Partnerships and licensing compounds help TAP transform research and development into search and development
Patrick McGee
Senior Editor
Over the years, pharmaceutical and biotech companies sought to remain competitive by enhancing infrastructure, thus allowing them to conduct discovery and development in-house. But as many pipelines were reduced to a trickle and cost containment became the industry’s new mantra, companies turned to outsourcing to farm out various processes as needed while focusing on their strengths. Web portal CanBiotech estimates that 40% of pharmaceutical drug development dollars go to outsourcing and that the value of the worldwide pharmaceutical outsourcing industry will increase to over $60 billion this year. Some pharma and biotech companies have come to outsource so much work that they are near “virtual” organizations.
Take TAP Pharmaceutical Products Inc., Lake Forest, Ill., which was founded in 1977 through a partnership between Abbott Laboratories, Abbott Park, Ill., and Takeda Pharmaceutical Company Ltd., Osaka, Japan. In the early years, the company developed new compounds in-house. These included two of its earliest drugs, Prevacid (lansoprazole) for the treatment of heartburn and other symptoms of gastroesophageal reflux disease, and Lupron Depot (leuprolide acetate) for the treatment of advanced prostate cancer and management of endometriosis. But over the years its model evolved to focus heavily on outsourcing.
“We are more of a search-and-develop company than we are a true R&D group. Our model is really based on partnering and licensing compounds in from different sources at different stages of development. We’ve found compounds in Korea, Japan, the United States, and Europe at different stages of development,” says Xavier Frapaise, MD, the company’s vice president of research and development. “Sometimes what you get from discovery is not necessarily what you would love to develop. The beauty of our model at TAP is we pick up the compounds we like, and if something wrong happens in drug development, as it unfortunately often happens, we have no emotional ties to a compound that [wasn’t] born in our company in our discovery labs. It’s a very rational decision-making [process] based on risk/benefit for the patients and that’s it.”
Outsourcing the pipeline
While other pharmaceutical companies use outsourcing to supplement internal pipelines, TAP relies entirely upon partners for its pipeline, says Steven Elrod, PhD, vice president of scientific affairs. “That gives us tremendous competitive advantage, because basically we go to a partner and we work with them just like their compound was an internal compound, so they’re not competing with any internal programs at all. They know that their compound is going to be judged on its own merit . . . so we feel that gives us a lot of competitive advantage.” Another advantage, adds Elrod, is that the painful process of killing a nonviable compound is much easier when it has been discovered outside the company.
James Mulvihill is the senior director of client relations for Paragon Biomedical Inc., Irvine, Calif., a contract research organization (CRO), that has worked extensively with TAP over the last decade. He believes the kind of arrangements that exist between TAP and Paragon are promising. “It’s difficult for pharma companies to carry the amount of resources in their own organization to account for the ramp-up and the ramp-down in their developmental cycles. Because of that, it is easier and more fiscally sound for them to outsource that work to midsized CROs” like Paragon, which has about 190 employees. Outsourcing is also a “critical component” for smaller pharma and biotech companies, Mulvihill says. “They have limited internal resources, so they really are dependent on finding a good clinical partner.”
TAP recently celebrated the 20th anniversary of the approval of Lupron Depot, but it is looking to the future with two new drugs, febuxostat and asoprisnil. Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase being investigated for its effects on lowering levels of serum uric acid in patients with gout. TAP licensed febuxostat from Teijin Pharma Ltd., Tokyo, because Teijin did not have the infrastructure to develop, receive approval, and market the drug in the United States, Frapaise says. TAP filed a new drug application (NDA) with the US Food and Drug Administration (FDA) last December based on positive results from a large controlled, randomized study.
TAP has also partnered with Schering AG, Berlin, to develop asoprisnil, the first in a new class of drugs called selective progesterone receptor modulators which will target the major clinical symptoms of fibroids related to excessive menstrual bleeding and fibroid size. If approved, it could reduce or eliminate the need for surgical procedures such as hysterectomies, and in the treatment of endometriosis, it may reduce pain and bleeding without affecting estrogen levels. Asoprisnil is now in late clinical trials and TAP hopes to submit it to the FDA this year. “If things go well and this is approved, it will be the first-ever long-term clinical treatment for fibroids, so we are pretty excited by this one too,” Frapaise says.
Exploring preclinical leads
Ferreting out compounds that can make it to clinical trials is the responsibility of Elrod’s group. He says that at any one time, TAP can be analyzing from six to 12 preclinical opportunities. Those leads come from biotech and small pharma in the United States; from biotech, small pharma, and some large pharma in Europe; and, conversely, from large pharma, small pharma, and biotech in Japan. “We tend to send scientists out [to evaluate compounds] rather than just the licensing folks and the negotiators. We send scientists out because we really like to engage our potential partners on a scientist-to-scientist basis. Once we determine that the opportunity we’re looking at may have some value, then we would get more of the business folks involved with regards to terms and that sort of thing.” A pharmacologist is usually the first to go out to a potential partner company when a possible lead for a drug is found: “They’re the ones that we look to first to make sure that, at least from a scientific perspective, what they’re saying technically makes sense.”
When it comes to preclinical development, the company’s model is competency based, so the focus is getting very experienced industry people with good judgment and putting them in decision-making positions. Because TAP does not own any laboratories, they design programs that are carried out at a CRO, then help evaluate the results and conclusions. “If you look at a lot of smaller pharma companies, they tend to outsource for competency. We don’t do that. We have the competency; we focus on development of that competency internally. We essentially outsource capacity things.” Elrod’s group comprises about 60 scientists, the majority of whom are PhDs with a few MDs. There are a number of pharmacologists who work in the chemistry, manufacturing, and control side of the process. The group has experienced researchers in molecular biology and pharmacology who evaluate opportunities that come from outside sources.
One of TAP’s strengths in development is its ability to become experts very quickly in any area, Elrod says. “If they’re outside of our current areas, then the barrier might be a little bit higher, but if the opportunity is big enough, we’re very confident in our ability to essentially get the appropriate competencies on board in time for development. One of the other things we’re also very good at from a development perspective is working with CROs and really knowing who has the expertise, what their capabilities are in a lot of different areas. So we can move very quickly to the folks that are really the premier contract organizations to do specialty types of research.” Although they don’t do any of the animal work themselves, his group is heavily involved in the design of those studies and their offsite execution, as well as being “very, very involved” in the evaluation of the results. On some projects, they will have staff from the partner company onsite through the critical parts of the development stage. European and Asian partners have had employees at TAP’s Lake Forest offices for a year or longer when working on a project.
Outsourcing clinical
The outsourcing picture on the clinical side is more mixed, says Dennis Jennings, PhD, director of clinical operations and scientific data analysis, a group that totals about 190
TAP Pharmaceutical Products reduced development cycle times for phase II and phase III studies by training employees in lean thinking, a set of practices designed to make a variety of processes more efficient, and Six Sigma, a data-driven approach to eliminating defects. (Source: TAP Pharmaceutical Products) |
employees. They work closely with Elrod’s group, particularly in pharmacokinetics and clinical pharmacology when they are trying to take compounds into initial phase I studies. The group sees outsourcing as another avenue to help hasten development, so they evaluate where their resources are most effective and where external resources will help the most.
“We can do all of our clinical trials management, all of our data management, and all of our statistics internally, and we think that’s a good thing because it allows us to have strong control over the data,” Jennings says. “The data is going to drive the conclusions that we make to make the next choices in our drug development stage. Monitoring and CROs, of course, are the big expense for pharmaceutical companies, and that’s a mixture for us. We have an internal group that can do monitoring and studies, but we outsource probably about 50% of it.” Jennings recently set up a translational medicine group to deal with the transition from animal to human studies and to look for early markers that could help predict whether or not a compound will be effective. They also brought in an electronic data-capture system to use for all clinical studies to ensure they run smoothly and to provide the data needed to make informed decisions. Jennings believes such tools enhance TAP’s drug development. “We can take the compound that these companies feel strongly about and do everything we can to develop them in the best, most efficient way, getting data that will be useful at the end.”
Of the many compounds on which TAP is working, two are selective androgen receptor modulators (SARMs) from Ligand Pharmaceuticals Inc., San Diego. SARMs are a novel class of nonsteroidal molecules with potential applications for a wide variety of disorders, including male hormone therapy, female and male osteoporosis, and male and female sexual dysfunction. TAP filed an investigational new drug (IND) application for the first SARM licensed from Ligand Pharmaceuticals, LGD2941, in April. The partnership began about four years ago after Ligand developed SARMs following a successful track record working on selective estrogen receptor modulators, says Andres Negro-Vilar, MD, PhD, the company’s executive vice president of research and development and chief scientific officer. “When they came in and expressed interest in this field, I think they had a vision that they needed to have some agent like SARMs to expand their franchise, in some cases related to areas that they are working in now,” he says.
“We worked for several years in developing these types of molecules . . . We brought molecular and cell biology, chemistry, pharmacology, some aspects of drug safety and metabolism, all of the components of the research team into the alliance, and they brought in the latest stage clinical development expertise in terms of toxicology, formulation and other work,” says Negro-Vilar. “They also brought the expertise to move those molecules through the IND into the clinic.” TAP and Ligand also formed two bodies to help manage their SARM collaboration. The joint research committee is involved from the early to middle stages of R&D. When the molecules reach later-stage preclinical development and clinical study, the development committee will provide oversight. “They will do the clinical work, but we will maintain an interface of activity . . . to provide input. Also, in the areas where we have expertise, we provide advice as well.”
Preferred provider
Although they do not provide molecular leads, Kendle International Inc., Cincinnati, one of TAP’s preferred providers, does provide phase II and phase IV CRO services. About 60% of Kendle’s business is in phase II and III and the remainder is in phase I and IV, says Susan Grundy, the company’s director of business development. Kendle International got its foot in the door by doing pediatric studies for TAP, one of its strengths, and is now working closely with TAP’s pediatric group on several studies. They are also working on two global studies that will lead to pivotal trials.
Grundy says Kendle International’s outsourcing work for other companies can run from beginning to end or focus on one area. For example, many sponsors don’t want to incur the expense of setting up a data-management shop, so they opt for preferred provider agreements. Companies would need large departments to analyze clinical data, but CROs can pull resources from other offices when there is a data crunch. “We do some of what we call direct entry where we’ll build the database, or they may even build the database, but we do direct entry into their system so they can see real-time data at any time. It’s very attractive to the sponsors.”
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Another popular area for outsourcing is project monitoring. “We’ll [increase] staff for it and halfway through the trial if the drug is not working or if there are other issues and it’s put on hold or stopped, then the people can be put on another trial.” There is also a move toward outsourcing safety assessment, and Grundy says there is a growing trend among larger pharmaceutical companies to downsize their own staffs and turn to outsourcing. When large pharmas outsource, they now tend to deal with fewer companies in an effort to build stronger relationships, Grundy says. “With my preferred providers, we meet on a quarterly basis, review our performance metrics, their performance metrics, and we talk about process improvement, so it is more of a partnership. That’s the trend we see happening.”
Mulvihill of Paragon Biomedical says his company has worked with TAP across a number of different therapeutic areas and compounds both domestically and abroad. The bulk of their work with TAP has been in phase II and III, mostly in project management and monitoring. Typically, TAP has an internal clinical team that Paragon coordinates with on projects they provide monitoring resources for. “We have usually provided a level of project management that assists them with site selection, site startup, and then also obviously, the management of the sites during the enrollment and closeout phases.”
Bringing in lean practices
While reaching out and teaming up with CROs preclinically and clinically, TAP is also bringing in tools to increase efficiency and quality. “Our primary focus is on the internal processes of TAP that support any endeavor we might have, both internal and external. We use quality tools such as process mapping to ensure we understand the user requirements, the customer and client requirements,” says Betsy Brown, the company’s director of quality performance management. Her group partners with members of the quality assurance team to audit vendors against established quality standards. If compliance issues need to be dealt with, Brown’s group teams with a department to ensure that quality requirements are understood and translated.
Rama Shankar, a quality performance manager, plays a key role in Brown’s group. She is in charge of bringing in quality management tools, setting up quality systems, and training all quality performance managers in trouble shooting. Shankar was involved in bringing “lean thinking” into the company, a practice pioneered by Toyota more than 30 years ago to make manufacturing processes more efficient. This year, she will also help train all quality performance managers in implementing Six Sigma, a data-driven approach to eliminating defects (See sidebar on lean R&D practices on page 28). While commonly used in manufacturing, applying such quality development tools in a research and development setting is highly unusual, Shankar says. “When I spoke to General Motors about this, they told me ‘We haven’t done it in research and development, and we’re just getting into it. We do this all the time in manufacturing, but we haven’t taken it into R&D.’ This is the same message I heard from other pharmaceutical companies.”
Yet, using these practices in R&D is not easy because researchers are more comfortable dealing with conceptual activities than with producing concrete entities. “We had to let R&D folks understand that there are processes surrounding both activities that actually have tangibles,” says Brown, “like the data being generated. [Researchers] can think of being able to identify non-value-added activities associated with those processes. It helped them reduce their cycle time and make them more efficient, and they could dedicate that [time savings] and focus more on the quality aspects.”
Filed Under: Drug Discovery
