May 2011

A CenterWatch Article Reprint

Volume 18, Issue 05

Sites worldwide rate PPD, Kendle, ICON top CROs

Survey: CROs continuing to improve relationships, training, project management
Top 3 global CROs
Percent of sites rating overall relationship quality good and excellent

By Karyn Korieth and Annick Anderson

84.3%

84.2% 83.7%

atings from a new CenterWatch survey show that for the third consecutive year contract research organizations (CROs) have continued to improve their relationships with investigative sites, particularly as CROs focus resources on improving project management and training monitors to make it easier for investigators to conduct successful, more efficient clinical studies. In this survey of sites around the world, the most important survey CenterWatch has done measuring the relationship between CROs and sites, three global CROs came out on top: PPD, Kendle and ICON. PPD dominated the results, being rated excellent or good by 84.3% of sites surveyed, followed in a near dead-heat by Kendle with an 84.2% showing. ICON took third place with an 83.7% rating. Scores for overall relationship quality were close among the top six CROs, with PRA International, Quintiles and Covance following closely behind the top three. This was the first CenterWatch ranking of CROs in a global survey of sites that included those in both the U.S. and Europe. PPD, Kendle and Covance also were highly rated in CenterWatchs 2010 European site survey; ICON and Kendle were among the top three in the 2009 U.S. site survey. PPD also received the highest excellent score for overall relationship quality (54.1%) and was consistently rated highest across most relationship attributes evaluated. The U.S.-based CRO earned the number one

PPD

Kendle

Icon

Source: CenterWatch, 2011 survey of global investigative sites; N=1205

spot by focusing on the needs of sites in a variety of ways, such as supplying technology and support, including a newly established online resource for document exchange and protocol information; providing clear protocols and timelines; and concentrating on strong training programs for clinical research associates (CRAs). We take the triangle of sponsors, CROs and sites very seriously, said Sebastian Pacios, vice president of global project management at PPD. Sites are our clients, the same as they are our sponsors clients, and we invest quite a lot in making sure that we are seen as facilitators. Overall, CROs received a combined excellent/good rating of 82%, up from 73% in the 2010 European site survey and 67% in the 2009 U.S. site survey. In this years survey, the CRO industry showed improvement in most of the critical areas, achieving the highest ratings in general project management and overall staff professionalism. These satisfaction ratings are important to CROs, since their success depends on the quality of their relationships with sites. As drug sponsors increasingly rely on CROs to conduct their clinical trials, CROs face mounting pressure to achieve

higher levels of performance and efficiency in managing site relationships. The relationship with sites is critical for sponsors and therefore for us to be able to deliver studies on time, said Alan Morgan, group president of clinical research services at Ireland-based ICON. As we are able to develop better relationships with sites, we are finding that is reflected in faster startup times and better adherence to overall timelines. The relationship with the site is critical to that. At the same time, sites indicated that CROs are not meeting their expectations in areas including professionalism of monitors, good protocol design, grant payments and some aspects of project management, such as setting realistic project timelines and being prepared for a study. While the top-rated CROs have practices that have been able to narrow the gap between site expectations and CRO performance, the survey results point to a need for industrywide improvements. We do take notice of what the surveys say. We try to learn and take feedback, said ICONs Morgan. Our relationships with the sites are the lynchpin of everything that we do, and its vital for them to work smoothly.

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Survey methodology
The 2011 CenterWatch Global Site Survey, which was conducted online during the months of February and March, surveyed principal investigators, sub-investigators and study coordinators about the quality of their relationships with CROs. The top-rated CROs were ranked based on responses from 1,205 clinical research professionals at sites worldwide, with more than 75% of respondents from North America and Europe. Sites were requested to rate the CROs they had worked with in the past two years on 29 relationship attributes. In addition, sites provided feedback on the importance of these attributes when conducting their clinical trials. Nine CROs with sufficient sample sizes were included in the analysis, which sought to identify CROs that have strong relationships with their sites and policies that can help their sites succeed. More detailed information about survey methodology is available in a CenterWatch White Paper and custom reports on survey results. some still maintain that sponsors have more highly-trained monitors and can answer investigator questions more quickly than CROs. But Stephen Cutler, Ph.D., the newly appointed president and CEO of Kendle, said that attitude has begun to change. I dont hear that so much anymore, he said. The sites that do a lot of trials are now very familiar with working with CROs and they can discriminate between who are the good CROs to work with and who are the not-so-good CROs. CROs are able to handle, treat and manage the sites perhaps a little bit better sometimes than the pharmas because they are used to doing it. Its part of our core competence and its a regular part of life for us, whereas the pharmas do it more ad hoc, unless you are a large company with a large monitoring force. For us, its dayto-day work. Sites today have a more positive view of their relationships with CROs than they did five or 10 years ago. Historically, investigators have tended to look at CROs as kind of middlemen, said Martin Lee, M.D., vice president of patient recruitment and site services at PPD. Yet the understanding is coming slowly in the clinical trials industry that CROs are playing a critical role in the management of the trial and its more important to become a partner with the sites. The site now views that relationship as positive. Its really becoming sort of a triangle where weve got the site, the CRO and the sponsor all working together rather than sites viewing the CRO as getting in the middle of things. However, investigators with more than 10 years of experience generally gave CROs lower marks for excellence on relationship attributes (43%), compared to those with five to 10 years of experience (54%). Its probably that sense of loss of connection with the sponsor companies that the older physicians are feeling, said Lee. Ten years ago, the relationship had always been between the sponsor and the investigator directly. Then CROs became more prominent and created this triangle between sponsors, CROs and sites. A lot of investigators didnt understand that. But the newer

The CenterWatch Monthly ISSN 1556-3367 Editor-in-Chief Drug Intelligence Production Cheryl Appel Rosenfeld Tracy Lawton Holly Rose

Shifting landscape
Analysis of CenterWatch CRO-site and sponsor-site relationship surveys conducted during the past six years reflect a shift in the clinical trial landscape. Overall relationship scores between CROs and sites gradually have improved as CROs, which manage an increasing number of sites without any direct involvement from drug sponsors, have focused their attention and resources on strengthening their relationships with high-quality sites. Meanwhile, scores in similar surveys of sponsor-site relationships show a slight decrease in satisfaction levels during the same period, as sponsors increasingly hand over more aspects of study conduct to CROs, particularly for phase II and III studies, and have less ability to reach out directly to sites. In the past, investigators preferred to work directly with drug sponsors on clinical trials;

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investigators have probably grown up in the time when CROs have been involved, so they are not used to working in any other model. The survey results indicate that CROs, which uniformly value the track record and expertise of their experienced investigators, may need to find new ways to reach out to their more experienced investigators. We want to have good, strong, transparent relationships with all of the investigators, said Kendles Cutler. Key opinion leaders, who tend to be the older investigators, are still very, very important for our customers, and hence, for us. There is obviously some work to do in terms of having them understand that the landscape has changed and getting them more comfortable with working with CROs.

Regional differences in average CRO ratings

Excellent Good Neutral Fair Poor

47%

(*d)

45%

49%

(*D)

43%

34%

35%

34%

35% (*c) 4% 2%

14%

3% 2%

15%

4% 1%

13% Europe

4% 1%

16% Asia

North America

South America

Europe: (*D) significantly higher than Asia p>.05; North America: (*d) significantly higher than Asia p>.1); Asia: (*c) significantly higher than Europe p>.1. Note: Africa and Oceana not displayed due to low sample size. Source: CenterWatch, 2011 survey of global investigative sites; N=1205

Boost in professionalism
Sites reported working with professional monitors or CRAs the most critical factor in conducting a successful study. CROs received high ratings for overall staff professionalism, and survey results showed a great improvement in the professionalism of monitors from previous surveys, jumping from a 46% excellent rating in 2010 to 53% this year, as leading CROs have put significant resources into improving oversight of CRAs, strengthening training programs and promoting interpersonal skills so monitors make good use of the study staffs time during site visits. Sites

viewed PPD, Covance, ICON and Kendle as having the most professional staff. Yet a significant gap remains between the importance sites place on staff professionalism and the overall performance of CROs. A total of 82% of sites rated the professionalism of CRAs as very important, yet only 54% of sites rated the average CRO as excellent in this area. Investigators say they want to work with well-trained monitors who know the protocol, understand how sites work and can give advice when necessary. According to Jennifer Aultman, a certified clinical research coordinator at the

Site ratings by experience and setting

Percent of sites typically rating CROs excellent 54%* 47% 43% 44% 52%#

50%

<5 years

5-10 years

10+ years

AMC-based Community -based

Gov. hospital

*Significantly higher than more and less experienced sites at p<.05 level; #Significantly higher than AMCs at p<.05 level Source: CenterWatch, 2011 survey of global investigative sites; N=1205

Neurological Research Center at Hattiesburg Clinic in Mississippi, CRAs who exhibit poor protocol knowledge or lack familiarity with IRB guidelines or regulations make her job more difficult and can result in unnecessary paperwork. Other examples of poor professionalism she has witnessed include CRAs who ask the research coordinator to fax them pages they failed to review or collect at the visit, CRAs who show up late for monitoring visits and then leave early, and others who spend time during their site visits browsing the Internet. I have never had a CRO contact me to discuss the performance of the CRA assigned, said Aultman. CROs could start by communicating with sites. They could provide a monitoring plan in writing at the onset of a trial. That way both parties know what to expect and can be aware of deviations from the plan. CROs could contact the site and ask for their ratings of a particular CRA, both negative and positive. PPD, which received the highest rating for staff professionalism with 61.2% of sites rating it excellent, requires monitors to complete a two-week training program and pass a test before they are hired. The company also provides ongoing training programs to ensure

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that monitors understand study protocols and can answer questions that arise. PPD also ensures that CRAs have the appropriate background and expertise at the local level. Our CRA workforce is geographically dispersed. We typically have CRAs in the country where the sites are. They have the same nationality, same language, and they understand the customs, said PPDs Pacios. That is very helpful to the sites because they find a person who is very knowledgeable and up-to-date about anything they need to know in GCP and for the project itself. And they can be approached very easily because they are local. At Covance, the second-highest rated CRO for staff professionalism (53.1%), the company follows rigorous selection, hiring and onboarding steps to ensure only experienced CRAs/monitors are deployed to work on clinical trials. Covance also has established continuous learning and training programs, not only to ensure staff members are up-to-date on recent regulatory changes and requirements, but also to refine soft skills focused on relationship management. We believe the mutual respect and strong relationships we have built with investigative sites is integral to achieving patient safety, data integrity, regulatory compliance and, ultimately, the success of our clinical trials, said Wayne Langlois, vice president and general manager of global clinical development at Covance. ICON, which received a 52.3% excellence rating for staff professionalism, recently made

The top 7 rated CROs

Totals reflect combined excellent and good ratings CRO PPD Kendle ICON PRA International Quintiles Covance Parexel Percent of sites rating excellent 54.1% 47.5% 48.7% 46.9% 45.7% 47.8% 41.7% Percent of sites rating good 30.2% 36.7% 35.0% 35.9% 36.2% 33.0% 35.6% Total number of attributes in the top 3 25 22 19 14 9 0 0

Source: CenterWatch, 2011 survey of global investigative sites; N=1205

a structural change, from a supervisory perspective, to put more focus on training, managing and supporting CRAs. ICON not only trains staff to understand the necessary procedures to meet regulatory and protocol requirements, but also runs specific programs to address inter-personal skills. The staff understand the importance of interacting with the sites, not simply for collecting data and source data verification activities, but also to be able to schedule visits and followup activities, said ICONs Morgan. Having highly experienced staff, and highly professional staff, is really important. Low monitor turnover is an important part of the strategy for providing experienced, professional staff at top-rated CROs. Kendle, which had one of the highest excellent ratings for low monitor turnover (45.7%), encourages its CRAs to develop long-term relationships

with sites by having them work with the same sites on subsequent trials whenever possible, even if the sponsor company or investigative drug changes. This continuity allows monitors to use their expertise to solve problems and encourage sites to meet timelines. We train our CRAs to be very focused on being flexible and responsible, said Cutler. If you get CRAs who have more experience and have been through a number of studies, they understand its not a one-size-fits-all with a site. Our CRAs take a pragmatic approach to help sites focus their efforts to get work done and not to feel too overburdened. Through that, they develop a good relationship.

Organization and timelines

CROs could improve their relationships with sites, according to survey results, by being more organized and setting appropriate timelines. The ability to be organized and prepared for a study was the second most important attribute for CROs, with 80% of sites rating this as an important area. Yet the sites reported only 53% of CROs are excellent in this area. At the same time, 74% of sites rated a CROs ability to set realistic project timelines as very important, yet only 47% rated the average CRO as excellent. ICON, which was the second-highest rated CRO for being organized/prepared with a 55.9% excellent score, behind PPD with 59.8%, has made a significant investment

Top areas where CRO performance can be improved

Percent of sites rating very important CRA professionalism Organized and prepared Overall protocol design Alignment of scientific rationale and operating realities in protocol Project management Study initiation 82% 80% 79% 74% 72% 66% Percent of sites rating excellent 54% 53% 49% 47% 51% 46% Gap 28% 27% 30% 27% 21% 20%

Source: CenterWatch, 2011 survey of global investigative sites; N=1205

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in project management and electronic data capture tools that help monitors prepare for more productive site visits. When monitors arrive at a site, for example, data that should be verified in addition to the standard checks already have been identified. We try to make the most of the monitoring visit. Source data verification is one of the most important parts of a phase III trial for the sponsor, so its our obligation to make sure we do that as efficiently as possible from a cost perspective and make sure its convenient for the sites we work with, said ICONs Morgan. PPD, which sites rated the top CRO for setting realistic project timelines with a 51.6% excellent rating, spends considerable time and effort during the feasibility phase, even before it is awarded a study contract, collecting input from regulatory experts and investigators in various countries to determine the recruitment rate and to identify any potential problems before the study launches. We put all of that information together to be sure that from the beginning, we have the most realistic timelines that we can achieve, said PPDs Pacios. It does not help to go with very, very aggressive but not realistic timelines if we fail to deliver. Its frustrating for the clients, its frustrating for us and its frustrating for the sites.

Most important attributes

Percent rating very important 82% 80% 79% 74% 74%

Professional monitors/CRAs

Organized/ prepared

Good overall protocol design

Protocols where Realistic project scienti c rationale timelines is aligned with clinical practice realities

Source: CenterWatch, 2011 survey of global investigative sites; N=1205

More protocol input needed

The 2011 survey results signal that CROs need to have stronger input into the development of protocols so that they are realistic from an operational standpoint for sites. Some 43% of survey respondents indicated that complex protocols result in study delays; as sponsor companies want to collect increasingly large amounts of clinical research data in a study, protocol designs are becoming more demanding and burdensome on site personnel and study volunteers. Yet the survey showed if CROs can improve their communication with sponsor clients about protocol development, and more forcefully represent site concerns early in the process, both site performance

and site satisfaction with their CRO and sponsor relationships will improve. Less than half of sites surveyed gave the typical CROs top marks when it came to providing protocols with good design; this was another area in which average CRO performance fell below the expectations of investigators. A total of 79% of sites indicated that good overall protocol design was a very important issue, yet only 49% of the sites rated the average CRO excellent in this area. In response to another question, 74% of sites gave high importance to being provided a protocol that aligned scientific rationale with clinical practice realities, yet only 47% rated CROs excellent in this area. Survey results show sites have witnessed some improvements in protocol design during the past three years. Some 49% of sites give typical CROs high marks for providing protocols with good design this year, compared to 43% in the 2010 European survey and 33% in the 2009 U.S. survey. As sponsors increasingly form closer ties with their CRO partners, top CROs already are involved in protocol development from an early stage at both large and small biotechnology companies. At PPD, which received the highest excellent ratings in both good protocol design (57.5%) and providing protocols that align scientific rationale with clinical practice realities (53.1%), the product development group has experts in many therapeutic areas who offer protocol design services. In addi-

tion, the feasibility group collaborates with the drug sponsor and investigators around protocol design at a very early stage to anticipate the effects of protocol design on patient recruitment and compliance. It used to be that the sponsor would develop the protocol, hand it to the CRO and say, Here. Go do it. What we are finding now is that the more sophisticated sponsors are reaching out to us much earlier in the process and they are actually engaging us as well as the sites, said PPDs Lee. ICON, which received the second-highest excellent rating in the study initiation category (48.4%) behind PPD (52.6 %), also said it has increasingly become involved in protocol design, both for large and small drug sponsors. Protocol design is one of the changing natures of the CRO marketplace, particularly for larger pharma sponsors, said ICONs Morgan. For smaller biotech sponsors, CROs like ourselves have always been involved intensively in protocol development. Now, as there is a redefinition of core competency within large pharma, there is a recognition that we have a lot of expertise in the operational aspects of how to execute a protocol and medical teams who can provide some of the scientific pieces in collaboration with statisticians. We find increasingly our sponsors are more appreciative of our input. As part of its protocol design, ICON considers the perspective of the patient and the investigator along with the scientific factors

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needed to achieve the appropriate results. By taking these various perspectives into account at the onset, Morgan said its easier for both site personnel and study volunteers to comply with protocol requirements. In situations where we dont necessarily have as much input into protocol design, we have to invest a lot more time in investigator training to ensure that we mitigate the risk of missing start-up timelines. If start up isnt done right, then its really hard to recover that during the duration of many trials, he said.

CRO personnel professionalism by region

Percent of sites rating excellent

North America
57% 58% 58% 54%

Europe
51% 58% 54%

South America
50%

Asia
52% 53% 50% 45%

Medical/scienti c

Study monitors

Administrative sta

Source: CenterWatch, 2011 survey of global investigative sites; N=1205

Grant payment issues

As in previous years, the grant payment process received some of the lowest scores in the survey. While sites indicated these processes have improved over the past four years, only 42% of sites rated the typical CRO grant payment process as excellent this year. Sites viewed PRA, PPD, i3, Kendle and ICON as having the best grant payment processes, with all of these CROs earning scores above the average excellent rating. The low scores are hardly a surprise since investigators commonly mention slow payment and not being reimbursed for all work involved in a clinical trial as hardships for operating their sites, particularly since their profit margins are generally low to begin with. Some 64% of sites rated the grant payment process as very important, but less than half thought CROs provided realistic grant payment schedules, fair grant amounts and prompt payment. There is a question about how we can improve the payment, since the majority of CROs have problems with this, said David Lopez Villezca, M.D., an investigator at Mexico-based Unidad Medica de Tratamientos Avanzados. At Kendle, which came in fourth for excellence in its grant payment process (44.2%), success in this area relies on representing the sites needs to the drug sponsor. Any potential issues or challenges with a protocol that could make the study more difficult to enroll are addressed early in the process, to allow

a reasonable compromise on a fair budget and what work is expected. We recognize that to get the best sites on board, you need to pay a grant that is fair and transparent, said Kendles Cutler. There have been times that we go back to our sponsors and say, If you really want this trial done, you may need to pay a little bit more, or there is an opportunity to pay a different amount or structure it in a different way. We try to represent the sites well to our sponsor. It helps for our sponsor to understand; they want to pay a fair and equitable grant. PPD, which received the second highest excellent rating in the grant payment process category (46.3%), slightly behind PRA International (46.8%), has put significant resources in this area in recent years. PPD also received among the highest marks for its grant payment process in the 2010 European site survey. The CRO has developed a system to ensure grant payments are fair by comparing information from databases about investigator fees in various countries for specific indications to actual study payment information. Those numbers are then reviewed by reliable investigators. In addition, the clinical trial management system designed to track when grant payments should be made is updated in real time. We can pay the sites on a timely basis and we dont have a lot of delays, which is something that frustrates the sites, said PPDs Pacios.

Looking ahead
Survey results show that CROs have improved their relationships with sites over the past four years, which has become critical since their success hinges on the quality of those relationships. But sites also would like to see continued improvements in their relationships with CROs. In particular, CROs need to reach out to their more experienced investigators as they work to strengthen relationships and meet sponsor demands for more efficiency and higher levels of performance from sites. Sites have a lot of choices these days with trials that they do, said Kendles Cutler. We believe we can get a competitive advantage over other CROs through having that good, strong, transparent, open, positive relationship with sites. 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. She can be reached at karyn.korieth@centerwatch.com. Annick Anderson has been conducting market research since 1998 in both the health care and consumer packaged goods industries. Annick holds a Masters of Business Administration from the Boston University Graduate School of Management. She can be reached at annick.anderson@centerwatch.com.

The CenterWatch Monthly | May 2011