Gil Roth10.10.07
Executive Interview: Robert Maguire of Wyeth R&D
Building a pipeline means building a new clinical model
by Gil Y. Roth
Wyeth has suffered some high-profile FDA setbacks in recent months, but the company remains committed to a radical R&D model implemented earlier this decade. With this new structure yielding a minimum of eight INDs annually, Wyeth faced the challenge of efficiently handling clinical trials for all these new compounds.
We recently caught up with Robert Maguire, M.D., Wyeth's vice president, chief of operations for clinical R&D, to discuss the company's approach to global clinical trials, its position on "exclusivity" with clinical sites, the learning curves for clinical operations in emerging regions, the company's approach to innovation, and the development of its Early Clinical Development Center (ECDC) network.
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Contract Pharma: Let's talk about the background of Wyeth's new clinical initiatives. How did it come about?
Robert Maguire: It starts five or six years ago, when Bob Ruffolo joined the company and installed a productivity model. In the past we'd been producing two or three INDs a year, and Bob wanted us to raise that to at least eight INDs a year (and more recently 12 a year). To support that model we initiated a number of breakthrough projects, involving discovery, our Phase I group, then later stage development up through regulatory, for us to be able to handle the increase in the number of drugs entering the pipeline.
So we did indeed hit the target that Bob set. We now have 60+ projects that have gone through IND in the past six years, so we have a very full pipeline. As you can imagine, those drugs are now hitting Phases II and III and some are reaching submission. Our goal is to have enough drugs in the pipeline to produce two NDA submissions each year.
Robert Maguire, M.D. Robert Maguire is a pediatric oncologist by training and has been in the pharmaceutical industry since 1983. After four years with Wyeth Clinical Research & Development, he joined Cytogen, a Princeton-based biotech developing monoclonal antibody conjugates for the diagnosis and treatment of cancer. At Cytogen Dr. Maguire was responsible for Clinical Research and Regulatory Affairs activities. In 1999, he rejoined Wyeth where he has held positions in Global Medical Affairs and CR&D. In July of 2004, he was named vice president of Clinical Development and chief of operations. |
With that many ongoing projects, the question for us became, "How are we going to handle all this increased clinical trial activity?" The number of trials per program has been increasing throughout the industry. The number of patients per trial has been increasing, the length of trials has been increasing: basically, it's been taking longer and costing more to reach decision points and get products to submission.
We were tasked with handling the pipeline more efficiently. We had known for quite a while that some of our sites weren't as productive as others; 30%, say, were producing zero or one patient in a particular trial. You can imagine all the inefficiencies associated with that, getting those sites set up and qualified, handling paperwork, monitoring them, controlling drug supply, etc.
We saw that as a challenge right away. At the same time, clinical trials and preclinical work were taking off in the Asia-Pac region. There was a lot of talk about markets increasing in those regions in the coming years. Clinical trial experience over there was also increasing, and it was noteworthy that many of the investigators in major clinical sites in the region were trained in the west and had experience with clinical trials and good clinical practices. We found that patients there were interested in participating in trials and getting access to medicines they wouldn't ordinarily have access to. Hospital administrators and high-level regulators also showed interest in participating in global research, not just in providing patients.
So, we had a huge influx of projects and needed to address the inefficiencies in how trials were being done, just while the Asia-Pac was taking off.
We had an initiative that was first known as Springboard and then grew into the Learn & Confirm model, in which we break the development process into two parts, rather than thinking of it in terms of Phases I, II, III, and IV.
L&C involves use of biomarkers and innovative study design, in which there's flexibility to make decisions during trials. We're reaching agreement with regulators as to how to approach that.
At the same time, we also made a series of process changes, including the global patient recruitment process. These included a big, serious look at our study startup process: how we selected countries and sites to participate in our trials. We now have a very well defined, detailed process. It starts about nine months before our study start date, identifying sites and making sure we have them ready. We still have room for improvement here and it is a current focus at Wyeth.
We also formed a global patient recruitment group. At one point, we drew about 80% of our patients from western countries [the U.S. and western Europe], and we've shifted toward a 55/45 model. We think that, over time, we'll see 20-25% of our clinical patients coming from the Asia-Pac region.
Our third process change was in early studies. To benefit the Learn phase (conventionally Phases I and II), we established Early Clinical Development Centers (ECDCs). These essentially comprise a global network of large, experienced hospitals with which we have a service agreement and a support infrastructure in place. We established them with the idea of starting and enrolling trials faster. In the process, it might also lead to less expensive trials, but that's not as much of a priority as allowing earlier decision-making and increasing the quality of data.
Those are the approaches we developed as we rethought our development model.
CP: How long did this rethink take?
RM: We started about two years ago, and began implementing around March 2006. It took six months to get our ideas on paper.
CP: How would you describe the learning curve?
RM: We're still ironing out some of the details, but I think it's really coming together.
Asia
CP: You mentioned the growth of the Asia-Pac region during that timeframe. How have your approaches to trials in Asia changed in recent years?
RM: We'd planned to increase our patient number from that region, and have done that. More than 10% of our new patients last year came from East Asia: China, Korea, Taiwan, Hong Kong, Australia and New Zealand, and Thailand (a new addition), as well as India (which is not run out of our east Asia office). It may hit 15% this year and we're targeting 20-25%, as I mentioned.
For East Asia, we used to have our regional trials hub in Sydney, Australia, but moved that to Shanghai about 18 months ago. We've come close to doubling our Asia-Pacific staff in the past two years. We have R&D offices in all those countries.
The thing to keep in mind is that the Asia-Pacific group is an operations group. The studies are designed at headquarters in consultation with the regional offices, but these groups run trials and do safety reporting. HQ designs the studies, and analyzes and reports the data. While we do receive input on medical need and standard of care from the region, for the most part, the regional groups are operational, conducting and monitoring our trials and guaranteeing the quality of data obtained.
Of the 15 ECDCs we've established, seven of them are in east Asia, and an eighth will soon be up in Thailand.
CP: How do you think this approach differs from that of other pharma/biopharma companies?
RM: We've been pretty conservative; we start with a small staff in an individual country with a few targeted hospitals, and then expand from there as we gain experience. We've had a bigger focus lately in China and a few other regions.
Some companies won't go to China, especially for Phase II studies. There's a big regulatory issue in China pertaining to the approval of trials; it takes between nine and 12 months to get approval to start a trial in China, and that makes it difficult, especially for early trials.
In large part, this issue led to process changes around our trial startup activities. This was chiefly to address to China, as well as some countries in Latin America. China has so much potential, and clinical trial application (CTA) approval is really the issue. If the country regulators and pharma can agree on a new process for approving study starts, China will really take off.
Some companies are staying out of China till this gets settled, but we decided to get in, get on the ground, understand how to conduct clinical trials there, and be ready, so that when a breakthrough occurs, we're in a good position.
CP: And to be part of the regulatory process as it's negotiated?
RM: We have frequent discussions with regulators on this issue. Wyeth was chosen to co-author a white paper requested by the SFDA on ways to improve the regulatory process. We're a big stakeholder, and we know it will improve the situation for everyone.
We're in the middle of the pack in China, I think. Korea has been a really good place for trials, we've found: very high quality work, good trial experience, strong patient recruitment. And their regulators are willing to discuss issues as they arise.
CP: Do you consider the growth of the Asia-Pac region to be more of a push or a pull?
RM: There was an initial push-impetus to go over to that region, but once we were there, there was more and more of a pull.
For Wyeth, it grew out of our L&C model. Our Sydney group was involved in trials since the late 1990s, and the people there were very excited about growing the group and letting us know about the contribution they could make to Wyeth. When we got over there and started meeting investigators and regulators, we found a strong pull. The hospitals were very experienced. Most of the groups we met were very interested in being part of the process: helping with study design, publishing papers, and more.
I think the pull is definitely increasing. You can feel the excitement when you're there.
CP: Do they show interest in "moving up the chain"?
RM: Yes. They're very adamant about becoming innovators, not just providers of a service. You definitely see that in India and China.
CP: How significant was the logistical learning curve? And the cultural one?
RM: Logistically, there were issues in the areas you might expect: drug supply and shipment of study samples, primarily. There's an issue of getting blood samples in and out of countries. Obviously, that's very important in a lot of trials. It can be overcome, but it can also result in delays.
Otherwise, all the sites we work with are connected to the web, and we use electronic data capture at all those sites. They all have SOPs in the hospital, so those aren't major issues at this time.
I think there are cultural issues. Relationships are as important as anything else in the Asia-Pac region. Our offices have local staff that work directly with the sites and regulators and serve as an interface for our study teams. They know how to handle the relationships because of their background.
CP: Have you done rotations of staff either from Asia into western countries or vice versa, to help bridge some of the cultural gaps?
RM: We've done it, but we probably haven't done it enough. We've brought a lot of folks from Asia to our western offices for three-to-six-month rotations, working with a study team, understanding our processes and seeing how we work. We have had an individual from HQ spend a year in the region. That person was sort of a jack-of-all-trades, examining our study processes and our IT applications and issues. We've moved a few people from our Sydney office to Shanghai, to help that transition. It was a must. I think that's helped, but we could probably do more.
Finding staff to work in management from those regions is difficult. Most of the staff consists of expats. That's going to change in the next few years as they gain more experience, but you can imagine that the competition for those personnel is going to be pretty intense.
ECDCs & Exclusivity?
CP: How would you frame the ECDC model in the context of Wyeth's outsourcing projects?
RM: I wouldn't consider it a standard outsourcing arrangement. The ECDCs are an expanding global network of clinical sites. They're mostly large academic centers that have the proven ability to recruit large numbers of patients across most of our therapeutic areas.
The whole idea of ECDCs was to decrease the number of sites and increase the number of patients per site. Starting off, this should dramatically decrease the logistical issues we were talking about. If you're recruiting half your Phase II patients from 15 sites, instead of hundreds of sites, it should improve your logistics fairly dramatically.
Any trial we place in an ECDC is run the same way as our other trials. Our goal is to get 80% of our Phase II trials enrolling at ECDCs and have over half the patients come from these sites. We have no idea if we have the right number of sites. The 15 sites we've picked are probably not THE right 15 sites; we need some time to work through all that. What we do know is that the logistics are dramatically decreased and the rate of patient recruitment at ECDCs is much higher than at other sites.
CP: Last summer, there was a controversy about statements from another major pharma company, in which the issue of exclusive arrangements with clinical sites was broached. The pharma company issued a clarification and said that it had no plans to set up exclusive relationships with those high-yield clinical sites, but it was based on a similar premise: that certain sites were vastly outperforming others. How does the ECDC model differ from that idea?
RM: We intentionally made these non-exclusive relationships. We didn't think exclusivity was a good thing to seek, it was not the sort of relationship we wanted to get into.
We have a master services agreement with each of these sites, so we don't have to go through the contracting process each time we want to place a study. That can become a major delay, of course. We also have preset pricing figures, so that does not need to be negotiated each time and we know what a trial's going to cost.
We have a small group at HQ -- three people -- that comprises an ECDC management team. And within each country where we have an ECDC, we have an individual in that region's Wyeth office who is dedicated to ECDC management. We monitor with our regular site-monitoring setup.
We also support some in-hospital staff to coordinate activities with our Wyeth staff in that country. If you're going to place between 10 and 20 studies at a site over the course of a year, you're going to need plenty of coordination. We start screening the ECDCs nine months ahead to see which ones are capable of doing the trial. That makes the logistics much easier for us.
One thing to note: Most of the studies we place at ECDCs are not for in-patient studies. They're for chronic outpatient treatments, like diabetes or asthma. That said, two of our ECDCs are oncology hospitals.
CP: Are there particular therapeutic classes that you're more likely to look to emerging countries for trial-placement?
RM: For sure, infectious diseases are one. A large portion of our Tygacil antibiotic trials were done in India and China. Diabetes is a big one; the access to treatment-naïve patients is potentially a huge benefit. Asthma is another one. Oncology, too, which some may find surprising.
One thing with oncology is, you may be getting patients a bit later in disease progression. They may have received fewer treatments. Certainly, there are fewer biological treatments over in East Asia, because of the cost. You can get more treatment-naïve patients in those categories.
We've had very big success with rheumatoid arthritis and other arthritic conditions like ankylosing spondylitis. There's a large and accessible systemic lupus erythematosis population in China. We've done very well with trials there.
Recently, we've done work with GI studies for constipation drugs. They have a very large number of patients. Depression and schizophrenia are other classes that recruit very well in those regions.
PK differences and genetic differences in response to medications can be an issue. We've done a number of PK studies in Japan and some in China and we find that it hasn't been as much of an issue as some have made it out to be.
Also, when you're doing studies in emerging regions, you have to be cognizant of the comparator drugs that you're using. Are they the standard of care in that region? We've run into problems with validated instruments for some of our indications. For example, it's not clear that the cognition evaluation instrument used for Alzheimer's in western trials is validated for use in China. That may result in needing to do a specific regional trial instead of being part of a global trial.
Things like that need to be considered, but emerging regions have in general been able to contribute to global trials.
Outsourcing
CP: Wyeth seems to be much more advanced in strategic outsourcing models than its competitors (or at least more willing to discuss these agreements publicly). What accounts for this?
RM: Good question. Wyeth's impetus to innovate comes directly from the top. Wyeth is very interested in any new idea that will improve the efficiency of how we run the business, including the clinical trial operations. If you can make a business case for an innovative idea, it will be considered. So there's a big push from the top, which may not be the case at other companies.
We do things differently because the industry has certain challenges, and we need to figure out new ways to get the work done. There's a need to identify what we need to keep internal at Wyeth, and what can be outsourced.
A lot of these ideas came through the Springboard project. Our DHL logistics agreement came from that, too. We thought, "If we don't need to do it here, let's figure out a creative way to get it done elsewhere."