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Nature Reviews Drug Discovery | Comment
Rachel F. Lane, Lauren G. Friedman, Curtis Keith, Steven P. Braithwaite, Julie A. Frearson, David A. Lowe, Frank M. Longo,Lorenzo M. Refolo, D. Martin Watterson, Katya Tsaioun, Diana W. Shineman & Howard M. Fillit
Nature Reviews Drug Discovery 12, 487–488 (2013) doi:10.1038/nrd4057
Contract research organizations (CROs) have a key role in drug discovery and development, but processes for evaluating, engaging and managing CRO contracts may not be well established in academic institutions or small companies. Here, we recommend an approach to optimize the execution of drug discovery programmes in such environments.
Academic laboratories and early-stage companies contribute substantially to innovative drug research and development (R&D). However, as the full range of different kinds of expertise involved is not always available or executed optimally within such organizations, a network of contract research organizations (CROs) is typically needed to supplement in-house expertise. For many years, large pharmaceutical companies have extensively employed CROs to complement their internal programmes and capabilities, and have established approaches to optimize their use, such as preferred vendor networks and measures for evaluating, contracting and managing CROs. However, such approaches are less established in academia or early-stage companies. Here, with the aim of helping to address this issue, we provide recommendations for effective interaction with CROs in early-stage drug R&D.
When to use a CRO
The clinical profile of a therapeutic strongly affects the experimental design and expertise needed during the early stages of R&D. Considerations include the therapeutic area, route of administration and length of treatment, patient population, safety and toxicity, impact on clinical practice, regulatory pathway and potential for commercialization. Interdisciplinary drug development teams are required to ensure that these factors are addressed early in the design of the programme and enable the development of a comprehensive project plan that helps to determine the need for CRO involvement.
The decision to outsource to a CRO should be driven by factors that include: the need for expert guidance in drug discovery science; technical expertise beyond in-house capabilities; key platform technologies; lack of development experience; time and cost efficiency; and the regulatory requirement for good laboratory practice (GLP) and good manufacturing practice (GMP). In addition to these practical considerations, CROs provide rapid evaluation and risk assessment for a project. This external reproduction and validation of data is crucial for the successful partnering of a programme with larger pharmaceutical partners, venture capital firms and private investors.
Evaluating CRO capabilities
Appropriate due diligence and assessment of CRO capabilities, in addition to project oversight and management, are critical. Here, we provide key areas for consideration when contracting with a CRO.
Size. It needs to be decided whether a full-service global CRO or multiple niche CROs best fit the needs of the programme. Full-service companies offer convenience, increased ease of project management and a range of technical expertise. When considering a large global CRO, sponsors should consider that some activities are outsourced to subcontractors. Therefore, evaluating the capabilities of the subcontracted companies is as important as assessing the parent CRO. Although niche CROs typically offer highly specialized techniques and flexibility, coordination of multiple CROs requires considerable investment in project management time.
Location. Although modern data management systems allow projects to be run across multiple continents, it is still important for an academic partner to be comfortable with the level of communication and oversight they have in their project. So, consideration should be given to challenges associated with language, culture, time zone differences and the need for face-to-face meetings.
Contracting. Multiple quotes for the same protocols, providing specific cost breakdowns, should be sought during the due diligence process. Once a project is in place, contracts that specify clear scientific milestones, payment and communication schedules as well as measures to ensure data confidentiality should be drafted. Depending on the stage of programme development, business models that are generally offered include a straight fee for service (fixed-cost), the engagement of a number of full-time equivalents (FTE) over a defined period of time, risk sharing and risk–reward models. The latter two models are particularly applicable to costly investigational new drug (IND)-enabling studies.
Experience. The CRO should have a proven track record with both the disease indication and the type of sponsor, in addition to documented experience in the specific capabilities being sought. Most CROs have one or two core strength areas but many will offer a wide range of services. It is important to identify core capabilities versus new areas of expansion with limited experience. CROs that primarily work with large pharmaceutical companies may have less financial interest in, or experience with, the requirements of smaller projects that typically come from academic sponsors. However, an increasing number of CROs pro-actively engage with academic sponsors as the projects provide added opportunity for innovation.
Objective references. All reputable CROs will provide objective references via direct access to former clients and third-party consultants. A list of previous clients will also provide insight into the quality, scale and nature of the organizations with which they have previously worked. US Food and Drug Administration (FDA) audits (available online) and on-site visits are important in assessing IND-enabling capabilities for later-stage programmes. The ability to perform work at a GLP level is verified by a CRO having passed one or more FDA audits.
Company structure. Accessibility of project managers and bench scientists within the CRO are one of the most important factors for evaluation. Where appropriate, a small pilot study provides an opportunity to directly observe responsiveness and reporting, as well as the validity and quality of data. Additional considerations include: how long the CRO has been operating; its financial stability; and the percentage of overall employees who have advanced degrees and industry experience. Due diligence should extend to the training provided to the technical staff, and records may be requested to ensure the bench scientists have the required training for the contracted techniques.
Data handling and communication. Data accuracy, confidentiality and security of data storage are all crucial considerations when assessing an organization. CROs should be transparent about their data management systems and provide insight to processes for accessing raw data, security, reporting and archiving. CROs should also make available historical control data and FDA audit records where appropriate. Regular conference calls on a standing schedule and in-person meetings with internal project management staff and technical staff are strongly recommended and should be outlined within the agreement. If eventual publication of data is a possibility, it is important to be aware of any relevant policies and to inquire about any limiting factors or prior experience. In some cases, the opportunity for individuals within a CRO to be co-authors might be of value in cost negotiations.
Consulting and project management. The efficiency and success of a programme is heavily reliant on a dedicated project champion or a project manager who can effectively bring together multiple CROs and individuals with diverse expertise. Project management requirements differ between early-stage discovery programmes and later-stage development programmes; the need for management and time commitment increases as a project moves through discovery and preclinical development.
For early-stage programmes, it is critical to decide whether the principal investigator or a professional with experience of managing most — if not all — aspects of the programme will be the project manager. If the project manager is the principal investigator, it is advised that external consultants are sought to provide independent guidance for the selection and management of CROs and to define crucial experiments to advance the programme. For later-stage programmes, having an experienced project manager or management company with experience of taking a drug from the bench to the clinic, performing site visits and managing CROs is crucial and will ultimately save time and resources.
CROs can provide huge value to drug discovery and preclinical development programmes undertaken in academic laboratories and early-stage companies. A network of trusted CRO vendors can mean a shorter and more streamlined path to value creation, IND, clinical development and successful partnering of a programme. However, identifying the right CRO and keeping the project on track is challenging. Undertaking appropriate due diligence and effective management of a CRO partnership is crucial to the project’s success. An effective project manager and experienced consultants are also crucial. The time commitment required for project management and the need for external consultants increases as a project moves into preclinical development, but is invaluable in avoiding costly and frustrating delays and in ensuring the successful advancement of a programme.
Ultimately, our key recommendations are as follows: first, the formation of interdisciplinary teams that include experienced consultants and project managers; second, the development of a clear project plan before initiating the programme; and third, appropriate due diligence and management of CROs with structured, open and frequent communication between all partners.