The pharmaceutical contract research market, worth $13.7 billion in 2006, is growing at an annual rate of 15%, according to a recent report from Biopharm Knowledge Publishing (www.biopharmknowledge.com). This is more than twice the growth rate of the pharmaceutical industry on which it relies for its revenues and it is a trend that looks likely to continue for the foreseeable future.
There are several reasons for this remarkable growth, but two are most significant, notes the report. First, after several years of weak pipelines there are now more drugs in development, especially in the phases nearer to launch where large-scale clinical trials are needed. Second, with growth low, pharmaceutical companies are trying to cut costs. One place where they can do it is in development. It is cheaper and probably more effective to outsource clinical trials, for example, than it is to manage them in house.
The “Pharma-Bio Outsourcing Conference” held in London recently showcased a number of CROs that offered various perspectives on the business. Trends include more frequent partnerships, expanding clinical trials to additional global sites, and new technologies for drug discovery itself.
Mid-size Pharma Niche
To survive and grow, mid-size pharmaceutical companies require partnerships, according to John Rountree, managing partner, NovaSecta (www.novasecta.com). “The whole concept of partnering is a natural consequence of being mid-size. Such companies are typically very experienced and therefore very good at it compared to some of their larger or smaller counterparts. Often mid-size companies are poorly understood by the industry. Our company specializes in this sector, and we help these companies establish partnerships for everything from discovery to clinical development.”
Rountree indicates that one of the key issues faced by mid-size pharmas is establishing good connections with companies appropriate for their needs. “We now run a unique multicompany R&D collaboration that enables members to exploit or access under-valued assets and capabilities and to capture greater value from their compounds, products, or technologies. We also assist with acquiring needed assets, in-licensing, or obtaining other capabilities from other companies.”
This matchmaker role can provide lifeblood to emerging companies. “The leading-edge companies come to us because they want to get even better. We know this sector deeply and are extremely well-connected in it. Most companies don’t have the scale or time to find and make the connections that a company like ours can provide. The ability to network, utilize partnerships, and explore mutually beneficial relationships can spell the difference between success and failure of a mid-size company.”
Clinical Trials in Asia
Employing global resources for the execution of clinical trials can save time and money, according to PRA International (www.praintl.com). PRA works with both pharma and biotech companies to design and execute global clinical trials. Nermeen Varawalla, M.D., Ph.D., vp, says the company has a presence in 60 countries and provides a full range of clinical services including coordinating and conducting global clinical trials. “Asia, which includes India, China, and South East Asia, is emerging as one of the hottest markets for hosting clinical trials. Part of the attraction is the similarities within the regions. There can be rapid recruitment of patients who have diseases of both the developed and developing world. Additionally, there is substantial cost savings and an opportunity to penetrate some of the fastest-growing markets in world pharmaceuticals.”
Dr. Varawalla says significant issues need to be overcome to ensure that clinical data from emerging countries is able to meet the expectations of global sponsors seeking to make submissions to the FDA or EMEA. “An important question is how to utilize these resources to deliver clinical data with ethical and scientific integrity.
“Furthermore, countries in Asia vary in their regulatory policies and ability to efficiently process applications for clinical trials. There is a wide spectrum of regulatory approval timelines that differ among countries. For example, the clinical trial approval process in China remains uncertain and can take up to nine months. In contrast, Singapore has made great strides with regulatory approval being granted within six weeks. India appears to be in transition and moving into more streamlined and efficient processing.
According to Dr. Varawalla, “Our company helps clients in all aspects of this process. This includes determining which countries to use, picking specific sites and investigators, and supplying critical global and local expertise to help sponsors utilize the benefits of emerging regions like Asia with mitigation of the risks.”
Competition for Sites
Although there is a wide array of clinical sites worldwide, there is also growing competition for them. “This is a huge challenge,” says Tony Hersh, Ph.D., clinical research director Parexel International (www.parexel.com). “Many good sites are already booked up, and it is getting especially difficult to recruit treatment-naive patients. But it is important not only to find the right sites but also to be able to accurately predict patient recruitment rates at those sites.”
Dr. Hersh indicates that in considering speed-to-market issues and the availability of treatment-naive patients, companies often want to expand to nontraditional, low-cost countries. Accurately assessing patient recruitment rates in these countries is especially difficult.
According to Dr. Hersh, Parexel has developed a means for more accurate forecasting of patient recruitment at potential sites. “We have a sophisticated technique for comparing new protocols with previous ones, down to individual inclusion and exclusion criteria, to give a good idea of likely clinical obstacles,” says Dr. Hersh.
“This can model the impact of small changes in inclusion/exclusion criteria that can make all the difference. In addition, we have developed a new technology, SPARC, (scenario planning and recruitment calculator) to predict the rate at which sites will enroll patients. This uses real-life, site-specific information to make predictions. Using both techniques together we can give our clients much more accurate information.”
Additional considerations factored into the company’s forecasting capabilities include examining which countries historically have had problems gaining license approval and factoring in when critical site staff are unavailable. “This, combined with our wide global presence, can provide powerful information to our clients.”
Adaptive Trial Design
Data gathered during the initial period of clinical studies can be used to modify subsequent periods of the trials. Such adaptive trial design can allow amending the study endpoint, recalculating sample sizes, re-evaluating control groups, or even altering key assessments needed to confirm methodological hypotheses outlined in the initial study protocol. However, in many adaptive trial designs, the data is received too late to adapt the study design.
To help meet these challenges, Cmed Group (www.cmedresearch.com) developed Timaeus, an intelligent data-acquisition and management system. According to the company, the idea underpinning the system is to unify the entire clinical trial data ecosystem as a single entity. Thus, Timaeus was designed to support multiple arms and cohorts with different electronic case report forms and database structures to control randomization/arm allocation and management sample size allocation, provide real-time access to data, and allow electronic data management review and reporting capabilities.
Fragment-based Drug Discovery
Fragment-based drug discovery is gaining increased attention as a method of generating lead-like compounds for biological targets such as enzymes in addition to difficult targets (protein-protein interactions). However, establishing the technology requires expert experience and expensive instrumentation. Therefore, some companies choose to outsource.
Evotec (www.evotec.com) established an Innovation Centre for fragment-based drug discovery that utilizes its EVOlution technology to identify novel small molecule fragments for biological targets and to rapidly optimize the fragments to subsequent lead compounds and development candidates.
Mark Whittaker, Ph.D., senior vp of drug discovery says, “Fragment-based drug discovery offers an important alternative approach that allows identification of novel small molecule fragments for many biological targets, especially those that may have been challenges using traditional drug discovery methods.”
The fragments, which are low molecular weight counterparts (~150–350 daltons) of small molecules (~500 daltons), bind with low affinity to a biological target. “They are important starting points for drug discovery, yet can prove difficult to identify due to their weak interactions with protein targets. That is where our EVOlution technology is critical. This technology allows us to identify extremely weak interactions between a protein target and a fragment; much weaker than can be detected using traditional methods. In addition to being highly sensitive, our approach is also high throughput and allows us to test thousands of fragments in a very short space of time.”
Dr. Whittaker notes that Evotec routinely tests its library of 20,000 fragments against protein targets. X-Ray crystallography studies are then conducted by Evotec to determine how fragment molecules interact with the target protein. This forms the basis of their structure-based optimization of the fragments into lead compounds.
According to Dr. Whittaker, Evotec has validated the technology against biologically relevant targets such as kinases, proteases, and protein-protein interactions related to the central nervous system, oncology, inflammation, metabolic diseases, and cardiovascular diseases. Evotec is currently building a pipeline of programs for early partnering with pharmaceutical and biotechnology companies in addition to discussing using the technology to identify clinical candidates for their partners’ protein targets.
Good Service Counts
With the marked increase in outsourcing in pharma and biotech, there is steep competition among CROs. This is changing the profile of the business, according to Mark Chadwick, Ph.D., development services business director, Excelsyn Molecular Development (www.excelsyn.com).
“We are seeing much more strategic outsourcing and closer, more long-term relationships, rather than just using us for one-off jobs,” he says. Additionally, with stiff competition from India and China, it is critical to build a level of intimacy between provider and client that is difficult to replicate.
“There are two important elements that CROs should consider in this competitive environment. First, the idea of managing projects as a whole, subcontracting where necessary, allows one-stop-shopping. The compounds coming out of discovery are becoming more complex and diverse, and timelines are being constantly squeezed, so it is better to provide a total solution for customers. Another way to differentiate yourself is the good old-fashioned idea of providing better service to your clients. This is not rocket science, but improving problem solving, quality, speed, responsiveness, and project management, and taking a flexible approach with each client, can make the package of partner and provider much more of a powerful resource.”
Dr. Chadwick notes that Excelsyn’s Molecular Development group starts where discovery ends. “Our clients have the molecule and want to scale up. We do everything to provide sufficient compound for preclinical studies right the way through to commercial production. We have seen remarkable growth in the last two years, adding over 40 new customers, with nearly all coming back for repeat business, which attests that this business model works.”
CRO Hybrid Model
ChemDiv (www.chemdiv.com) believes there are significant benefits to creating CROs that reflect more of a hybrid model. According to Nikolay Savchuk, Ph.D., president and CEO, “Outsourcing plays an increasingly important role around the globe. Outpartnering using a hybrid model is propagated with emphasis on discovery services and asset-based business models that build partnering networks involving the CRO, client, and sometimes outside experts. This requires a much closer working relationship between the partners, with a high level of trust, mutual respect and an emphasis on joint problem solving and cooperation.”
According to Dr. Savchuk, ChemDiv is a global chemistry-driven contract research organization that conceptualized this model in order to leverage industrial and academic efforts to bring new approaches to life-threatening disease.
Dr. Savchuk reports, “For 17 years ChemDiv has provided Discovery outSource™ solutions including medicinal and synthetic chemistry, preclinical development, and screening libraries. We work with broadly based academic networks such as Johns Hopkins, Stanford, Harvard, Yale, Academia Sinica (Taiwan), Tokyo University, major European universities, and many others.”
ChemDiv’s re-envisioning a traditional CRO service-based business model as a more global and hybrid model of collaborative R&D has provided the company with annual growth of 15–40%, while expanding their discovery business opportunities in areas such as oncology, inflammation, and the CNS.