molecules, tens of thousands of molecules synthesized, most of them rabbit holes that provide no benefit or frankly are toxic, until you weed those out to optimize a couple of compounds that you then nominate and move forward.

But you had a shift, a paradigm shift, really. Tell me about that, in the ’90s, as you pursued Gram negatives. Why?

Pfizer was broadly involved in anti-infectives. Pfizer is currently broadly involved in anti-infectives, and we follow scientific leads. We were involved in antifungals. We were involved in antivirals, and we were involved in antibacterials. We have to manage that portfolio.

Again, the science will lead us, and we have to merge that with either the existing medical need or what we think will be the future medical need, to nominate compounds or candidates at that time to move them forward into both animal and then human testing.

So why did you go after Gram negatives?

We first imagined that that would be the medical need at the time that we were working on Gram positives. We were developing therapeutics that didn’t differentiate on Gram positive or Gram negative. They would have activity against both classes, but we thought more targeted therapies would be the future. …

I guess what I’m trying to get at … is that you saw this rise of resistance coming, and you saw it particularly in these very difficult Gram-negative organisms, and you organized your drug development and science to pursue that.

… With the Gram negatives, … because they have multiple resistance occurring and we have limited therapeutics, we were worried about the future, although it didn’t seem to be, at that particular time in the 1990s, a problem.

But you thought it was coming.

We thought it was coming, and we devoted resources to it.

And what happened?

The biology is very difficult, so that’s why I think a diversity of entities working on this [were necessary], rather than, say, one company, Pfizer, although we were looking for solutions.

The biology is very difficult to develop completely novel chemical entities that aren’t part of existing chemical series like, say, the carbapenems and just optimize your molecules. That’s fine; that’s the easiest way to go. But to come up with a completely novel antibiotic either for Gram negative or Gram positive is tremendously difficult work. …

So while Pfizer was beginning to tackle this difficult Gram-negative problem maybe a decade ago, shall we say, there were a number of other companies that just pulled out of antibiotics. … What was the view of Pfizer about what was happening? … What was the view of others pulling out of the business?

We are singly focused on our own internal capabilities in science. We thought there was medical need. That’s what really matters. And we thought that given our history and being able to develop penicillin, the antifungals, antibiotics, that in fact if we put our minds to it that we would succeed.

But this is a highly risky and unpredictable enterprise as you know, so just by concentrating effort and working with the best minds in academia or NIH laboratories does not guarantee success.

But you thought that, unlike the others, you could succeed by putting everything you had into it?

Not so much comparing Pfizer to other companies. I would prefer that many entities, whether it’s public sector or private sector, are trying to tackle very difficult problems like this.

What we knew that we could do was concentrate resources. We had excellent bacteriologists. We had excellent medicinal chemists. We project-manage. We deploy capital to problems, and we aim for success. You have to be very optimistic in research and development and innovative medicine to be able to bring a medicine from what was previously a new chemical entity.

… So in that period in the 2000s when you were aiming at the Gram negatives, you felt you had a chance of success and it was worth the capital investment.

… The odds of ever developing something that is therapeutic are low, in single digits. That being said, we had succeeded before. …

We have strong medicinal chemistry. We have strong project management. We have been able to keep the focus on what that therapeutic might look like, adjusting, of course, as needed after feedback from wherever that may come, including regulators, to actually make it. From idea to a medicine, it takes about 10 years when you succeed.

… New pressures came up that maybe didn’t exist in the ’50s and ’60s for pharmaceutical companies to perform. New priorities were established. Can you talk a little bit about the shifts in the last decade and what those economic pressures were?

Everybody has to manage a budget. You manage a household budget. I have to manage my household budget, and we manage an R&D portfolio budget.

…It’s been well described in the literature that in terms of an economic return, the chronic therapies that a patient will take either for years or their lifetime provide a continuous return versus any acute therapeutic that may be used for two days or five days or seven days or 10 days, so there are differences in the economics between treatment of chronic diseases and treatment of acute diseases.

… Are you saying, then, that a drug that treats someone for a lifetime produces more revenue and is a different economic proposition than one like an antibiotic that you take a short period?

I don’t really look at it as revenue, but I think some people do. What I look at is a return on innovation, because I have to stand up and defend programs that I think are going to provide something in 10 years, so part of that is to get our investors to believe in the story. If I am saying that I’m going to work on a particular therapeutic, there needs to be a return on that.

And antibiotics didn’t fare well there because people took them for short course, isn’t that right?

I think that the true value of antibiotics may not be recognized by society, and hopefully [through] an interview such as this that maybe you can shed some light on the true value of antibiotics.

… Explain what you mean.

If you look at the course of a therapeutic to treat pneumonia, OK, … we make something, a macrolide, that does that. It’s now generic, and probably the whole course of therapy could cost $30 or $35. Even when it was a branded antibiotic, it may have been a little bit more than that.

So to cure pneumonia, which in some patient populations, particularly the elderly, has a high mortality, that’s what people are willing to pay for a therapeutic. I think that there are differences across different therapeutic areas, but for some reason, with antibacterials in particular, I think that society doesn’t realize the true value.

And did it become incumbent upon you at some point to make choices about which things would be in your portfolio based on this?

Based on our scientific capabilities and the prudent allocation of capital, we do make these choices across the whole portfolio, not just with antibacterials.

But talk to me about the decision that went into antibacterials. Pfizer made a decision in 2011 and announced the decision. Obviously you were making choices among priorities. You had to answer to your shareholders, as you’ve explained, and you shifted. What went into that decision?

I think that clearly our vaccine platforms are state of the art. Our leadership of the vaccine group are some of the best people in the industry or even across the industry or anywhere really. We believe that we have a higher degree of success in those candidates and programs that we are currently prosecuting.

So it’s a portfolio management decision, and if our vaccine for Clostridium difficile —

A bacteria.

Yeah, a bacteria which is a major cause of both morbidity and mortality of patients in hospitals, the type of thing that I would have been consulted on as an infectious disease physician, that in fact we will prevent that, and we’ll have a huge impact on human health in the hospitals.

But did that mean that you had to close down the antibiotic thing to focus on vaccines? Why couldn’t you do both?

Oh, good question. And it’s not a matter of closing down antibiotics. We were having limited success. We had had antibiotics that we would get pretty far along, and a toxicity would emerge either before we even went into human testing or actually in human testing that would lead to discontinuation of those programs.

Again, the science was difficult, and we have these other platforms, these vaccine platforms that are state of the art that we think that the prudent allocation of capital addressing very, very important medical need, we would devote the resources to those programs.

So you decided essentially to shift the capital away from antibiotics and toward vaccine platforms.

Yes.

And there were, according to people we’ve talked to, promising compounds at that time. You certainly had what some people described to us as the best and the brightest in the world working on some of these things at Pfizer. But you just said to me that there were problems with them and that there were difficulties, so I just wonder, was this program not the best and the brightest and one of the best in the world?

I don’t know which programs you’re referring to. Could you be more specific? Some of these programs right now haven’t even been moved into animal testing.

Specific compounds, you mean, haven’t been moved?

A series of compounds, the lines of things we’ve made, multiple compounds, and so it’s not clear even from animal testing whether or not these will be saved.

One of the issues we have in antibacterials, because of the relationship between the small molecule and the target, is the actual milligram quantities that will need to be used therapeutically are hard.

You think about it. Antibiotics are often prescribed as 500 milligrams or 1 to 2 grams every four to six hours. When you start getting into gram amounts of a therapeutic as opposed to, say, 5 or 10 milligrams of Lipitor, there are differences, and your margin between therapeutic and safety is smaller when you’ve used higher milligram quantities.

Again, it’s a difficult area from the regulatory science. It’s a difficult area from the benefit-risk of the emerging molecules. But vaccines, because of the state of the art of our technology platforms and the fact that you’re actually preventing an infection, we deployed our resources, both people and capital, to those programs.

… You had a world-class team of people researching on this, and it seems to me that when you made that decision, you sort of had to disband that team. It must have been hard.

There’s a lot of movement in the industry. There’s movement from academia to biotech, from biotech to academia. There’s a lot of movement, and we think that’s a good idea. We think that new people come into teams, they cross-pollinate with ideas, they bring new capabilities. …

And often we’ll move somebody from, say, infectious diseases into implementation because they bring a particular skill set or whatnot. Movement in the industry is not something unusual. It’s pretty standard.

No, but what I’m getting at is if you had a world-class team here working on antibiotics, and you decided you wanted to shift emphasis elsewhere, who’s going to work on antibiotics?

I think that that is a societal concern, and it does concern me. I think as the science emerges, there will be plenty of people who want to work on antibacterials.

I gave a talk … last year in Washington where I was asked to summarize what would invigorate the entire ecosystem. Part of this is going to be public-sector financing of academic laboratories to really get meaningful careers happening in bacteriology in academic laboratories. I think it does start there very often.

You just said public sector, so are you suggesting that really then we need to get the government into this in a bigger way?

I think the government is involved in a very big way, and the NIH has had a major impact on human health and particularly in infectious diseases. The NIH is a welcome partner.

I’m speaking broader of their role in providing the next generation of scientists. They have a huge role in the United States in just providing that infrastructure.

I know, but my question was, who is going to work on drug development in antibiotics if a company like Pfizer is not? And people say this problem you described as society’s problem isn’t going away. This medical need isn’t going away. So what are we going to do about it?

What we’re doing about it is [use] our top technology, our top science, our top people on the vaccine programs that I mentioned to you.

Right, but not on the antibiotics. You gave up on that part, right?

We didn’t give up on antibiotics. I think if the science emerges and we have a technology platform and a medical need occurs with a return on innovation that anybody would get back in when the confluence of those business factors work.

It doesn’t have to be Pfizer. It could be any of the other companies. It could be a nonprofit. There are many different entities, if these factors coalesce, that could get involved.

There’s a big “if” in the way you just put that: if the economics come back and it looks profitable; if the science gets better; if somebody else will do it. I guess what I’m getting at is medical need doesn’t seem to be waiting for “if.” It seems to be real and now.

I agree with that.

So what does society do about it? Doesn’t it worry you that fewer and fewer companies are working on this?

Pfizer is working very hard in this area. We have done innovative development work, novel clinical trials. I think of the studies we’ve done in catheter-related infections, in hospital-acquired pneumonia.

I was on a call this morning with a large, pretty competitive group that was set up after the GAIN [Generating Antibiotic Incentives Now] legislation, with FDA [Food and Drug Administration], with academics, with other companies, and we have turned over blinded data for third parties to analyze, to see if we can optimize drug development in this entity.

We have worked in many other public-private partnerships and many government-convened discussions both in Europe and in the United States, so we are actively contributing what we have learned, both our successes and some of the difficulties we had in these entities.

My hope is that by committing these types of ongoing resources, which sometimes is above and beyond what I need to accomplish as part of my day goals, will in fact reinvigorate the discovery and development ecosystem so that we do have the therapeutics that everybody wants.

Is Pfizer going to take some of the compounds and the molecules, the ideas, and outsource them, and pass them around for others to work on?

“Outsourcing” is not really the word I would use. Recently you probably saw that we had a drug named Sutezolid, which again, against all odds, that we progressed through. We did some de-risking on it, and we actually took it to Phase II for treatment of tuberculosis.

When we looked at our portfolio, we realized that actually, in discussions, again, in many different environments, that a company that was solely focused on tuberculosis might do a better job than Pfizer in developing that further.

We did all of the hard work and the discovery, the early development work, de-risking, the tox work, so we announced this summer actually that Sequella would take over the licensing of Sutezolid and take it forward. We want to make sure that if we’re not prosecuting a molecule that’s in our portfolio, we make a decision that we do make it available to other entities to develop.

We have similar agreements with the NIH to look at compounds that they have a particular interest in that we just don’t have the resources to prosecute, and to collaborate with the NIH for their scientists or the scientists they fund to then take these molecules forward.

We don’t want to get in the way of some of our early innovation work that we just don’t have the resources to prosecute. We’ll let others do that through a licensing agreement.

When we look at what’s happened here in recent years with the antibiotic pipeline, some people say capitalism is failing. Capitalism itself is not going to change that pipeline. Maybe we need something different. What do you think?

I believe in a heterogeneity. I don’t think capitalism is necessarily failing. …

When you look at centrally planned economies and innovation, just that part of it, because I don’t want to criticize some of the good parts of central-planning economies, on innovation they really haven’t provided the solution.

I do think a mix, though — and I’ve been a part of public-private partnerships both in the public sector and now with Pfizer in the private sector. I do think consortium approaches to very difficult problems is the way to go. …

What’s so hard about these “nightmare bacteria,” these Gram negatives? …

So those are [Centers for Disease Control and Prevention director] Tom [Frieden's] words: “nightmare.” The bacteria are ever-present. The Gram negatives tend very often to be in water systems, actually even in the external environment in water. I’m generalizing a little bit because they’re very big differences, but in general they’re not all that pathogenic.

But in a hospitalized sick patient, for instance, they can cause a pretty bad disease. So these are very often thought of as possible pathogens, the Gram negatives that we’re talking about that we’ve had research interest [in]. There are Gram negatives that are different than that, that are in the outpatient setting.

So the difficulty, just to get back to your question, is that they’re surrounded by a polysaccharide layer.

What is that? It’s a hard layer, right?

It’s not hard, no. It’s actually more of an amorphous, fatty type of layer. Lipo is more fat; polysaccharide are complex sugars. It sits on the outside of this molecule, and it’s actually very difficult to get chemical matter to penetrate.

I think that there will be technologies of the future. Here again we have to be optimistic in discovery and development that will be well suited to treat that. …

… You had here in Groton, [Conn.], a group of people working on this problem of Gram-negative bacteria, right, and looking for new compounds that might get through those layers and might attack those nightmare bacteria.

Yes. We had people working at a variety of locations on the Gram-negative program, including New York and Sandwich, [England], advising from Sandwich, but the actual laboratory work for bacteriology was done here in Groton. …

… Was there progress? Were there some promising compounds at least? And what happened to them? …

… Compounds are often moved to where people would better prosecute them. … We all have different capabilities, and we will license in intellectual property molecules, and build off of that.

Again, there isn’t just one group in one place working on this. We are looking at collaborations and particular agreements with a variety of entities, because if we think the science is right, and there’s something maybe over there that we can bring in to coordinate and move it forward, we’ll do that.

But I’m asking you concretely about those compounds that came out of this effort. Were there promising compounds, and what did you do about them? Or were there problems? Were there scientific problems that made them not so promising?

I don’t look at things as sort of dichotomous like that, in black and white and problems. We’re always de-risking molecules as we move forward.

What do you mean by de-risking?

You start with an idea. There’s a risk at spending any money on an idea and to putting people on it. Then you might synthesize some molecules, but they’re not exactly what you want. So you de-risk by synthesizing more molecules. Finally you get a handful of promising leads that then you might decide to start running in cell screens, after followed by animal testing.

And anywhere along the way things basically may not progress because of failure or risk or they’re not doing what you originally intended. That happens all the way along the line. And again, tens of thousands, hundreds of thousands of compounds get tested in that way before you even get into a human study.

You described before this idea that you had to make a shift. You had to decide where to put your capital, where to put your resources. You had to stand up and defend those decisions. I’m trying to understand what went into this decision to shift.

For Gram positive and Gram negative?

Well, and from Gram negative to the vaccine.

I think it’s about managing a portfolio, and there are things that you’re keeping an eye on. You define very carefully in a meticulous project plan what it will take to get to the next stage gate. If that criteria is not made, you either regroup and say, “OK, we’ll try another angle,” or you kill it.

And is that what happened with Gram negatives? Do you recall why the decision was made to put capital instead into vaccines?

The Gram negatives had some limited success. The chemistry was very difficult, and we had a number of different series that we were working on, and again, for a whole variety of reasons, you may not be able to dissolve it out.

If you want to give something intravenously, you have to actually make it a liquid. We may not have been able to do that without it crystallizing, to do our next series of experiments. Or we could predict that it wouldn’t be something that we could actually solubilize.

We’ve actually had programs in human testing that started having safety signals early. We killed those. We don’t want to take dirty molecules forward into further testing. Anything that has an early safety signal we will kill.

Were those signals received in some of these Gram-negative compounds? Is that what happened? Was that a factor in that decision?

We’ve had some series that cannot be solubilized. It’s not one thing or the other, but it’s a very multivariant type of process where you are looking at a number of different reads from the data and then you make decisions.

You can tell whether a molecule is what we call “druggable.” You know pretty early on. I think people underestimate what we know before we even go into the first human test, how much de-risking has gone on to make sure something is as safe as possible before we actually study the first human being.

Many, many compounds — I mean hundreds of thousands of compounds — die before we think they’re safe enough to put into a human. … It might look good on that petri dish, but as we move it forward, it’s for a variety of reasons not a druggable chemical entity. …

… When you’re making this decision about where to put your capital, make your big investments, what was it about Gram negatives that was getting difficult in terms of government regulation?

It’s not so much government regulation. It didn’t seem like there was a pathway forward. There’s been a good discussion in many different forums, whether it’s in academic societies, other convening entities like the Pew Trust that have brought people together.

Actually, pharma has been doing a fair amount of that as well. We bring people in, often people that were former regulators that may have gone back to academia or joined the private sector to say, “What is the level of evidence needed to progress a compound to approval?”

And that hasn’t been easy. This is really no one’s fault. The dialogue’s been going on. It’s just that you want a reasonable level of certainty that a drug will work and that we have minimized the side effects and any sort of unintended adverse events.

I think with some of the recent legislation that’s been passed, for instance the GAIN legislation, that the FDA is really focusing on being part of the solution and working in a broad way in coming up with guidance documents that will allow a greater certainty that if you do the following programs that that will lead to an approval.

So it was government approval that was the problem, a sort of roadblock? You didn’t have enough certainty you could get these compounds approved.

I think government is part of the solution, and I think that Congress passing legislation helped focus the regulators on this particular therapeutic area and this particular area. The regulators have a large volume of work to do in many, many important therapeutic areas, so this helped focus the attention on antibacterials.

… A lot of people have said to us when Pfizer said they couldn’t do this work on Gram negatives, when they made that shift, it sent a signal to a lot of people that if Pfizer couldn’t do it, maybe it couldn’t be done. How do you respond to that?

As an optimist in discovery and development, I do think that we can bring new therapeutics for Gram negatives. When I say “we,” I’m talking about the collective, society. …

It sounds to me like you’re saying you’re optimistic that other people will do it, not Pfizer.

Again, we manage a scientific portfolio. Right now we are managing a very exciting portfolio that will serve medical need in vaccines. … If we were to have a scientific breakthrough, it would allow us to use some of our resources to prosecute programs in Gram negatives, but I suspect that our approach might focus on our core strengths, things like vaccines or large molecules.

… What would it take to bring you back to that Gram-negative topic? Is it economics? Is it science?

I’m not sure that the question is what would it take to get Pfizer back. I think it’s all the factors that I mentioned. It’s the medical need — we think that’s clear, OK? It’s the scientific capabilities. And then I think a reasonable regulatory pathway and then a return on innovation and investment is part of the factors that are needed. So it’s complicated. It’s not yes or no. It’s multifactorial.

… The science, the regulatory pathway, the economics were reasons why Pfizer made the decision to close down that particular research unit in Groton in 2011.

I think the difficult science, unclear regulatory pathways and an unclear return on innovation led to discussions over a long period of time to then deploy our capital resources to vaccines.

It seems that having a team working on something like those Gram negatives is an asset. You get the best people; you recruit them; you hold them together. A lot of people have said to us disbanding a team like that makes them wonder, is it possible to do this kind of work if Pfizer can’t hold them together?

… There’s a school of thought now that a lot of turnover frequently keeps teams alive and dynamic and allows them to innovate [more easily] versus the first generation, the second generation, the third generation, a little more stability in organizations. So I think maybe a combination of both is what’s needed.

So I don’t think it’s such a bad idea or a bad occurrence when a team has been working very hard on something, is not progressing. In a way, continuing not to have success is not going to be motivation to tackle tough problems. I think disbanding and then re-forming different teams is fine, in terms of just the human-person part of this. …

… What about society’s needs here? One of the things that I’d like people to take away is that there still seems to be a societal need. Who’s going to fulfill that?

That’s a broad philosophical question, and I think that you’ve had a broad background, including being outside the United States. When you look at the budget — so we look at our budget, we deploy people and capital. I think governments have to do it, too, and to decide is 28 or 29 million for the NIH enough. It’s a small budget compared to other areas that the U.S. government spends money on.

Are you suggesting then that really this is an area where the government should do more?

I am a strong advocate of NIH funding, and I’ve worked with and given talks in public settings, speaking on the value of public-sector investment, particularly the NIH, and I served pro bono as a peer reviewer on many different NIH study sections, yes.

Many people see the NIH as a basic research foundation, whereas the applied work is done in places like this, in Pfizer and research groups. You’re not suggesting to change that, are you?

No, I’m not suggesting changing it, though I am always interested in that dialogue. I don’t think we’re static on the right way to do things, so I’ll get involved in any conversation looking at how to do things differently.

We also do basic research. The academics also do basic research. Biotech also. That’s the ecosystem. And again, it takes passionate people wanting to prosecute programs that have their management’s support to do that, and we do that very successfully.

And it’s an equation that’s multivariate that we evaluate, and we choose programs, and we hope to get more right than wrong. But there’s a lot of attrition and a lot of failure in what we do in the pharmaceutical industry.

Looking back at the Gram-negative program, which you saw before everybody else, you pushed hard, and then you shifted on it. Do you think that was a good set of decisions in retrospect? Do you have any regrets about those decisions?

I am concerned about serving medical need in the Gram negatives. I just think that where we were going with the programs that we had, we were serving greater medical need by moving those resources to the vaccines at that time.

So I do worry about it, and it’s why we have an ongoing commitment to sharing what we learned, both our successes and our failures, in many of the entities going forward, trying to address this need through whether it’s the foundation for NIH, whether it’s the Clinical Trials Transformation Initiative [CTTI] — those are two — and we’re looking also at the IMI [Innovative Medicines Initiative], which is the European entity that’s trying to address this as well.

Given this experience that Pfizer had in putting resources and people into researching Gram negatives and spending time with it, what are the lessons learned from that for the potential of this kind of research?

I think there’s quite a bit of insight that we think we have accumulated over that time period, and that’s why we are eager to continue to publish in the scientific literature on some of those insights that we’ve had.

Give us an example. What’s the biggest lesson learned? What’s top of your list?

There’s no one thing, but let me mention a couple. …

In hospital-acquired pneumonia, it’s a leading cause of morbidity and mortality in hospitals. You come in to have, say, bypass surgery. You develop a complication; you stay in the hospital longer; you develop a pneumonia with a very high mortality.

We have done studies with many, many of our now-approved medicines that have been used for five, 10 or even longer period of time. These are very difficult studies to do. It was an enormous commitment to do those studies in the first place, and yet for us or for anybody else trying to follow that pathway, there are insights to be learned from that. So we are sharing data sets. I have statisticians and clinicians that are attending meetings providing those insights from those programs.

We’ll publish this so that people can benefit from what we’ve learned, and it also helps coalesce our own thinking about it when you have to publish something or give a presentation. It really demands that you think about what you’ve learned from these programs so that you can convey that in somewhat of an articulate manner.

In our discussion today, I get the sense that you have to make some very ruthless decisions about where to put the company’s capital, about where to invest, about where to put your emphasis. And there are whole areas where you don’t invest, and I guess the question we’re asking is, do you learn lessons about that? When you pulled out of Gram-negative research like that and shifted to vaccines, do you look back on that and say, “We learned something about this”?

These are not ruthless decisions. These are portfolio decisions about how we can serve medical need in the best way. …We want to stay in the business of providing new therapeutics for the future. Our investors require that of us, I think society wants a Pfizer to be doing what we do in 20 years. We make portfolio management decisions.

But you didn’t stay in this field, right? In Gram negatives you didn’t really stay in that field. You told me you shifted to a new approach.

We were not having scientific success, there was no clear regulatory pathway forward, and the return on any innovation did not appear to be something that would support that program going forward.

The return on the investment?

That’s right. And I think there are many, many efforts, us included, that are trying really very hard to think of better ways to bring new therapeutics, and we will bring new therapeutics in infectious diseases to the clinic.

It sounds to me, though, that there is a societal loss in some of this, and someone’s going to have to make it up. That’s the question I’m getting at. If Pfizer doesn’t do this, if you couldn’t make it work, how is somebody else going to?

I don’t agree with that. I think, without talking about specific companies, there were companies that stopped moving specific chemical matter forward. New companies form. That’s with all the faults of capitalism.

You asked me about capitalism earlier. New companies, new groups of people configure, they get a license to those molecules, they see something that somebody else didn’t see, and they move it forward.

And I think that what we just need is maybe more diversity, a little more funding from a number of different areas. Doesn’t have to be just NIH, by the way. Some of the foundations and other groups within civil society have donors or themselves have significant funds to be able to fund some of this work, get it started, get it to the next stage gate. Somebody else might be interested in moving it forward.

But what about capitalism? Isn’t this why big companies like Pfizer borrow money, raise shares, sell shares? Has Wall Street been unfriendly to this particular process?

I think there may be better people either within Pfizer or elsewhere that can comment on the dynamics of quarterly reporting that Wall Street requires versus, say, more of a European system.

I think that there is no perfect system, but I do know that when you look at patents filed, innovation, that Wall Street’s ability to raise capital, the capital markets are pretty strong and robust in this country to move innovation forward. …

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