Trends for Preclinical CROs

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Check out our Preclinical CRO section for more information or to find companies that provide these services.

Preclinical CROs: An Introduction

Contract research organizations (CROs) provide a number of preclinical and clinical services to their pharmaceutical and biopharmaceutical clients. In general, they work like any other contractor—they provide services to clients who seek a more cost-effective answer to their development needs, perhaps due to lack of expertise or the time to perform the task themselves; in turn, the client is billed for services rendered.

CROs fall into one of several categories: CROs that provide preclinical services exclusively, clinical services exclusively, or some combination of both types of services. Among the preclinical services are bioanalytical (e.g., immunochemistry, ELISA), studies on the fate of the drug candidate in cells and in animals (e.g., ADME studies), toxicological studies, and medicinal chemistry services, just to name a few. Clinical services include patient stratification, administration of dose, dose-escalation studies, proof-of-concept studies, and others. Other CROs may manufacture API and have their own cGMP or GMP facilities to generate sufficient quantities of a compound for preclinical and clinical use. “There is not a generic preclinical CRO. If you look across the whole range of these organizations, you’ll find everything from a boutique CRO that provides a specific niche all the way to a much broader base CRO covering all of preclinical,” says Chris Perkin, BS, DABT, corporate senior vice president and global preclinical services head for North America and Asia Site Operations for Charles River, a CRO headquartered in Wilmington, Mass. This article will focus on preclinical services provided by CROs.

Ricerca Biosciences LLC (Concord, Ohio) is a growing CRO that is completely focused on the preclinical segment of the business. Ian Lennox, chairman and CEO of Ricerca, points to several trends in the CRO industry. One of those trends, he says, is a consolidation, and closing, of preclinical facilities globally. “For example, we've seen Charles River, which is the second-largest player in the market, close two facilities because there was too much capacity for their market to absorb,” says Lennox. A more notable aspect of this trend, he says, is the massive restructuring of many of Ricerca’s pharmaceutical clients. “For example, large pharma is shutting down toxicology and chemistry facilities,” says Lennox. “That should be a long-term and very positive trend for the outsourcing industry.”

Preclinical Services

Bioanalytical Services

To assess the desired and undesired biological effects of potential drug compounds, a CRO must often perform assays that measure the impact of that drug on a biological activity (e.g., cell growth or enzyme activity). Bioassays, such as immunochemistry and enzyme-linked immunosorbent assay (ELISA) are immunoassays that detect the presence of an antigen/protein in a cell or biological fluid (e.g., blood plasma), respectively. Immunochemistry is frequently used to detect the effect of a compound on the functioning of a drug target, especially where the functioning or lack thereof is relevant to the disease process. ELISA is frequently employed to measure the presence and quantity in a biological fluid of a specific disease-associated protein/biomarker.

ADME and Toxicological Testing Services

Undesired biological effects—often known as side-effects or adverse events—must also be measured by a CRO to gauge whether or not a drug will be safe to administer to humans in clinical trials. This is all part of a larger group of studies known as absorption, distribution, metabolism and elimination (ADME) testing, which are conducted during preclinical stages of development. In ADME studies, the compound is first tested in a large number of cell-based toxicology models, and then in a range of appropriate animal models. For the most part, toxicological assays focus on the potential hazards that may arise from exposure to a drug candidate, and more importantly, may also include studies on the metabolism of a drug compound in liver cells. Cell-based models include specialized liver cells, which are grown in cell culture and used to determine whether a drug candidate is enzymatically altered in the cell, a common way in which organisms detoxify and remove compounds. For animal-based testing, many animal models are currently being utilized to test for safety, including several normal and genetically engineered rats, mice, primates, and dogs. Charles River offers a large portfolio of animal models that range from basic models such as wild-type mice, to specialized mouse models such as SCID-hu. Charles River has invested in the early stages of discovery all the way through preclinical. “Our view of what it means to be a preclinical CRO is being there for our clients from the bench all the way to proof-of-concept in man and all the preclinical services needed to reach the market,” says Perkin.

In the same vein of making safer pharmaceuticals, the current goal of the pharmaceutical industry is to fail unsafe compounds as early in the development process as possible. One CRO that is very interested in supporting this philosophy is Gentronix Ltd. (Manchester, UK). Says Company Commercial Director Steve Beasley, D.Phil: "Gentronix is very interested in helping companies reduce liability early in the discovery process." Gentronix is a developer of genotoxicity tests (e.g., human cell-based Green Screen HC & Blue Screen HC assays) that predict which compounds are genotoxic and thus could prove unsafe for human use. "The new tests we provide give much more accurate results than the current regulatory battery of assays," says Beasley. "Moreover, because we are coming in earlier than the regulatory assays, we identify compounds that have problems much sooner and fail those compounds that are toxic before they go into process development and preclinical development. This saves companies valuable time and money, a double win."

Medicinal Chemistry Services

Medicinal chemistry is the science of chemically altering a synthesized potential drug compound for the purpose of increasing its efficacy and/or improving its safety/toxicology profile. Medicinal chemistry is a big part of the preclinical drug development process. In fact, it can be performed at many points during the process. In general, after a compound that acts on a drug target is found through a screening process, it is known as a hit. That hit is then optimized through the medicinal chemistry process to become a lead, which is then further developed though preclinical studies. Many CROs perform medicinal chemistry services for their clients.

Trends and Predictions

According to Lennox, a major trend in the CRO industry is the emergence of Asia as a powerful player in CRO space. Globalization of pharma in China has largely been due to an unmet healthcare need in most of China’s citizenry, and when pharma moved to China, CROs soon followed to capture part of that market. “What drives globalization is looking for cheaper ways to do it and that is the balance between price and quality,” says Perkin, who adds that, at present, “virtually every multinational has a physical presence within five miles of Shanghai.”

Lennox says, “Globalization is not a new trend, but [the] real issue for Asia, I think, is that they have been using cost over quality as their leverage to access North American and European clients.” He adds: “Over the next five years, quality needs to lead over cost.” Globalization, particularly movement of large pharma into China, has been, and continues to be, a driving force in the CRO industry.

“Nowadays neither the CRO nor the pharma company could survive without the other,” says Perkin. “Traditionally, the relationship between the pharmaceutical industry and the CRO has been more transactional. But I think, in the next 10 years, we will see greater moves from transactional to a true partnership.”

Check out our Preclinical CRO section for more information or to find companies that provide these services.