Non-clinical contract research organisations (CROs) are an integral part of modern drug development. Delivery of GLP toxicity data to support clinical trials with any novel agent is a critical step and requires a professional organisation with dedicated management, infrastructure and a broad array of technical and scientific skills.
The last few years have seen a large growth in demand for outsourced non-clinical safety services in a market estimated to be worth $4-5 billion a year and predicted to grow to almost $7bn by 20251. This growth is being driven by the current spike in R&D spending as well as an increase in the outsourcing of studies many pharma traditionally kept ‘in-house’. This trend reflects increased confidence that CROs are able to deliver quality products cost-effectively.
Consequently, in a growing market CROs have embarked upon a variety of strategies to establish their own identity and compete for market share. Some have sought to broaden their services through merger and acquisition to offer greater scope and capacity. These CROs offer almost every aspect of the drug discovery and development process from in vitro high content biology, medicinal chemistry, through to manufacturing, clinical and regulatory services.
Some major players have become even larger in an effort to become a one-stop-shop solution and several now boast multi-billion-dollar annual revenues. Others have deliberately focused on excellence in specialist areas and on retaining a more intimate customer-centric feel. The growth in the global CRO market has been supported by the shedding of staff from big pharma over recent years providing a steady stream of talent into the service sector. As a result, nonclinical CROs now possess a wealth of technical, scientific and regulatory expertise. But when faced with a dizzying array of CROs of different profiles, sizes and locations, all promising excellent service and unique attributes, how do sponsors know who to trust?
In selecting a CRO, you will be looking for a quality product, on time and at a fair price. However, it is likely that one of these will be a more important driver than the others. Some may find it acceptable to pay a higher price for a CRO that can deliver sooner, if it supports an earlier regulatory submission whereas others, for whom cost is the primary consideration, may be willing to accept a longer lead-in time for a more competitive price.
Cost
Study costs vary significantly across different CROs and it is always worthwhile requesting quotes from several providers. Factors that influence the cost include the location of the CRO (i.e. their cost base), the availability of laboratory space, animals (especially non-rodents), and study-specific requirements. The dosing route, frequency and duration are important variables that will affect the amount of resource needed for the study. Supporting activities such as formulation preparation, development and validation of bioanalytical assays, the number of biomarker and pathology samples and toxicokinetic analyses, all add to the cost. So, it is worth providing as much information as possible at the time of quotation. Placing several studies at a single CRO can – in some instances – allow negotiation of better rates. At other times, it can be more cost-effective to use specialist suppliers for different aspects of the work.
Timelines
There are three key phases that define the timeframe for completion of toxicity studies. These are: study scheduling, the in-life phase and the reporting phase. To keep costs competitive, CROs need to be lean and efficient, so do not run with large excess capacity. Lead-in times can vary considerably depending on various factors and it is not unusual for there to be several months before a study can start dosing. This is dictated by availability of the test compound, animals, rooms and personnel. With so many moving parts, and enquiries from multiple customers, an indicative timeframe will be given initially with confirmation of the study dates usually only after a formal commitment.
The time taken during the live phase is governed by how long the pre-study and dosing phases are and whether recovery groups are included. In the reporting phase, there are multiple parallel activities on the critical path including tissue preparation, sample processing, data analysis and QA audit and most CROs have developed efficient processes to minimise the time to audited draft report. This phase will take several weeks as each GLP study generates hundreds of pages of data which requires accurate evaluation, interpretation and peer-review. With a good relationship however, it is usually possible for the Sponsor to view some data as it emerges, ahead of the draft report.
Quality
There is sometimes an assumption that every GLP lab will produce more or less the same product to a consistently high quality. However, compliance with GLP reflects the standard of working practices and facilities but says nothing about the scientific validity of the data interpretation. Toxicity studies are large, complicated experiments and mistakes do arise due to human error. The best CROs are open about any errors and should immediately flag this to the sponsor. Higher levels of staff turnover, inexperience and/or poor training can lead to suboptimal dose selection, an increase in technical errors and inadequate attention to detail.
When selecting a CRO, there are also several other important considerations that are frequently overlooked:
Communication
Due to the nature of the work, unexpected events can arise during a toxicity study that require a rapid response. The objective of this work is to reveal the toxicity profile of a compound and it may be necessary to deviate from the intended plan to maintain the objective of the study. Decisions may need to be made regarding an individual, or group, to shorten or extend the dosing period, to reduce the dose, or to suspend dosing for a period. These decisions should always be made in association with the sponsor or the sponsor’s representative, and it is crucially important that there are open and clear lines of communication. Although the study director has ultimate control over the study, healthy dialogue with the sponsor is necessary to determine the best course of action. The sponsor should ensure they have a sufficiently experienced individual acting as study monitor, who can react quickly and provide a measured response. If such expertise is not available within the sponsor’s organisation, a consultant should be considered.
Report quality
The final study report is the single most important output from the study. The report will form a fundamental part of the regulatory submission and should be written in as clear and succinct language as possible, using short sentences and scientific language. When submitted to regulatory agencies it should leave the reader in no doubt what was done and what was found. This may require the definition of no effect levels and/or no adverse effect levels and importantly, a clear view on which findings are considered compound-related, and which are not. These can be difficult decisions, especially if the effects are of low severity or low incidence and may require extensive discussion between relevant experts before a consensus is reached. The discussion should not simply be a repeat of the results but should pull together all relevant data supporting a statement of target organ toxicity (e.g. hematology changes and bone marrow histopathology), or lack of relationship to drug (e.g. lack of dose response, presence in controls). Under time pressure from sponsors, and with multiple studies running in parallel, study reports do not always get the time and attention they deserve.
Geography
Recent years have seen a significant expansion of the CRO industry in emerging economies such as India and China. In part this has been in response to growth of the local pharma sector, but they have also successfully attracted business from Western clients looking to take advantage of the lower cost base. However, before selecting a CRO based far from the Sponsor, it is worth reflecting on potential complications that can result: in addition to the time zone, there may be language differences as well as lower levels of technical and scientific experience. As China is not an adherent to the Organization for Economic Co-operation and Development (OECD) mutual acceptance of data (MAD), Chinese CROs currently cannot offer Good Laboratory Practice (GLP) as defined by OECD. It may be possible to validate the work of a Chinese CRO on a study-by-study basis, and country-by-country basis, but this is an expensive exercise if the initial intention was to save money.
The external expert
One solution to navigating this landscape successfully can be to work with independent experts such as an experienced study monitor or external pathologist. Both these roles provide a valuable third-party perspective to the benefit of both the sponsor and CRO. They will be familiar with multiple CROs, recognising their various strengths and weaknesses, with an appreciation of market rates. An effective study monitor simplifies communication, will be on hand to deal with day-to-day decision-making and can provide an informed impartial opinion on resolution of key issues.
Larger companies may have dedicated internal groups of study monitors that develop long-term working relationships with CRO staff. Smaller companies may not have these roles but deploy a researcher or manager to work with the CRO as an addition to their day job. A lack of time, expertise and experience at monitoring could compromise the quality of the studies. A team comprising the CRO, sponsor and an expert study monitor is likely to provide the optimal conditions for producing a good quality study and final report.
An external peer-review pathologist reviews and verifies the accuracy of pathology interpretation. Review is conducted before study completion and an experienced peer-review pathologist assists the study pathologist in refining diagnoses and interpretations. They also provide a link to other relevant data the sponsor has generated and can be extremely helpful in discussing whether a change is compound-related or not2.
To maintain efficiency, CROs inevitably have a preferred way of working, based on sponsor history, and can be reluctant to adopt new or innovative approaches. Studies should always be customised to best support the clinical goals, therefore an independent, external perspective can often challenge a study design, the conclusions of the report and even pricing in a way the Sponsor cannot. It might seem an easy solution to take a hands-off approach and let an established CRO do everything. However, in reality, few CROs are good at everything and as the major providers merge and become even larger they can struggle in areas such as communication, customer service and innovative thinking. Many CROs still have room to improve by focusing on really excellent customer service, communication and flexibility.
Today’s CROs play an integral part in the continuing effort to improve all aspects of nonclinical study design and conduct, including the 3Rs (reduction, refinement and replacement). The partnership between CROs, pharma and independent experts plays a key role in driving improvements in our industry that deliver better data to regulators as well as better value to the Sponsors.
- 1 Preclinical CRO Market Analysis By Service Type (Bioanalysis & DMPK Studies, Toxicology Testing, Other Preclinical Services), By End-use, And Segment Forecasts, 2014 – 2025
- 2 Morton et al Toxicologic Pathology, 38: 1118-1127, 2010
Dr Richard Knight is co-founder and director and Dr Guy Healing is a senior toxicologist, both at ApconiX
