Bioanalytical Contract Research, A Brief Commentary

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By By Nuno G. Santos, Saleh Hussain and François Vallee

Contract research may be described as a service sector within the scientific community that has silently contributed to modern day advancements in drug discovery and development. In generalized terms, contract research is simply the outsourcing of in-house research projects by one organization to another independent organization. Although contract research spans numerous scientific disciplines and industries, it is most commonly associated to the pharmaceutical and biotech (BioPharma) industry. This industry in itself is subdivided into two main branches, those being the generic and brand name (innovator) sectors.

The global number of contract research organizations (CROs) servicing the BioPharma industry is always in constant flux as a result of mergers, closures and hopeful new ventures. Never the less, one can safely say that this number steadily grows year after year. The overall quality of a current CRO has also improved dramatically over the past decade. What was once thought to be a European and North American niche market, has expanded globally. One can now find competitive CROs in other regions such as India and China. This reality will likely shape the future of contract research in the years to come.

Evolution
CROs have had to evolve over the past years in an effort to survive and adapt to the competitive nature of the industry. In addition to the traditional research and development (R&D) services, CROs may also provide additional expertise and services such as regulatory compliance, product testing, manufacturing, statistics, clinical trials, analytical, bioanalytical, the list goes on. An estimated $14 billion is spent annually by the BioPharma industry on outsourcing services provided by CRO's, globally (Source: Contract Pharma, May 2006) and this number is steadily growing. In fact, by 2010 more than 40 per cent of BioPharma R&D expenses are expected to be outsourced, up from 28 per cent in 2006 (Source: Frost and Sullivan, 2005). How successful a CRO is depends entirely on how large a piece of that outsourcing pie it can grab.

Regulatory Hurdles
However, not just any organization can join this pie grabbing contest. Due to the nature of the industry, all work realized for a BioPharma company, with the exception of R&D, is governed by strict regulatory requirements. The main reason for the existence of these regulations is to guarantee the safety and efficacy of the drugs and thereby protecting the end users. Despite their extensive nature, the regulations are often summarized into the following categories: Good Laboratory Practices (GLP), Good Clinical Practices (GCP) and Good Manufacturing Practices (GMP), each governing its specific areas of research. Each region and/or country has its own set of regulations and regulatory agencies, such as FDA (USA), HPFB (Canada), EMEA (Europe), ANVISA (Brazil) to name a few. However, the FDA regulations and guidelines for laboratory, clinical and manufacturing practices are so well recognized that they form the foundation for many CRO standard operating procedures. Since BioPharma work impacts human beings across the globe, international agencies have made some efforts to harmonize the regulations and guidelines governing this ever-growing industry. The International Conference on Harmonization (ICH) is an on-going project between the regulatory authorities of Europe, Japan and United States and experts from the BioPharma industry in the three regions to discuss scientific and technical aspects of product registration. Although not directly involved, other agencies, such as Canadian regulatory authority, HPFB, observe and review all ICH discussions and documentations. Thus far, the ICH has produced several guidelines that harmonize those three region's regulations however, to date they have not been completely adopted or accepted by all regulatory agencies, even by those involved in the ICH project.

Competition
Regulations aside, the competition within the CRO service sector is especially fierce and challenging for existing and new CROs (or new sites opened by established CROs). Often there are many criteria (such as pricing, work quality, timelines and communication efficiency) for the new CRO to satisfy before they are awarded any outsourced work. For the most part these criteria are pre-determined by the regulatory agency to whom the outsourced work will be submitted for approval. To a lesser extent, the BioPharma company outsourcing that work may add their own 'flavour' to the criteria, especially to those associated to the procedures and conduct of their project. The existence of these concrete (agency) and subjective (client) criteria force many BioPharma companies to adopt cautious attitudes when choosing a CRO. Some avoid the doubt altogether by mainly working with CROs that have been audited by a regulatory agency, preferably FDA.

These audits are often associated to specific studies submitted for review and approval to an agency and often include facility inspections at the various locations (clinical, analytical etc.) where the study data were generated. Although most regulatory agencies do not provide any type of 'certificate of approval' for a site upon completion of a successful inspection, simply having completed an agency audit often provides reassurance (although sometimes false) to the BioPharma companies that the CRO has well-established procedures and methods. This criterion may be especially challenging for new CROs to satisfy. This reality is primarily due to the lengthy timeframes associated to the study's inception to final submission. Even if directly invited by a CRO, most regulatory agencies do not perform inspections of the CRO upon request as such it is very unlikely that any regulatory agency inspections would occur within the first few years of the CRO's lifespan.

The number of CROs has steadily increased over the past years. An estimated 88 CROs are currently providing laboratory analysis services in North America alone. (Source: Biopharm Knowledge Publishing, The Contract Research Annual Review 2006). From the BioPharma "consumer" perspective, a wider range of choice translates to lower costs for the same, if not better, quality of work. A BioPharma company is no longer willing to pay premium dollar for the analysis of its projects and it also demands more aggressive study timelines and bullet-proof data quality. From the perspective of the CRO however, this ability to 'shop around' has made it increasingly more difficult to manage the operational costs against the shrinking revenues. The end result is a more fierce competitive environment between CROs, each struggling to differentiate themselves from the other through innovation, aggressive study quotes, added value services and above all, quality.

Bioanalysis
Historically, one of the services provided by the CROs was 'bioanalytical analysis', or 'bioanalysis' for short, with the BioPharma company as the 'sponsor' of the outsourced study. By definition, this service involves the analysis of biological samples to assess concentration levels of the pharmaceutical product(s) being tested. Outsourced bioanalysis started to appear back in the 1980's likely due to pharmaceutical in-house resources no longer being able to meet the increasing demands of their own product pipe-lines. By the 1990's, contracted bioanalysis exploded as more potential pharmaceutical compounds were discovered, block-buster drugs went out of patent and the biotech sector started to flourish. Today, bioanalysis accounts for approximately 21 per cent of the CRO market (Source: Wall Street Equity Research, 2005) and includes service such as Bioanalytical method R&D and validation according to regulatory agency requirements in addition to incurred sample analyses.

If the life-line of a BioPharma is its compound pipeline, then the same can be said for the method development schedule within a Bioanalytical CRO. The method development schedule outlines the current and projected analytical methods in R&D and/or validation. As with a BioPharma's compound pipeline, this schedule is generally not divulged externally however, the analytical method list is widely (and enthusiastically) marketed. The analytical method list outlines all the validated methods immediately available at the Bioanalytical CRO without further R&D or validation. In this case, 'bigger is better' since the more validated method assays a Bioanalytical CRO has available, the greater the likelihood that it may have an assay that a potential BioPharma client may need. In short, an extensive analytical method list and a good reputation are the most effective ways for a Bioanalytical CRO to distinguish itself above and beyond others, especially when dealing with the generic sector.

The generic sector BioPharma clients are primarily focused on bioequivalence (BE) or bioavailability (BA) studies. Therefore, their ideal goal is to have their generic equivalent approved by the regulatory agency as soon as the brand-name original is off patent, or as soon as possible thereafter. The clients are now more price conscious and demand short study timelines. When given the choice they would more likely outsource a study to a Bioanalytical CRO with an established validated method rather than incur additional costs or time due to R&D and/or validation prior to analysis.

Consequently, to succeed with the generic sector the Bioanalytical CRO must be capable of anticipating their market trends, quickly determine where to focus their R&D efforts and revise their method development schedules accordingly. This type of philosophy towards managing their R&D is risky since the Bioanalytical CRO must divert resources (financial, personnel etc.) from revenue driven activities to speculative work that may not provide immediate returns in the near future. Never the less, the Bioanalytical CRO that adopts this vision views this speculative work as an investment and stays focused directly on the generic BioPharma needs.

Although a strong method assay list may impress the generic sector, a Bioanalytical CRO must use a different approach when attempting to win contracts from the brand name (innovator) sector. These BioPharma clients are primarily involved in proprietary new chemical entities under (or soon to be under) patent with little or no established analytical method information.

Furthermore, to outsource any type of work involves the release of vital confidential information to the CRO prior to product approval, a move that could be (potentially) detrimental to the BioPharma's future. As a result, a Bioanalytical CRO wishing to deal with this sector must demonstrate scientific prowess, quality and confidentiality. Reputation is the golden key.

Of the three aforementioned qualities, scientific prowess is the most challenging to achieve. Although significant advancements in equipment, instrumentation and automation have greatly improved the quality of the data and simplified many laboratory activities, the heart of a Bioanalytical CRO's scientific knowledge and capabilities lies within their personnel. Without experienced teams of scientists and technicians in place, the Bioanalytical CRO cannot hope to meet the R&D expectations of the brand name BioPharma, even with the state-of-the-art equipment in place. The diversity in experience and education within its personnel further strengthens its capabilities to research and develop precise, accurate and rugged methods for any new chemical entity, in any biological matrix.

The secret to success is to focus on the team and not the individual. A few CROs with multi-site bioanalytical facilities have taken this sense of R&D cooperation to a whole new level not attainable for other Bioanalytical CROs. Essentially, the multi-site bioanalytical facilities are encouraged to communicate and discuss technical and scientific issues encountered at each site, share experiences and problem resolutions and harmonize and simplify procedures. In essence, they have created a science
'think-tank' within the organization, independent of any one site, budget and above all any one 'exceptional' scientist. The think-tank's goal is simply to better satisfy their client's needs and expectations, thus creating a marketable edge while dealing with the brand-name BioPharma sector.

Conclusion
As a final remark, it is likely that if given a choice, most BioPharma would prefer to keep most of their work in-house. This is the safest measure as they have absolute control over all procedures and processes. Unfortunately, their own needs outweigh their capacities.

Outsourcing is viewed as a cost-effective way to increase productivity and resources without the overhead costs associated to self-expansion. This is good news for a CRO as this guarantees its future.
The CROs are here to stay. Which ones stay is a whole new story.

References
1.     Anapharm, 120 Newkirk Road, Unit 17, Richmond Hill (ON) L4C 9S7
2.     Anapharm, 2050 boul. René-Lévesque Ouest, Québec (QC) G1V 2K8

Nuno G. Santos, B.Sc. (Honours), coordinator, Bioanalytical Projects, Anapharm. Santos was hired as a bioanalytical project coordinator and as such, helped to establish Anapharm's new bioanalytical laboratory in Richmond Hill, ON. Santos currently oversees and coordinates projects related to the research, development and validation of bioanalytical methods and to the analysis of biological study samples for the brand-name and generic sectors.

François Vallée, M.Sc. Pharm.,B.Sc.,vice president, Bioanalytical Operations, Anapharm. A co-founder of Anapharm, Vallée has an academic background in medical biology (B.Sc.) and a master's degree in pharmacy (M.Sc.Pharm.). Vallée has over 24 years of analytical experience in the pharmaceutical industry. He has taken on various duties and is responsible for designing the laboratories and developing procedures that comply with good laboratory practices.

Saleh Hussain, Ph.D., director, Bioanalytical Operations, Anapharm. Hussain received his PhD in Pharmaceutical Sciences from the University of Alberta. Hussain spent more than 15 years working with pharmaceutical contract research organizations and acts as director, Bioanalytical Operations for the Richmond Hill laboratory. Saleh was responsible for analytical and bioanalytical method development and validation, drug metabolism and pharmacokinetic studies, non-clinical and clinical research.