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Budding Relationships

As CROs become more actively involved in all aspects of study conduct, drug sponsors increasingly rely on them to select investigative sites to conduct their clinical trials. To meet those expectations, CROs are employing various strategies to develop stronger relationships with top-performing sites and improve the chance of investigative site success.

Global CROs are developing strategic partnerships with sites – using performance-based metrics in site selection as well as providing more resources and support to investigators – in order to establish long-term relationships with those sites capable of delivering high-quality clinical data faster and more efficiently.

As sponsors form closer ties with their CRO partners – and outsourcing plays an increasingly important role in drug development – CROs have moved to the frontline in the relationships with sites. According to an Association of Clinical Research Organizations (ACRO) survey, member companies conducted more than 9,000 clinical trials in 2008 involving nearly two million participants, with CROs managing an increasing number of sites without any direct involvement from drug sponsors.

“The balance of expertise, particularly in the case of large Phase 3 studies, is shifting from sponsors to CROs,” said John Vogel, a drug development outsourcing consultant and trainer at John R Vogel Associates.“The vast majority of these studies are contracted to CROs.The primary interaction that occurs in the course of a clinical trial is not between a sponsor and a site; it’s between the CRO and the site.”

Since drug sponsors expect high levels of efficiency and performance when handing over site selection to CROs, the service providers will continue to look for new ways to expand their investigative site networks and earn loyalty from highquality sites. “The globalisation of clinical trials, and the trend towards sponsor expectations of more efficient utilisation of resources and recognition of leaner cost models, will force CROs to examine the way they do business and come up with more creative ways to deliver upon those expectations,” said Rebecca Griffith- Eskew, Associate Director of Feasibility and Recruitment Planning at ICON Clinical Research.

Exploring New Models

A CenterWatch survey found that a decade ago, sponsors used CROs to select and manage sites for nearly twothirds of Phase 1 to 4 studies; for the large Phase 3 studies, CROs were managing and selecting investigative sites nearly 90 per cent of the time. Today, global CROs report they are involved in site selection activities in nearly 100 per cent of outsourced studies in all phases of development.

In some cases, when a drug sponsor outsources responsibility for site selection, the process becomes a collaborative effort; some sponsors give the CRO a list of countries, sites or thought leaders they want involved in the study or maintain final approval of which sites are used. But increasingly, many sponsors are moving away from involvement in site selection once they decide to outsource.

“In fact, they want the CRO to own the project from start to finish and be accountable to deliver the study within agreed upon specifications,” said Lollo Eriksson,Vice President of Clinical Research Services at Parexel International.“Today, it is more common that sponsors leave the full responsibility to the CRO to plan and execute on the study, including identification, qualification and selection of investigators.”

As a result, CROs have begun to explore new relationship models, such as strategic alliances or preferred partnerships, to cultivate stronger ties with top-performing sites.These relationships require a larger investment of personnel and resources to qualify sites, integrate systems and provide ongoing support. Ultimately, CROs hope to establish long-term, semi-exclusive relationships with quality sites. Quintiles, a company that has been at the forefront of developing CRO-site partnerships, launched its Prime Site programme four years ago to form strategic alliances with large hospitals and healthcare systems that have sizeable patient populations and want to expand their clinical research infrastructure.

Quintiles recently added two prime sites in Asia, adding to its six existing sites in the US, Europe and Africa.The company also has developed strategic relationships with smaller sites through a partner site programme, which involves more than 1,100 sites in 20 countries.

The formal agreements, which generally last as long as both the company and the site are happy with the partnership, don’t include a guaranteed number of studies either for the site or the CRO. Partner sites have access to all Quintiles studies in their therapeutic speciality areas, as well as support for patient recruitment and retention activities. In return, the sites agree to work with Quintiles to grow research within the institute, start studies faster and enrol them more quickly. The prime partnerships involve a joint steering committee that includes senior executives from both organisations and functional experts, which sets goals and devises tactics to achieve them. The agreements don’t include incentives or penalties related to study performance.

“The risk to either side is that the collaboration doesn’t work, despite the time and expertise that each side contributes,” said Adam Chasse, former Global Head of Prime Site Strategy at Quintiles.

At the moment, the strategic alliances do not integrate systems or operating practices, but there may be technological collaborations between the CRO and partner sites in the future. The model has resulted in greater operational efficiencies, including study start-up times that are 30 per cent faster than at non-partner sites, and a more predictable delivery of patients and quality.

At PPD Inc, a group within the site and patient recruitment department has stepped up efforts to develop strategic collaborations and preferred provider relationships with sites that can bring large numbers of patients into clinical trials. For example, PPD signed an exclusive alliance with DiabetesAmerica, which runs 17 healthcare centres across Texas and Arizona and has more than 16,000 patients in its database. PPD provides clinical research training and support to more than 20 investigators conducting diabetes trials; and in return, DiabetesAmerica has agreed to work exclusively with PPD for three years to provide clinical research services for endocrine and metabolic disease development programmes.

“The goal is to work with organisations that can bring large volumes of patients into clinical trials,” said Martin Lee,Vice President of Site and Patient Recruitment for PPD.

Other global CROs also are exploring programmes to simplify site selection and study start-up processes. Kendle, for example, is putting agreements in place to formalise existing relationships with investigators, especially with sites working in therapeutic areas in which the CRO has expertise. The investigator relations group at Covance is also moving toward establishing contracts with its top-performing sites.“We are trying to identify the best sites that create the greatest value for our sponsor and create a preferred network status for those sites,” said Kevin Renahan, Executive Director of Investigator Relations at Covance.“We want to have a mutually beneficial relationship between us, the sponsor and site.”

Non-exclusive professional affiliations and collaborative models are also on the rise. Recent examples include Parexel’s alliance with Safe Implementation of Treatments in Stroke (SITS) International, the world’s largest network of clinical sites with specialised capabilities in the area of stroke; and PPD’s agreement with the Himalayan Institute and Hospital Trust, a large teaching hospital in northern India, to provide infrastructure support and staff training to create a large clinical research site.

Building Site Relationships

Traditionally, the support CROs have provided investigative sites has been fragmented and CRO-site relationships have suffered from the high turnover rates among study monitors and other staff that interact directly with site staff.

Some investigators report feeling frustrated when they discover CRO project managers have no knowledge of their track record with the CRO in conducting high-enrolling, high-quality clinical trials. For example, Larry Seidman, President of Philadelphia Clinical Research – which specialises in endocrinology and obstetrics/ gynaecology – has conducted more than 200 trials during his 14 years of research and has earned a reputation as a highly regarded clinical investigator.Yet, when he contacts a major CRO with which he has worked many times before about a study in a therapeutic area in which he has had great success, he often must re-introduce himself and obtain references from other project managers within the company.

“Ultimately, when I show them who I am and what I’ve done, I get the study. But I shouldn’t have to jump through hoops as much as I do,” said Seidman. “Why aren’t the good sites having the companies come to them? Companies could be missing out on good investigators.”

Large CROs have begun using a variety of techniques to improve their personal relationships with sites and make it easier for investigators to conduct trials in an efficient, professional way. In recent years, the industry has seen a consistently high turnover rate among investigators: one-third of those active in the prior year drop out, often disenchanted by the amount of work clinical research requires. Surveys show that sites want to work with CROs that make it easy for them to run trials and, ultimately, that’s what drives their loyalty to certain CROs.

“It is important for a CRO to approach and interact with investigators in a customer-centric way,” said Parexel’s Eriksson.“It is important for the success of the overall study to monitor and address investigators’ satisfaction and needs, which can work to foster continued positive CRO-investigator relationships.”

Strategies include making sure investigators understand industry pipelines so they are ready for upcoming studies, working with sites to improve start-up processes or recruitment techniques and simplifying the paperwork required during site selection. Large CROs have taken steps to improve communication and minimise the number of people contacting research staff. Some CROs have set up special teams dedicated to assisting sites. Many have adopted electronic communications systems that allow sites to file questionnaires and documents, such as medical licenses and institutional review board (IRB) approvals, more efficiently.

“It’s our job to make it easy for the sites to work with us,” said Joan Meyer, Global Head of Study Start-Up at Kendle.“To do that,we simplify the processes as much as we can so that the sites can focus on the patient.”

ICON has bundled its study startup services more closely with an organisational alignment so that feasibility, patient recruitment, site identification and study submissions work in concert.The CRO has instituted a single point of contact model for sites during the feasibility and site identification period; this person is available as support to the sites if they are working across multiple studies with ICON. In addition, each site network, site management organisation and large study site is assigned a coordinator who works with them exclusively to provide performance metric feedback and insight into upcoming opportunities. “Our culture is changing to view study sites as a true partnership, with performance-based metrics on both sides,” said ICON’s Rebecca Griffith- Eskew, Associate Director, Feasibility and Patient Recruitment.

CROs also are strengthening the relationships between clinical research staff and the CROs’ study monitors and project managers who work directly with them. Investigators often say they want well-trained monitors who know the protocol, understand how sites work and can give advice when necessary. One initiative at PPD, for example, requires monitors to complete a two-week training programme and pass a test before they are hired.While the programme aims to train monitors before they start work, an equally important goal is to ensure proper interactions with investigators and clinical research site staff.

“For each individual project,we want to make sure they are well-trained so that when they go out to interact with the investigators, they are providing the right kind of information, the right interaction, and they are making a valuable use of the investigator’s time and the study coordinator’s time,” said PPD’s Lee.

Performance-Based Metrics

Performance-based metrics have become an important part of CRO strategy. Rather than using the old siteselection approach that one executive described as “throwing mud at a wall to see if it sticks”, CROs now use commercial or in-house databases and analytic systems that allow a more scientific method.These metrics allow CROs to evaluate and compare the past performance of investigators in a particular country, therapeutic area and protocol design.The databases also can include metrics on experience, enrolment rates, number of queries, data quality and cycle time, including how long it takes sites to get through their IRB or ethics committee approval process.

“A global investigator database with quality records is essential for a CRO,” said Parexel’s Eriksson.“Updates and maintenance are very important. It requires dedicated resources that specialise in database maintenance, data mining techniques, different types of reports and interfaces with other key systems used in clinical trials, such as investigator portals or web survey tools.”

Large CROs use their performance-based data to identify sites with the highest probability of clinical trial success. Both CROs and drug sponsors have been frustrated by the overall performance of sites in recent years; for any given study, about 20 per cent of sites deliver the majority of the patients and about half of sites fail to meet patient recruitment targets. In fact, recruitment delays have become the number one cause of lost time and increased expense in the drug development process.

“Running a clinical trial with poorly selected sites has short-term cost implications, but more importantly, it has long-term cost implications in terms of quality data and being able to register data at the appropriate time,” said Covance’s Renahan.“Drug sponsors are becoming very keen to understand which sites tend to be higher producing sites because that, in turn, gives them a quicker to market development plan versus relying on sites that don’t have appropriate metrics.”

Some CROs augment their quantitative databases with qualitative information about how sites function. Covance, for example, has developed an investigator relations department that is placing individuals across the globe, including Asia-Pacific and eastern Europe, to understand the dynamics of site operations in various regions. According to Renahen, Covance expects to have the department completely staffed later this year.“We’re trying to understand the best possible sites for us to work with. Sometimes there is analytic data that can lead you there, but often, it’s in interacting with local medical societies that you are able to really identify those sites that would show the highest potential performance,” he said.

But some question whether metrics used by CROs are reliable in predicting site performance. Both sponsors and CROs have used various measures and subsequently found they didn’t work in predicting site performance. For example, for many years the industry measured how long it took sites to enrol their first patients as an indication of how fast they could get studies started. Now companies realise the measurement isn’t entirely effective, as study performance depends on enrolling all patients, not just the first.

As performance-based metrics continue to evolve, CROs are acknowledging the limitations of quantitative databases and are looking at ways to account for qualitative factors such as the amount of time an investigator will devote to a trial, site interest and commitment, and quality of protocol to improve their ability to predict site performance.

Looking Ahead

As CROs face pressure to achieve higher levels of performance and efficiency in managing site relationships, some have begun exploring the possibility of adopting different relationship models for the future.

One option under consideration involves CROs owning their own investigative sites or networks for Phase 2 or 3 studies. While some global CROs already own Phase 1 sites, studies at these facilities mainly enrol small numbers of healthy volunteers. Since Phase 2 and 3 studies enrol large numbers of patients, CRO executives have expressed concerns about the implications of getting involved in the medical care of patient volunteers. Costs associated with owning investigative sites and the challenges in scaling up this model are also a concern, particularly since some recent joint ownership agreements between service providers and sites have been cancelled. But despite the drawbacks, some CROs consider site ownership a way to ensure high-quality investigators, control over data quality and the ability to use electronic medical records to quantitate the patient population.

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Karyn Korieth has been covering the clinical trials industry for CenterWatch since 2003. Her 30-year journalism career includes work in local news, the healthcare industry and national magazines. Karyn holds a Master’s of Science degree from the Columbia University Graduate School of Journalism. Email:
Karyn Korieth
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