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
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.
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
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
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 riskreward 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.
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.
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.