In the vaccine field, the most common approach to evaluating the immunological performance of a vaccine is to assess the serological response generated by subjects enrolled in a clinical trial. Usually, this occurs by testing serum or plasma, although other matrices may also be tested (e.g., urine, saliva, stools, etc.). Serological methods are most often ligand-based assays (e.g., ELISA) or functional based assays (e.g., bacterial or virus killing assays). Cell mediated immunological (CMI) assays are also in the armament of vaccine evaluations. New vaccines usually must demonstrate efficacy for their intended use and in those efficacy trials vaccine manufacturers will evaluate impacts on disease and causative agents using a variety of technologies beyond immunology including many molecular techniques.
These diverse needs, and more often than not, requirements, will often go beyond the abilities of a single laboratory with respect to available technology and expertise as well as internal facility and/or resource constraints. As a result, it has become more commonplace for Pharmaceutical sponsors to seek out, and partner with, Contract Research Organizations (CROs) that can provide the specific scientific expertise. Employing such a strategy requires that all regulatory and quality standards mandated for the sponsor be extended and enforced within the CRO. This becomes a difficult task considering the global nature of the business. Many sponsors have come to rely on certifications, accreditations, and/or licensures of the CRO, in addition to sponsor-specific requirements, in order to ensure a more harmonized approach to test methods, quality systems, and to minimize sponsor oversight. The problem then becomes, to which standard should a CRO be held?
Today, there are a number of organizations, accreditation bodies, and government agencies that have documented various standards for use by clinical laboratories. Within the United States (US), the Centers for Medicare & Medicaid Services (CMS) regulate all clinical laboratory testing (non research) through Clinical Laboratory Improvement Amendments (CLIA) certification. In turn, many CLIA certified laboratories recognize the College of American Pathologists (CAP) Laboratory Accreditation Program as the 'gold standard' which has served as a model for various laboratory accreditation programs throughout the world. CAP standards are considered to be more stringent than the regulations described within CLIA and now represent the majority of US clinical laboratory accreditations. Within the European Union (EU), ISO 15189 accreditation is considered the ‘gold standard’ and will soon be a required certification for laboratories in many of the EU countries (i.e. France, Germany). Additionally, the United Kingdom’s Clinical Pathology Accreditation (CPA) is also aligned both by reference and function to ISO 15189 requirements.
However, no specific regulation was written that applies to a clinical laboratory involved in clinical research or, more specifically, involved in the evaluation of patient samples obtained from a clinical trial. Good Clinical Practices (GCP) tends to be vague and doesn’t clearly define laboratory requirements for the assessment of patient samples from clinical trials whereas Good Laboratory Practice (GLP) focuses more on the pre-clinical phases of clinical trials. This resultant ‘gap’ has caused many variations in how laboratories interpret and implement the perceived requirements as defined in both GCP and GLP standards.
To close this gap, Good Clinical Laboratory Practices (GCLP) was created. GCLP is comprised from all of the relevant and applicable sections from GLP, GCP, 21 Code of Federal Regulations (CFR) part 58, 42 CFR part 493, and CLIA regulations. This standard was first documented in 2003 by the British Association of Research Quality Assurance (BARQA) and was entitled “GCLP, A Quality System for Laboratories which undertake the analysis of samples from Clinical Trials”. In turn, the United States National Institutes of Health Division Acquired Immunodeficiency Syndrome (US NIH DAIDS) 2008, World Health Organization (WHO) 2009, and the Medicines and Health Care Products (MHRA) 2009 have also published guidance documents in support of GCLP guidelines.
Collectively, these guidance documents provide a sponsor with the laboratory requirements that should be applied within any CRO contracted to perform laboratory evaluations for human samples generated from clinical trials around the world. The use of specialty CROs for performing clinical immunology, molecular or microbiology testing may seem an obvious requirement as many vaccine and pharmaceutical companies struggle to meet internal demand with limited resources and capabilities. However, it is a much more complicated area than it may seem from the outside. Particularly in the pediatric vaccine market, there has been a substantial growth over the past 10 years in the governments’ immunization schedule for infants. This rise has put increased pressure on the development of new vaccines by what is known as ‘concomitant testing requirements’ which are determined by regulatory agencies. Proving non-inferiority of an existing vaccine is not the only requirement, but it has become critical to prove that any candidate vaccine does not interfere with existing efficacy of currently scheduled (approved) vaccines. Consequently, the volume and types of immunological tests have grown substantially in this area. To accommodate this, some CROs have started to adopt newer technology such as multiplex ELISA-based assays (multiple analyte assays) to reduce the strain on serologic sample volume (particularly important in pediatric clinical trials). These newer assays face many challenges before they can be utilized as commercially viable testing options. The gold standard assays have typically been around for many years and used in regulatory submissions for clinical efficacy, so proving equivalency is a major challenge. Despite this, CROs continue to push for approval of these newer technologies in an effort to provide a full “menu of services” that can replace or compliment the older assays.
Moreover, the mere existence of these specialty CROs is partly due to a key clinical assay that has set a gold standard for a particular disease or therapeutic area, making them a center of expertise for matters related to those assessment areas.
All pharma/vaccine (sponsor) companies have their unique processes for working with CROs, consequently there is no “one size fits all” solution to that relationship. Indeed, the recent myriad of publically disclosed partnership deals between the large CROs and major pharmaceutical companies has increased the pressure to make these relationships work in all areas of the business. As this pertains to clinical immunological testing, it is somewhat difficult to force a technology platform or expertise where the partner CRO does not have that particular competency. The consequence of this is either a large time investment by the sponsor or the justification not to work with those partners because of impracticable aspects of the technology/ competency. Overall, there has to be a fine balance between using the partner's labs and yet seeking those best suited because this means more internal oversight and resources drawn into managing the relationship. There is also the risk of putting “too many eggs in the basket”, most labs are stable in terms of their workforce but there can be geopolitical aspects, capacity and of course regulatory risk. It may, therefore, be necessary to have multiple labs with the same capabilities to mitigate those concerns. This puts the burden on the sponsors to ensure comparable performance at all testing labs which conduct the same assays.
Worldwide there are certain laboratories which possess clinical immunology assays based on defined technical expertise of certain individuals or groups and are often referred to as key opinion leader (KOL) labs. These KOL labs can be both scientifically and technically recognized by regulatory authorities as reference labs (e.g., WHO reference labs). One of the biggest challenges with these labs is the varying levels of GCLP quality compliance. While most KOL labs have the basics, it is sometimes necessary for sponsors to get more involved in helping meet these GCLP standards. This can require anything from guidance in written procedures (to cover areas lacking in compliance) to situations where it is necessary for resources to be deployed on-site and assist with the deficiencies. The latter is more of a partnership with the KOL rather than a policing or watchful relationship. Ultimately, there has to be mutual benefit to these relationships because the direct involvement helps de-risk compliance concerns, ensuring regulatory filing of the generated data will be successful. These KOL’s often build their reputation by working with sponsors to gain further global recognition.
As KOL and CRO laboratories are located in all parts of the world, one might expect a significant degree in cost variance. The growth of emerging markets has often lead to the assumption that lower labor costs will help keep overall testing costs down. Consequently, most of the larger CROs have recently (in the last 5-6 years) commissioned new labs in those regions to support clinical trials there. However, the centers of expertise often still reside in the western labs because the more challenging assays or technologies are simply not available in those regions, albeit that there are ongoing efforts to change this distribution.
Overall, there are many regulatory, financial, and political drivers which result in using certain KOL or CRO laboratories for vaccine clinical immunology, molecular and microbiology testing but in the end what has been found critical is managing the relationship to ensure success.
Rod Cameron obtained his Ph.D. from the University of Cambridge in 2000 and currently works for Sanofi Pasteur. Rod is the Deputy Director of the External Testing group in the Global Clinical Immunology (GCI) department which is based in Swiftwater, PA.
This article was printed in the September/October 2012 issue of Pharmaceutical Outsourcing, Volume 13, Issue 5. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com and subscribe for free.