May 15, 2012 (Vol. 32, No. 10)

Helping to ensure that the drug discovery and development process continues evolving, contract research organizations (CROs) are of increasing value to biotech and biopharma. These guardians of the pipeline keep the process alive by providing the best-in-class assay and technological support to insure that viable, new drug candidates are commercialized.

The support needed at each phase of the drug pipeline is available from a CRO, whether it be a small niche organization that has specialized in a specific assay or platform technology, or a large organization that serves as a one-stop-shop with extensive technologies/services to take an optimized lead candidate through clinical trials to full commercialization.

Indigo Biosciences was born out of expertise with a specific assay technology, in this case one focused on nuclear receptors. This small CRO was spun out of Penn State University when Jack Vanden Heuvel, Ph.D., founder and CSO, realized that his nuclear receptors expertise could be leveraged for drug discovery.

Of the 48 known human nuclear receptors, Indigo has developed a reporter gene assay system using a mammalian cell line for 25 of them. The most notable receptors in this class are the PPAR receptors, a family of nuclear receptors whose activity is associated with on target effects for many metabolic diseases including diabetes, obesity, and chronic inflammation. These receptors are also valuable as off target markers for toxicological studies and for the analysis of drug-drug interactions.

The nuclear receptor assays are now also available in kit formats, so the luciferase-based reporter assay can be run in a firm’s own lab if it chooses not to outsource.

“We’ve come to be known as the ‘Nuclear Receptor CRO’. We use a single point assay in medium to high throughput to screen tens to hundreds of compounds across a panel of up to 25 receptors in 384-well plate format,” says Dr. Vanden Heuvel.

“The assay is run in 15–30 µL reaction volumes and yields results within 24 hours. We work closely with the customers on both ends of the analysis, first to develop the study plan and then to help with the interpretation of the results. The completed study is usually turned around in two weeks.”

Once strictly a service provider, Indigo Biosciences is now dedicated to establishing itself as a premier provider of cell-based nuclear receptor reporter assay products.

In Vitro ADME/Tox Services

The focus of BD Biosciences’ Gentest™ contract research services is on metabolism of drug candidates as measured by the induction or inhibition of cytochrome P450, a superfamily of drug-metabolizing enzymes. “BD has a large suite of drug-metabolizing enzymes with more than 50 different P450, UGT, and other enzyme products sold under the BD Gentest brand,” shares Roseann Vardaro, product manager, BD Biosciences—Discovery Labware.

“The services business is closely integrated with the product business. This helps assure that datasets are comparable whether customers do the work themselves or outsource it to us.” Another key focus area for both products and services is transporter proteins. Like cytochrome P450 enzymes, ATP-binding cassette and solute linked carrier transporter proteins can mediate drug-drug interactions.

“A trend that we’ve noticed recently is more repurposing of established drugs. These drugs often have little or no data applicable to newer standards of in vitro drug-interaction testing, such as those outlined in the FDA’s 2012 drug-drug interaction guidance document,” says David Stresser, Ph.D., program manager, BD Gentest contract services. “Before investing in another round of clinical trials, our customers want to confirm there are no drug-drug interaction or safety issues.”

Lead Optimization

Molecular Imaging (MI) is dedicated to the use of small-animal imaging in the drug discovery process. “We use a full range of imaging modalities for anatomical, functional, and molecular outputs, enabling us to provide our customers with combined pharmacology and imaging biomarkers that assist in their go/no-go decision-making process,” says Patrick McConville, Ph.D., co-founder and CSO.

“We customize our approach with every project. The customer brings us their compounds and we do the rest; we order the animals, acclimatize them on-site, induce the disease state, and interrogate the pharmacology. Imaging is then performed using one or more modalities usually over multiple time points to extract predictive biomarker(s) with the aim to perform the analysis in real time.”

The increasing reliance on imaging in the pharmaceutical industry as well as parallel improvements in the technology has enabled MI to add a broad base of imaging assays. These assays are validated and applied to the noninvasive study of disease in the context of the otherwise normal physiology of the animal.

MI is currently primarily focused on oncology and inflammation diseases. The latter also extends its reach to the broader area of metabolic and cardiovascular disease. It plans to expand its offerings by developing expertise in other disease areas, and this expansion will occur in parallel to the addition of emerging imaging platforms. Using ancillary technologies such as MRI contrast agents, PET tracers, and optical probes to study these disease states, it is looking to pull together richer, more reliable datasets.

Another trend is the use of whole-animal imaging for drug safety and toxicology studies. MI is an active participant in the consortium set up by the Health & Environmental Science Institute to define guidelines and set the industry standard for imaging in preclinical safety assessment.

Avacta Analytical was spun out of the University of Leeds in 2005. The business focuses on providing extended protein-characterization services, specializing in biophysical and physico-chemical analytics. Avacta offers a range of techniques not traditionally found in every lab or even at CROs.

Its experience of using these techniques and applying them to different types of therapeutic proteins is central to its success. It provides smaller organizations with the ability to access additional analytical resource and provides extra capacity for larger multinationals.

“We mainly work in the R&D phase of drug development, looking at stability, comparability, aggregation, formulation selection, and general protein characterization,” explains Richard Perkins, business development manager.

“We advise our customers on the pros and cons of various analytical techniques, making sure the package we provide is fit for purpose. Techniques such as analytical ultracentrifugation, FTIR (fourier transform infrared spectrometry), and circular dichroism are not familiar to most, so we have learned that extensive consultation and open communication with the customer before and after projects is vital.”

The Traditional CRO

One needs to be careful regarding the CRO acronym, as the definition depends on where the company focuses its service offering. Charles River Laboratories and MPI Research are contract research organizations that partner with clients from late discovery up to first in human trials.

On the other hand, Quintiles is a clinical research organization that partners with clients when their drug candidates are ready for human trials. Finally there are companies that cover both disciplines; these companies with a large footprint include Covance.

Charles River is best known for its research animal models. But the firm is also involved in safety assessment for both small molecule and biologics testing. Covering the entire spectrum including safety pharmacology, reproductive tox, and genetic tox, Charles River provides both in vitro and in vivo services to help its customers make critical go/no-go decisions before investing in expensive clinical trials.

Charles River uses all the standard assay formats. “Our services offering is driven by customer demand. We can’t just build it and they will come; we are focused on enhancing our portfolio to meet client needs. We either build the capability internally or look outside to acquire that expertise,” notes Nancy Gillett, Ph.D., CSO.

“Our focus is on streamlining the process, providing all of our customers the same set of assays and platform technologies that add value to their drug discovery and development process. I tell my teams that we need to stay one step behind the cutting edge of science, focusing on offering those assays that have been validated and widely accepted by the industry.” Charles River has expertise in oncology, inflammation, metabolic disease, respiratory, cardiovascular, and CNS diseases.

The Charles River network has grown by acquisition, but rather than building in redundancy across the network, specialized services are provided in Centers of Excellence. “Charles River has evolved this way in response to the harmonization that has occurred in big pharma. They want to work with fewer vendors and interface on multiple levels so that issues that arise are resolved rapidly,” Dr. Gillett says.

“We are building strategic partnerships with our customers where we sit on the same side of the table to share forecasts, protocols, and best practices and work together to strip down costs and improve efficiencies in the drug development process.”

Charles River is best known for its animal research models, but the firm is also involved in safety assessment for both small molecule and biologics testing.

MPI Research is also focused on driving increased efficiencies and scientific integrity within drug development. By leveraging its scale of resources, breadth of experience, and investment in leading-edge technology, the company works with global biopharma organizations in developing their therapeutics faster and more effectively. From lead optimization through nonclinical trials prior to human testing, MPI Research partners with its clients in achieving approval with regulatory agencies worldwide.

“We are experienced in conducting drug development research in virtually all therapeutic areas, including areas of specialization that are not typically offered such as neurobehavioral, otological, and ophthalmologic disease,” says Tim Derrington, president and COO. “We also have state-of-the-art surgical suites that are often used for research on medical devices as well as drug therapies where a combined drug/device approach is required.”

The CRO industry has evolved over time; 10 years ago CROs did the same work done by pharma but did so at a lower cost based on lower overhead. In the second phase of growth in this industry, companies like Parexel, Quintiles, and Covance brought improved informatics and IT to provide better and smarter ways of doing things based on their own expertise. Today the focus of CROs should be about “faster, better, smarter,” to help drive improved efficiencies in drug research. CROs have invested in scale and spread the costs over multiple drug programs.

“This is an exciting time in the business for CROs,” says Derrington. “Scale will be a factor to drive unit costs down, but science will be a key differentiator to build better drugs. Understanding the customer and the challenges they face will help build the right services and solutions to overcome issues and deliver new drugs.”

Formed at Corning in the late 1990s, Covance was spun out as an independent entity in 1997. Covance is a combination of a number of best-in-class companies that span the entire drug development continuum. Its service capability has grown through acquisitions of company assets and staff to supplement or expand its portfolio. The firm covers all therapeutic areas and supports the development of both small molecule and biotherapeutic drug candidates.

The service it provides is customized to customer needs. For the small virtual company Covance provides scientific, medical, or regulatory data outputs that can assist in an exit strategy to enable selling the assets or the company. For large pharma, Covance provides all services necessary to move drug candidates through the pipeline with a continuity of support at all phases.

From its headquarters in Princeton, NJ, Covance has operations in over 60 countries with discovery and early development facilities in the U.S., plus many large central lab facilities and clinical sites for trials that are globally distributed to stay within the guidelines of local regulatory agencies.

“The regional distribution of Covance sites also provides customers easy access to monitor, manage, and visit ongoing activity,” says John Watson, strategic partnering president and chief commercial officer.

“We take a team approach, but also provide our customers with access to all levels in the organization. We look to develop true strategic partnerships with our long-term customers that go beyond the simple fee-for-service projects of old.”

Unlike Covance, Quintiles primarily gets involved when the drug is ready for Phase I trials.

Jeffrey Spaeder, M.D., chief medical and scientific officer at Quintiles, joined the organization just in August after spending time in global pharma at Abbott and Takeda. Dr. Spaeder brings a unique perspective to Quintiles, having served as a sponsor of a number of projects at Quintiles prior to joining the organization.

Quintiles has 25,000 employees operating in 60 countries. The company is focused on the four Cs: clinical research (clinical trials), commercial service (brand management), consulting (customer guidance through the drug development process), and capital (equity investment in drug development either via in-kind service or fee for service models).

While Quintiles gets involved in the process when the drug candidate moves into Phase I, it may engage customers even earlier through its molecular medicine offerings. It provides data management, IT, and database support to manage studies on a global basis.

“While the M&A activity in the biotech and biopharma industry has driven a lot of consolidation, it is also resulting in the emergence of small and mid-sized companies from the talent pool displaced by the consolidation process,” Dr. Spaeder indicates. “But by virtue of the breadth and depth of Quintiles, our business model is not changed. We are a nimble organization that can serve the newly formed drug development companies without missing a beat.”

MPI Research has a number of surgical suites that are often used for research on medical devices as well as drug therapies where a combined drug/device approach is required.

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