It might seem that science breakthroughs are all about the first researcher to race through the tape at the finish line, but in reality much of the work is accomplished through team efforts. Different research groups put their heads together, compare data and determine the most productive path to the finish line. At the National Institutes of Health in Bethesda, MD, David Wholley, director of the foundation’s Biomarkers Consortium, and Charles Pucie, director of its public affairs and communication department, manage a $450 million dollar budget—including money from Microsoft founder Bill Gates—to further the goals of medicine. Here they talk to ABILITY Magazine about their most exciting project: the biomarker.
ABILITY Magazine: What is a biomarker?
Wholley: A biomarker is an objective, generally accepted measurement of a biological process. A common example is the various blood cholesterol measurements or quantifying blood sugar in diabetes patients. These are outward signs that everyone trusts to measure whether you have a disease or not, your susceptibility risk, the progression of the disease, how effective a treatment is for you, and whether or not that treatment has safety issues. All these things are ways that we use biomarkers. So they’ve been around quite a while.
Science is now getting to the point where we’re going from the empirical level down to where we’re striving to understand the molecular basis of disease, as opposed to just its outward manifestation. So there is now an explosion of biomarkers that have become available because of this transformation. They offer the hope that we can make biomedical science and research something that is personalized, as well as highly predictive and preventive.
ABILITY Magazine: For example?
Wholley: One example is imaging in cancer. There’s a whole class of cancer drugs called anti-angiogenic agents. They’re trying to starve a tumor of its blood supply. We really cannot be quite sure how well they work, because it’s difficult to get in there and measure the tumor to see whether it has actually shrunk or not. So there’s a variety of imaging technologies, such as DCE, MRI or PET technologies. These can be pretty expensive. But basically, they seem to be able to tell us not only whether a tumor has shrunk, but by how much. The problem is that you’ve got all these different makers of different machines to do this, and you haven’t got a common set of standards that everyone agrees measures shrinkage and how you relate that to actual effectiveness of, let’s say, a given therapy.
Currently, we have two projects in PET technology, one in lung cancer and one in lymphomic cancer, which look at different kinds of modalities across multiple clinical sites. We’re exploring how we can standardize measurement, because once you’ve got an agreed-upon measurement—what they call “qualified” biomarkers— then the drug industry can use them in their drug development processes.
ABILITY Magazine: But is it a standard within one methodology? Are you crossing different silos to come up with this idea of a standard measurement?
Wholley: That’s a good question. This process is, I think, just starting out because of the complexity involved within a particular technology. You tend to have protein biomarkers, biochemical biomarkers, imaging biomarkers. But some of the studies that we’re looking at actually involve using both approaches, or using a variety of biomarkers to determine the efficacy of a treatment or to measure the progression of a disease.
What we’re really talking about is taking these biomarkers, which appear to have had enough traction in the literature, and developing them. As I say, measuring their effectiveness or refining them in some way, and then “qualifying” them, as the FDA puts it; they don’t use the words “standardize” or “validate” much. The idea is that, at the end of the day, you arrive at something that all the partners agree has value in treating disease, or in measuring the effectiveness of a treatment. The goal is to do things that are as proximal as possible to the drug development process or to clinical practice.
Our primary concern is the patient. We’re looking for projects that address an important unmet medical need. It has to be practical and address “a translational aspect,” something we can take from the pure research arena to the bedside. Projects need to be feasible, which is not the same thing as practical. By this, I mean that these can be done effectively in the near term, and that they represent a particularly effective use of resources.
There are two ways that you can approach a question. You can start now and say that over the next seven years you’re going to prospectively enroll 500 patients in a trial, it’s going to cost $25 million, and then you’ll begin to do the analysis. Or you can take a look at existing resources out there, and figure out how you can creatively use those to get the same results, given that there’s a tremendous amount of data out there among various companies, we well as in the NIH’s own academic studies. That’s not to say that we’re not doing trials. In fact, that’s a lot of what we do. But even in those cases, we’re piggybacking off existing trials and trial networks, which in many cases the NIH has set up.
One wonderful example is the Adiponectin Project. Adiponectin is a marker that has been shown to relate to glycemic efficiency or, in other words, how blood sugar levels are managed. But there’s been no real conclusive measurement of how that association actually works, and whether it’s completely valid. A few years back, a number of pharmaceutical companies tried to develop a class of compounds called PPAR-gamma compounds to address diabetes. They have a good deal of clinical trial data as a result. They’re at a stage now where they actually could share part of that data.
ABILITY Magazine: Is this the Consortium part?
Wholley: Yes. So we got four of them together and they agreed to share information. Of course the data is going to de-identified and put into a big pool. You mix it all together so you can’t tell whose is which, to get rid of the biases. Quintiles Transnational Corp., a neutral third party with IT capabilities, is going to manage the data pool. Then a data analyst from Quintiles, and one from NIDDK, the agency of the NIH that addresses diabetes, will analyze the data separately. Each will check on the other, which also helps remove biases. Their results are going to be reviewed by a project team, a kind of committee, which has FDA, NIH, industry, and academic members. This group of experts reviews results; what comes out the other end gets published. If there’s a good result, it’ll get published in a journal. If it’s not significant, we’ll just put it up on our website. That’s an example of taking an existing resource and using it.
ABILITY Magazine: How are they going to start sharing their marbles when they’ve invested all this money? Why are they going to partner with other entities if they don’t have something at the end of the line that says that they’re going to get their investment back?
Wholley: You’re exactly right. The focus of the consortium is to do things that are in a pre-competitive space. There are things that are really close to commercialization. We’re not funding commercialization. You need to find areas where the companies or other entities are willing to share, and usually it’s something around a clear public health goal, but also something where if you figure out the answer to a problem, it raises everyone’s stature. Because one of the things that has happened over the last five to 10 years is, I think, the growing realization on the part of industry that the competitive part of what they do begins with the molecule. You can’t put IP claims on molecules.
ABILITY Magazine: So it’s within everyone’s collective interest to share and potentially get the boost to what they’re doing individually.
Wholley: Right. So we also look for projects that the consortium can uniquely address, where getting these parties together through this type of organization is the best way to find an answer. These projects require largescale agreement around standardization, and/or scientific expertise of each one of the parties to really move things along. It may also require pooling financial resources.
ABILITY Magazine: So you have to figure how the puzzle pieces fit together.
Wholley: And they don’t always. We get a lot of suggestions for projects and for one reason or another they don’t work out. The science isn’t right or they don’t fit the pre-competitive mold, or there’s an IP issue or, frankly, at the end of the day, they’re going to take far too long or cost far too much money for what will be an uncertain result.
ABILITY Magazine: At the end of the rainbow, how does the private company make revenue on shared knowledge?
Wholley: You might look at it this way: It would cost them a lot more money to take on some of these projects, and they might not have the inhouse expertise to do it. Besides, they would lack the community validation of their effort. They could stand up and say, “We found this,” and yet there may not be enough people who agree with their findings. So they’re benefiting from community-based science, taking results and using them in their own research.
ABILITY Magazine: So they go off on their own then?
Wholley: They go off on their own. Although I will tell you that in many cases this affects projects that they’ve already developed. Because there is, for example, no agreed-upon biomarker for measuring the efficacy of a particular entity, it may be harder for them to get approval for the drug or, once it’s out there, for them to market the drug effectively. I think I’ve heard that 50 percent of people will get the benefit from a drug; the other half won’t. What if you could figure out why one gets the benefit and the other doesn’t? If you had a set of biomarkers to figure that out, it would be a much more powerful case for reimbursement from Medicare, Medicaid and the managed care community in general. So I think industry really does feel that this has benefit for them. It raises all boats to act in concert with one another, the NIH, the FDA and academia.
ABILITY Magazine: How long has your foundation been around?
Wholley: 12 years. We were founded in 1996 by an act of Congress: the Public Health Service Act.
Pucie: We really started rolling in 2002.
Wholley: But the NIH cannot, except in very specific ways, take money directly from industry.
ABILITY Magazine: So this is like a “friends of” concept? Have you heard that term before? Friends of said nonprofit or other entity will work with some government entity, because this entity has these rules and regs.
Pucie: Very much like a “friends of the university,” which might raise money from the public to build a stadium that the university perhaps may not be able to erect.
Wholley: Yes, it’s similar to that. Before 2002, we did a lot of educational things, but we really began research projects around that time frame. Since then we’ve done about $360 million in partnerships.
ABILITY Magazine: Was partnership your original intention?
Wholley: Yeah, I think the intent was probably differently interpreted. But I think the idea was to do this. In the early days, the partnerships—
Pucie: —tended to be educational. In other words, funding of fellowships, for example, post-docs, pre-docs and the like. Very early on, when this was a twinkle in the eye of members of Congress, in the 1980s, and legislation was being discussed, they thought it might be a way to fund a compensation for some of the government scientists, they could help that whole situation improve, so the partnerships moved into other areas. The legislation was drawn very broadly, and I think the intent of Congress is that the board of directors expects the foundation to be innovative.
Wholley: Meanwhile, the conditions that favor largerscale public-private partnerships began to emerge. We basically pioneered some of the early examples, such as the osteoarthritis initiative and the Alzheimer’s disease neuroimaging.
Pucie: The Mouse genome.
Wholley: Right, the mouse genome and so forth. We currently manage about a quarter of a billion dollars of Bill and Melinda Gates Foundation money and run programs on their behalf. We have funds from other nonprofits as well, managing them on behalf of a significant number of programs to address global health issues in the developing world.
ABILITY Magazine: You’re global?
Wholley: About half of what we do is global health work. All of NIH science is globalized. If they receive a good proposal over the transom, they will fund it, unless it’s somehow verboten politically.
ABILITY Magazine: Like stem cells?
Pucie: Not, so much stem cells. I’m talking about, I don’t know if we could make a grant to the University of Tirana.
Wholley: Or the Kim Il Jong Institute for Biomedical Research.
Pucie: The rules for the NIH are the kinds of rules that apply equally to potential grantees in the U.S. and potential grantees in Europe and the like. I think last year I saw a number that there were grantees in the UK for $35 million or $40 million. Lots of NIH monies go to researchers in undeveloped countries, and one of the main benefits is that this brings in a lot of scientists for exchange programs.
Wholley: Going back to biomarkers: They’ve been around for a while, but because of our increasing understanding of medicine and science at the molecular level, there’s now a lot of them, and in some case it requires a unique process to develop them, standardize them, qualify them, and get them to the point where they can be actually useful to your readership as patients. And we’re one of the organizations, and I think an important one, in getting that work done. Most people believe biomarkers are going to revolutionize medicine, that they are going to provide this highly objective set of measurements as opposed to what we do today, which is sit back, for instance, and see whether you’ve got more red spots or not. That’s really what we’re about. We’re very focused on doing the right kinds of projects, and we’ve got four projects launched, and a bunch more that are nearly ready to go.
ABILITY Magazine: How long have you been involved, Charlie?
Pucie: Several months.
ABILITY Magazine: You sound like you’ve been around for a lot longer. It sounds like the fabric of this organization is already embedded in you.
Pucie: I’ve worked on a couple other projects for the foundation over the last two and a half years.
ABILITY Magazine: What’s your background?
Pucie: Business. I had 16 years at IBM and then was a senior executive in two venture-funded health care Internet-based startups. From one of my pharmaceutical clients, I heard about a large-scale follow-up to the Human Genome Project, which was being managed out of NHGRI. I agreed to join the foundation and help manage that project. We have another one that we’re doing on drug safety, which we’re about to launch.
ABILITY Magazine: Can you talk about that?
Pucie: Yeah, that’s something called the Observational Medical Outcomes Partnership. Essentially the problem it addresses is adverse drug safety events. The way adverse symptoms are currently chronicled is through something called the Adverse Effect Recording System (AERS). This is a voluntary system where, if your doctor encounters a product that creates an adverse effect, he or she fills out a report. They can often do this online, and the information is put into a database by the FDA. That database is available to the public, I believe. The problem is, because it’s voluntary, they can’t enforce data standards, so it really only captures a fraction of the adverse events occurring out there, and gives you no background information. You don’t know whether you have developed this issue because of the drug, or because you’re taking that drug in combination with another drug, or because you’re a smoker and you took the drug… You don’t understand what the clinical context is. The theory is, then, that you can look at observational data, which is electronic health care claims and electronic health records, to see if you can detect these events and then evaluate them, and understand the larger context. There’s a science to this, which is still being developed.
ABILITY Magazine: What are some of the ways that you can use this information?
Pucie: Because drug safety is a tremendous cost to industry, it’s a tremendous cost to the patient, and to our health care system at large. So Congress put out something called the FDA Amendments Act in November, and one of the things they said is that the FDA needs to build a big database of this type of information, and use it to create a surveillance system. Then, when a drug comes to market, they’ve got a way to start tracking how it’s being used by the public, and whether they see any signals of adverse drug events. To manage this process, we’re building a public-private partnership with industry and the FDA, and creating a pilot system to test out this capability, and really to focus on the science aspect of it.
No one really knows the best analytical methods to use to detect an adverse effect. How do you know you’ve found one, whether you’ve got a false signal or not? How do you strengthen the true signals? And how do you evaluate them? Over the next two years, we’re going to put together a big database, all de-identified, from commercial and other sources, along with input from a research team that really addresses the data, the methods, and the best practices. We will publish it, and put it out into the public domain.
ABILITY Magazine: I think everyone’s aware of autism. If something like this was out there on the data of how many children—
Pucie: —I think the problem with that is, you’d have to cross-reference a lot of different databases, and there’s a lot of environmental data that you would need to go along with that. I think that would be an extreme example of something that you’d try to track through this. My understanding is that a bunch of studies have shown that there’s no real correlation.
ABILITY Magazine: The medical community keeps saying that, and more and more people are saying that they’ve found evidence that the CDC isn’t sharing with everyone.
Pucie: It’s like Lyme disease. There are conspiracy theories everywhere. I don’t think anybody’s hiding anything, but that’s just my opinion. Anyway, to go back to the biomarkers consortium, this is really what we’re trying to do. I think these public-private partnerships are increasing in popularity and will be very important in the future of medicine, because getting these different— as you call them, “silos” or as I would say different cultures and organizations—can only benefit the readers of your magazine and patients in general in the end. That’s who we’re focusing on.
ABILITY Magazine: Where do the trials occur?
Pucie: You’re using a lot of academic networks to run trials. We’re not picking a pharmaceutical company and saying, “We’re going to fund your trial for drug X.” We’re assuming that once drug X is on its way, or they’re looking to develop a lot of drug X’s, they will need a biomarker to figure out when somebody who has diabetes is getting better. That will be true no matter whether you’re company A, B, C, D, or E. You’re not focused on whether drug company A’s drug is working. You’re basically saying, “We have no way of measuring whether this entire class of agents is objectively being effective or not.”
ABILITY Magazine: Are most of the pharmaceuticals competitors?
Pucie: Sure. They’re all competitors. But they’re all focused around curing disease. Your question assumes that everybody already knows how to address this, and it’s just a matter of who’s going to get their drug to market. That’s not the case. People really are lacking tools to measure these things, and when they get the tools, then everybody benefits. That’s where we come in. We’re not about promoting one drug over another or even developing drugs. That’s what the industry does. What the industry is saying is, “Give us a set of tools that we can use in phase 2 and phase 3 of clinical trials, in particular, that are going to tell us when something’s working and when it isn’t.”
If it’s not working, they want to kill it early. If it does work, they’d like a way to be able to prove it to the FDA, so that they can get approval more quickly. And they’d like to be able to target medicines more effectively. Personalizing medicines is a big part of it.
Wholley: Meaning to know what’s not going to work on you, but will work on someone else, and what the side effects are.
ABILITY Magazine: How did you get the Gates Foundation money?
Wholley: He [Bill Gates] came to us in 2003 and said that they were looking for something that could help them manage these so-called “grand challenges in global health,” which was going to be a program to do grants around very interesting, practical things. How do you develop a vaccine that doesn’t spoil in the tropical heat? It costs a tremendous amount of money to refrigerate these things. The power fails in hospitals in Nigeria all the time, and there goes your precious supply of vaccines. They wanted someone who could manage a project downstream: to figure out what these programs ought to be and then monitor the grant. So that’s what we did.
Pucie: I think it’s the contrast to the classical solicitation of grant proposals in general, most of which just don’t get undertaken. We say we want proposals in this, that, or the other area. The follow-up with grantees is very much structured to milestones.
Wholley: It’s very proactive, too. I think the Gates Foundation deserves a lot of credit for that. That’s really been their MO. They’ve brought a very strong business approach to this, and are very results-oriented.
Pucie: Also, our grants provide real assistance along the way, and cross-pollination between different grantees, when the insights of one have some applicability to another. So instead of putting the money out and waiting for the published paper four or five years down the line, there’s a very close collegial interaction with the grantees to get things done. Also, there was an emphasis that when consortia were put together to make grant proposals, that they have two features that were very important. One was that they incorporate—insofar as is feasible—nurturing and development of the science research infrastructure right in the area of greatest impact. In sub-Saharan Africa, for instance, there would be scientists from those countries directly involved. The other was to have a concrete access plan so that when the findings surfaced, they were universally available and couldn’t be locked up by a for-profit, which would dilute the impact.
ABILITY Magazine: This is what the Gateses were saying coming in, or is this what you were saying?
Pucie: This was their intention, though they may not have articulated it in those terms, because this was a whole new idea. There was a lot of conversations, sharing of insights and revisiting the subject, until we felt we got it as close to right as you could possibly get, so we could get rolling at that point. It went from a $200 million grant to the NIH, to the Gateses throwing in another $320 million, because of the impressive quality of the proposals that were coming in. The Canadian Institute for Health Research and the Burroughs Wellcome Fund came in for the balance.
ABILITY Magazine: So there are a bunch of grants.
Pucie: About 43, 44 grants. Up to $20 million for five years. All under the foundation. $200 million are directly administered by us. The initial $200 million.
Wholley: We’re very efficient. About 98 percent of the funds go into the programs, and between 2 percent and 4 percent of the monies get spent on the back office, fundraising.
Pucie: We’re probably one of the most efficient biomedical nonprofits.
Wholley: Maybe too efficient. We feel overworked.
Pucie: Yeah, but it’s great work.
National Institutes of Health