Animal Research in a Global Environment: Meeting the Challenges
John Baldoni
Good morning, everyone. It is a pleasure to be here. I thank the organizers for the invitation.
It is really humbling for me to be here because I am not in your field. I am a chemist by training, have moved through the pharmaceutical industry in various jobs, and now head up a group [at GlaxoSmithKline] called Preclinical Development.
I thought for this talk I would go through a bit of scene setting first, describe what it is to work in a core function such as preclinical development in the pharmaceutical industry. Give you some examples of the challenges to drug development on a global footprint on a generic basis, not only in terms of the care and use of animals but also both in geographic terms and what it takes to develop a drug. Finally, I am going to try to translate that to some of the responses that we have implemented to these challenges relating to animal usage in R&D at GSK.
Background on GlaxoSmithKline
First, I would like to give a little perspective on GlaxoSmithKline. GSK is a multinational company with a goal to improve the quality of human life by enabling people to do more, feel better, and live longer. All pharmaceutical companies have a goal and aspiration such as this. This is the reason to operate. This is the hope of every company that develops medicines: to make people better and to give people hope and to enable them to do more things in their lives.
At GSK we have around 100,000 employees; the number is fluctuating all the time. You read the newspapers. There are changes all over in the pharmaceutical industry, and GSK is not immune to them. We have roughly 15,000 people in research and development on more than 20 sites in 10 countries at this point.
Our R&D organization is a little bit different from many. That is one of the challenges that we have in GSK that others may not have. We have therapeutically aligned centers of excellence for drug discovery (CEDDs) in Europe, in the United States, and in China. So you begin to see the geographic diversity of our R&D organization.
In each CEDD there are multiple discovery units, which focus on specific biochemical pathways or specific biological targets. Sometimes it is a biochemical pathway and trying to intervene in that pathway, and sometimes it is a very specific protein that we are trying to design a molecule to modulate.
There is extensive externalization at GSK via partnerships with biotechnology companies. This has been much publicized in the popular press, regarding GSK strategy and externalization. I am going to get a little bit more into that. It is one of the dynamics that is important for us to consider and perhaps for you to consider when you think about your remit in this organization.
We have a very clearly stated strategic intent: to globalize our research. We have acted on that strategic intent tactically, where we have set up a fully integrated functional R&D organization in Shanghai, China. The intent of that organization is not to develop drugs for China but to develop drugs for the world. The organization was set up in June of last year (2007). By June of this year (2008) we had over 270 employees in that research laboratory in a new building and construction of an additional building.
I am giving a perspective on GSK. Any global major pharmaceutical company now will have a similar story. But we are not typical. There are other pharmaceutical companies looking at how we organize, and going from big R&D units to small R&D units, essentially taking advantage of the wisdom of a crowd of discovery units as opposed to that of a single monolithic discovery unit.
With regard to our R&D units, there is a great deal of complexity related to the core processes that we use in conducting our work and delivering our products. We have an extensive network of research facilities in the UK, three in the US, France, Poland, Croatia, Italy, Spain, Singapore, Shanghai, and Canada. This creates opportunity for us to take advantage of the science occurring in these geographic regions. For example, our interest in Croatia was a very specific platform that we felt would transform our ability to address a specific disease. We bought a company in Croatia and have made them a bit entrepreneurial. They are now exploring opportunities to address a specific disease target.
Not all of these sites are fully integrated from discovery all the way through commercialization. The UK sites are, but the Ireland site is not. Italy is, but Spain isn’t.
Trends in the Pharmaceutical Industry
There is a mix in a pharmaceutical organization, a confluence of behaviors and attitudes and regulations and cultures. A modern pharmaceutical R&D organization is always going to be driven by innovation and risk taking. This is
because the regulators around the world have clearly told the pharmaceutical industry, “We want different kinds of medicines. We don’t want medicines that are incremental and expensive; we want medicines that are transformational and cheap.” This is a big change for the pharmaceutical industry, which in the past has been supported by products called line extensions. If you look at the names of drugs and see XR or CR or something like that after the name, it typically indicates a line extension. These extensions create benefit for the patient, but they don’t often affect the therapeutic outcome, sometimes they just provide dosing convenience. Many are now questioning the relevance of line extensions.
Scientific rigor is absolutely paramount—without it we are not going to get those transformational ideas. We now assess the risk of developing a drug from a biochemical pathway target, all the way through to the animal model, all the way through to the manufacturing, all the way through the commercialization and the system to distribute and sell the drug.
Our ability to sell a drug 15 years from now depends absolutely critically on the scientific rigor used to identify a target and its pathway, and picking the right molecule to affect the target. Three simple questions: Is it the right target? Is it the right pathway? Is it the right molecule? The answers to those three questions cascade a series of events that ultimately cost over a billion dollars today.
Declining Productivity
There has been a lot in the literature about the productivity of modern pharmaceutical R&D organizations. There have been fewer new drug approvals in the last few years than in the previous ten. A lot of money is being spent in pharmaceutical R&D, and all that money has generated a huge benefit to society. But the financial consequences of that benefit to companies are dropping off very quickly. Within the next four years, over $200 billion of pharmaceutical sales will be lost to generics, it is a big number. Those generic drugs are going to be much cheaper and they are going to be very effective. The next generation of drugs that pharmaceutical companies are developing has to be better than those and to answer different questions, with a different safety profile and with more efficacy.
R&D has to increase its productivity to give us more meaningful medicines. I want you to think about entrepreneurism here, and entrepreneurial spirit. In almost all R&D organizations now, they are talking about entrepreneurism. Looking at the biotech industry in the United States, on the East Coast and the West Coast, there is a lot of entrepreneurial spirit. There is a lot of success. [Companies there] break through barriers, they do things differently, faster, and cheaper. They leave huge gaps in their programs that have to be filled later, but at the end of the day you know whether you have a meaningful medicine, and you can invest very heavily in that meaningful medicine and fill the gaps later.
Increasing Externalization
The trend is to be geographically diverse: “Go to the science.” GSK has made a decision that we are not going to bring the science to us, to our sites, to our geography; we are going to go where the science exists. So we made decisions to go into Croatia, into China, and we continue to do that. We have purchased companies in Boston and we have left them in Boston. We purchased a biopharmaceutical company in Cambridge, England, and we left it in Cambridge. We didn’t put it into one of our five sites in England. We are leaving the science where it is developed. That creates more diversity in culture, more diversity in behaviors, and we have to ensure that the core principles in our company encompass those people and bring them into using our core principles. I will talk more about that as it relates to animal use.
At GSK, we are exploring our pipeline in different ways. We have in-house expertise; we are partnering externally extensively; and we are going with virtual drug development companies, people who have ideas. We buy the idea and they develop the drug on the outside. That is virtualization.
Externalization means that there is a company out there that has a molecule or a biochemical target that we don’t have. We are paying them to explore that target, and when they give us a reason to believe, we will buy that molecule back from them.
At GSK in the past, I would say 80 percent of our work was done in-house. In the future I would say more than 50 percent of our work is going to be done externally—externalization and virtualization.
Maintaining Quality with Simplified Governance
Empowerment is a word that I want you to think about as it relates to the care and use of animals in R&D, against that geographic background. We are empowering our people that run or work in these units, which define the strategies for success. If their strategy for success is to use an internal chemical development group to synthesize their drug, they can do that. If their strategy for success is to externalize synthetic chemistry to a contract manufacturer in China or India, they can do that.
What they can’t do is negate the quality standards or the core principles of our corporation. So there is a diligence that we have as a company to ensure that as we discover and develop drugs we don’t go outside the boundaries of our core principles or our quality standards in developing drugs anywhere in the world.
Simplified governance falls under empowerment. We are doing away with a lot of review bodies in GSK but keeping key ones. Those retained ask questions like where is the quality in the product, what is the animal model, how are you ascertaining the efficacy of the drug. I already talked about integrating quality into the drug discovery and development process. It is paramount. It is abso-
lutely critical that we have quality at every level, from the biology to the chemical manufacturing controls to the regulatory to the clinical trials.
The industry as a whole is moving very quickly away from industrialization. Industrialization was a platform approach, a checkbox approach to developing drugs. If a machine can make 50,000 compounds a day, I am going to make 50,000 compounds a day. If I have a machine that can screen those 50,000 compounds against 200 biochemical targets, I am going to take 50,000 compounds and screen them against 200 biochemical targets a day. This process generates data that would fill unbelievable computers.
But it hasn’t been successful. Over the last ten years during this industrialized pharmaceutical R&D we have gone through a nadir in productivity of new drugs in the pharmaceutical industry. To varying extents, many pharmaceutical companies are now deindustrializing their processes and going to a judgment-based approach, putting smart people on a narrow focus to address the issues at hand in their biochemical pathway or their biochemical target, and design molecules very selectively.
Against geographic diversity, with all of its political and cultural diversity of behaviors and attributes, you can see there is a storm brewing here in the pharma world.
Preclinical Development at GSK
I am going to shift now and tell you a little about my department—it is one of those core functions that enable a lot of the stuff to happen. Then I am going to talk a bit about some of the challenges that we see and our responses to those challenges.
As I said before R&D in GSK is set up with discovery units. On the front end of those discovery units we have machines that generate reagents, biochemical targets, proteins, and we work with the discovery scientists to come up with cell-based assays, to test their hypotheses. That is called molecular discovery research in GSK.
On the back end we also have some major functions, one of which is preclinical development. Behind that is clinical development and behind that is the office of the chief medical officer, and behind that is regulatory and compliance. There are lots of layers of big engines in a major pharmaceutical company.
The one I am most interested in and the one I am most proud of is preclinical development. In preclinical development we have five major departments: drug metabolism, which investigates the absorption, distribution, metabolism, and excretion of our molecules; pharmaceutical development, which develops the dosage form and the manufacturing processes for those dosage forms; safety assessment, which assesses the hazards and identifies the risks of molecules; chemical development, which actually makes the drug substance and scales it up and transfers it to factory; and laboratory animal sciences, which you
heard about yesterday from Margaret Landi, whose group ensures the care and ethical use of animals in R&D in our company.
Preclinical development spans the whole drug development process, encompassing research, development, and commercialization—from the target, lead candidates (the hundreds of molecules that might be drugs) selection of a candidate for development, and then first time into humans, first proof of concept, safety and efficacy trials, filing for approval, and commercialization. To varying degrees each one of those five departments spans the whole drug development process. In GSK about 4,000 out of 15,000 employees work in this core function called preclinical development.
In preclinical development, we take scientists’ ideas and translate them into a chain of events that results in the conversion of the idea to a drug substance in chemical development, to a drug product in pharmaceutical development. We distribute those supplies for clinical trials around the world, which then get into patients’ hands in very controlled settings in order to ascertain the safety and efficacy of our drugs in an experimental basis.
We do this using two different processes. One is to understand the risks from a biological perspective, which involves in vitro work, and to understand how our drug behaves in in vitro systems and ultimately in in vivo settings. Preclinical in vivo studies involve conducting animal model efficacy studies with discovery scientists, regulatory-required preclinical studies required to demonstrate the safety of a molecule and, importantly, investigative toxicology studies, which constitute a lot of what we do. The drug development process is fraught with a lot of surprises, and a lot of them are manifestations of toxicity. The relevance of those toxicities in humans has to be investigated prior to human testing, thus a lot of investigative toxicology studies.
The other pathway is to deliver the product from the chemistry and pharmaceutics perspective. We develop the physical product that you hold in your hand, whether it is a tablet, an inhaler, an ointment, or a cream or the like. We transfer that to manufacturing and ultimately it is that product that makes people feel better, live longer, and do more things.
So that is a picture of what we do in preclinical development, at a very high level. It is not that simple. It is a very complex process—both of these pathways are among the most regulated processes in the industry.
Challenges of Globalization
Now I will talk a little about the challenges to R&D. In looking at a picture sent to me by Margaret Landi and Jeff Everitt, I saw this sky and asked why the sky is red? It is either a sunrise, which may be the dawn of a new era for pharmaceuticals, or it might be a sunset, which I hope has no metaphor for pharmaceuticals. Then I thought I would take a realistic approach. This is a fire-
storm and the sky is red because the world is changing in the pharmaceutical industry. So this is the metaphor I am going to use here. I think when that firestorm is out, it is going to be a sunrise, and it is going to be beneficial to everybody, because the whole pharmaceutical industry realizes that it has to change.
I mentioned meaningful medicines. What are they? To us they are medicines that are affordable, accessible, and sustainable, and that have greater safety than current molecules with enhanced efficacy. Affordable and accessible—they go together.
It is great for most of us in this audience from the Western world to have access to the most modern and fantastic medicines that make us feel better, that make our families feel better, make us better, able to do more things and to live longer.
But we are actually a small population in the grand scheme of things. There is a world out there that doesn’t have access and doesn’t have affordable medicines.
Access and Sustainability
When you go to the drugstore to get your prescription filled, or when it comes in the mail, you get a bottle of 30 or 60 or 90 tablets. When people in a developing country get a prescription filled, they say “I have three cents and I can buy one pill. So I am going to buy that medicine for today and I am hoping I can get another three cents to get that medicine tomorrow and the next day and the next day.” That is not accessibility.
That is a big challenge for us in our industry. It is a challenge that we at GSK are taking very, very seriously. At the top, the middle, and the bottom of this organization we are thinking about how we can have our medicines be more accessible and more affordable.
What does sustainable mean? It means that when we get a medicine on the market and people are expecting that medicine to make them or someone in their family feel better, or the person they are taking care of feel better, they have to have confidence that that drug is going to be on the market forever. There aren’t going to be hiccups in quality that cause a recall. Our company has been burned by that; most have. We are getting better and better at that. But it comes into this global environment in which we work, and global standards.
So we have a single quality standard. It starts very early in the drug development process. We ensure, as we go through our drug development process, that we build quality into our product so that if and when that product launches, we have some assurance that it is going to be sustainable in the market from a quality perspective.
Transparency and Regulation
There are many stories around the safety of our drugs. As we get more experience with patients in the real world different safety issues arise, and we have
to understand those, we have to react to them, and we have to have programs in place to address them. We strive for greater safety.
The industry is very transparent on this. You can go to websites for every pharmaceutical company and look at every drug that is on the market and look at the safety reports for all those drugs. There is a lot of transparency.
I have already addressed the issue of greater efficacy. There is a patient need, there is a financial need, and there is a payer need for drugs with greater efficacy.
There are some challenges, though, to creating meaningful medicines. There are societal expectations: people expect that with all the money they are spending on drugs, the return on that expenditure is better drugs. There is activism—in the animal world, in the patient world, and in the political world, people asking of pharmaceutical companies: What are you doing? How are you doing it? Why are you doing it that way? How can we get this done?
There is also public perception, positive and negative. When people find out that I work for a pharmaceutical company, the binary nature of the reaction is remarkable. My neighbor comes across the street, “I hear you have got this new diabetes drug, is it going to help me?” “Talk to your doctor,” I say. Headlines in the New York Times, “Glaxo diabetes drug safety issues.” He comes to my door, “What the heck are you doing to me?!” I say “Talk to your doctor.”
The examples are real. These are real issues that we have to be concerned about. If we don’t do things right, we lose our ability to do what we do, because people will lose confidence in us and in our industry. That is the worst thing that can happen, for them because they will be hesitant to take our drugs which will make them better, and for us because then we don’t have a reason to exist.
On the other hand, with all of these challenges to pharmaceutical companies, there are some things we can do. We can respond to the social issues. There are cultural differences. There are also some hard issues—there are legal differences in geographic regions, the regulatory requirements in geographic regions are different. The regulatory stringency is ramping up.
We have a group in R&D called the Good Manufacturing Practice (GMP) Quality Council, which I chair. On a quarterly basis, we look at what is going on in the world and ask what is going on that is different from what we know now? What do we have to do in our quality organization to adapt to that? This isn’t a talking session; this is a real conversation session. We are very rigorous on ourselves.
As a consequence of what is changing in the world and the geographic expanse and the lack of harmonization in many instances, we are changing our quality approach to adapt. The way we were doing this wasn’t sustainable. It wasn’t sustainable for us to have a quality standard in R&D that was slightly different from the quality standard being used in Cork, Ireland, for example, or in Shanghai. So we are reacting to that.
The challenges to the industry are coming from two areas (this isn’t a comprehensive list, I am using examples here). There is the social, the cultural part of this, and then there is the hard reality, the legal part.
Responding to the Challenges
Those are all things that are putting pressure on meaningful medicines and tipping that balance, so to speak, between what we have to do to develop our drugs—the innovation, the biochemical pathways and all of that—and what we have to do to ensure that we maintain the capability to keep developing drugs.
If I were to present this as a balance, there are a lot of things that are pushing us into the red zone, the danger zone. There are also some things that we can do to respond. For example, we can be better at understanding the science. If we are better at understanding the science, maybe we can have supportive business processes that enhance our ability to build trust. If we build that trust and engage shareholders, we will be able to address the social and cultural parts by taking an approach that links the science to societal needs, so that people have a reason to believe in what we do in the industry. I want to talk about one of these areas as an example.
Ensuring Good Science and Animal Welfare
First, this is fundamental: Understand the science, justify the experiment. Good animal welfare is absolutely necessary for good science. I don’t think I have to tell you that. Some of our studies are conducted over a year, two years, and we have to ensure that the variability of the animal does not contribute to the variability inherent in a testing of a biological hypothesis.
We in GSK are now requiring a justification for the rationale for an animal efficacy model on a target-by-target basis. What do I mean? If there is a diet-induced obese model being used to explore diabetes, and one of the biochemical pathways they are exploring is insulin sensitization, justify that diet-induced obese model. If it is the glucose transporter target, question why are you using the same model? Force people to think through the biochemical pathway and the relevance to the efficacy model that they are proposing. This creates a lot of positive tension in the organization; we are asking people to challenge the past and look to the future. Why is the model for insulin sensitization the same as for a glucose transporter in the kidney? If it doesn’t make sense, justify it.
Another area we are addressing is to understand the biological variability that could impact the interpretation of the hypothesis to be tested in that efficacy model. At GSK we have statisticians working with our biologists to understand the variability of the efficacy model and correlate it to the variability required to test the hypothesis, both in animal numbers and in the biological response,
We require a challenge for replacement, reduction, and refinement in our review of each protocol. But there are additional challenges coming, too. The biopharmaceutical area is emerging—it is going to explode in the next ten years. That is going to create new challenges for us. RNA interference entails new challenges for us in the use of animals in R&D. Recently we have been getting a lot of questions around how we are going to assess the safety risks of nanotech-
nology. We in GSK have a nanotechnology program and we are thinking that through right now.
Importantly, we invest in platform technologies that underpin our corporate policy in the use of animals in R&D. What does this mean? We spend money exploring technologies that allow us to adhere to the 3Rs and to our core principles that Margaret Landi talked about yesterday (I’ll give an example of that later).
Implementing Supportive Business Processes
The second response to the challenges is: implement supportive business processes. You heard about laboratory animal sciences (LAS) in GSK yesterday. It is a global organization. Before we do any work in any site, in any place in the world, that group assesses that organization against our policy on the care and use of animals in R&D. LAS was instrumental in setting that policy with the highest levels, including the CEO of our company. It leads the policy implementation and adherence to that policy, so there is an audit function to it. It reviews internal operations to the relevant standard. We adhere to the most rigorous standard where we conduct work—country or corporate standard.
We evaluate external work done on behalf of GSK, even if GSK isn’t sponsoring the work. We set expectations of adherence to GSK core principles for those partners performing work being done either on our behalf or in conjunction with us. If we have scientists working in an academic laboratory doing animal work, we assess that academic laboratory for adherence to our core principles. LAS drives consensus on best practice around the organization, which creates a lot of constructive dynamics and constructive debate in our organization. It maintains knowledge and activities in various regions. So, therefore, they have to have cultural and legal acumen. This again is a major activity in the diligence group in the LAS organization.
Importantly, we reward and publicize desired actions and behaviors. I will give you a couple of examples. We have a group of people that thought there was a technology that would reduce the volume of blood required to do our toxicokinetic (TK) studies. We gave these people a budget, and they came back and developed a technology using materials off the shelf—they just were very creative in how they put it together—that resulted in our ability to take microliters, as opposed to milliliters, of blood from rodents to do TK studies. So the number of animals was reduced and the amount of intervention stress on the animals was reduced significantly.
That is an example of where we built a platform, and that platform is being rolled out across the organization right now. It is not applicable for every compound but it is applicable for over 90 percent of our compounds.
We also have this policy that we want self-disclosure. If somebody in an animal handling facility or an animal facility has an issue, they are encouraged to talk about it, to self-disclose. We have a session where they talk and
learn from each other by asking what happened, why did it happen, how can we do it better.
Senior leaders in the organization, including myself and the head of drug discovery, visit animal laboratories to ensure that the people that work in our animal facilities understand that this is an important function to the organization. They understand that they can approach us if there are issues in their organization or in the way work is being done in their laboratories.
Audits, “Constructive Conflict,” and Stakeholder Engagement
Finally, Margaret’s organization does internal, independent, and third-party audits. We take this very seriously. We are audited both by our internal group in preclinical development and by a corporate group, so we go through two audits: a self-audit and a corporate audit. Then of course we are audited by regulators.
We have a public statement on the use of animals in research to build trust; I think Margaret talked about that yesterday. We use GSK core principles, which are independent, as I said before, of location, an outside company’s relationship with us, or the study size.
Importantly, we get world-class experts in laboratory animal sciences and we make them influential. We put them in front of people, we put them in front in the debate—there is a lot of constructive debate that goes on, there is a lot of conflict. We are a better organization because of that conflict—I call it constructive conflict. We can’t have growth in this area unless we have constructive conflict.
We ask challenging questions. A very senior person at GSK when visiting a discovery laboratory asked how much human tissue was used, and the scientist said, “We use a lot, we are really moving in that direction.” This very senior leader in the organization said, “How has that impacted your use of animals in research and development, how much has it diminished it?” It is challenging to have the most senior person in an organization ask a scientist at the bench a question like that, but that is our approach.
We acknowledge success and address deficiencies. There is transparency and interpretation of rules and implementation with judgment on legislated standards. That drives the constructive debate that I talked about earlier, not just in our organization but in settings such as this meeting.
With regard to stakeholder engagement, I already talked about knowledgeable senior leaders in the organization. There is a regular dialogue among the users, the caregivers, and the comparative biologists in our organization to ensure the relevance of the animal model, as I described earlier. We have a culture of continuous improvement. We share knowledge across the organization, across those ten countries and those 20 sites.
I sit on the R&D Executive Committee, and on a regular basis we have a session where we talk about the use of animals in R&D. We keep metrics on the use of animals and we act on those metrics.
Externally, we engage stakeholders in meetings such as this. We endeavor to understand the local regulations and, importantly, the environments in which our people are working, so that we can understand the culture in which they work and the stress they are under and how we can help them, through mutual education and exploration of differing views, and, as I mentioned, we encourage audits by external and internal groups.
Conclusion
In summary, the pharmaceutical environment has changed and will change in the future. Standardization across geographic regions and cultures and jurisdictions is not realistic now, because it is too dynamic. We will rely on core policy, principles, and values.
One of the most important principles is that of peer review. This creates the challenge we want to understand of the scientific hypotheses to be tested in animals and to question how replacement, reduction, and refinement are being considered. The first few times we went through this, it was difficult. Now we have our CEDD heads engaging our people and asking them to justify their experimental models. That is the transformation we are looking for, the kind of drive we are looking for in an organization.
It comes only with deep expertise in comparative biology. These people are going to be with some of the world-class scientists in the therapeutic area discussing a biochemical pathway in an animal model. Our comparative biologists have to go toe to toe with them. They have to be just as world-class in their discipline. And they have to have courage, if I could use that word, because they are put in challenging situations.
Diligence ensures adherence to principles and dissemination of learning. It is not good enough to just audit. We have to audit, we have to talk about it, we have to put it out there, we have to air findings and share corrective actions, and we have to make people understand when things have to change.
Finally and importantly, operations based on publicized core principles and continuous improvement enable geographic flexibility in where work is conducted. The standard creates the corporate way of working. We have assurance that, through our policy and processes, through the science that we emphasize, and through our audit functions, we will meet our standard anywhere in the world. If the standards cannot be met, we don’t do work there. That drives good behavior in our organization and in those organizations with whom we work.
