Sponsors have done a good job of maintaining, but not improving, the overall quality of their relationships with investigative sites during the past two years, according to a new CenterWatch survey, but performance gaps have widened across several of the attributes sites identify as the most important for conducting a successful study.
Leading sponsor companies have made strengthening their relationships with investigative sites a top priority in recent years and have created a wide range of initiatives designed to incorporate investigator viewpoints into improving clinical development processes and easing site burdens.
The 2017 CenterWatch Global Investigative Site Survey suggests that investigators have raised their expectations for sponsor performance in providing better study support, good protocol design and easily accessible staff as investigators face increasing compliance, regulatory and financial pressures when conducting clinical trials.
Many companies that received the highest ratings in the 2015 survey continued their strong performance in 2017. The 10 highest-ranking companies were Novo Nordisk, Servier, Otsuka, Teva, Boehringer Ingelheim, Allergan, GlaxoSmithKline (GSK), AstraZeneca, Janssen and Eli Lilly.
Overall, the average sponsor received a combined good/excellent rating of 82%, which is the same as the 2015 survey and a 2.5% increase from 2013.
Two new survey attributes in 2017 measured investigator-perceived importance of sponsors designing patient-friendly protocols and actively involving patients/patient groups into protocol design. Investigators acknowledged that a primary component of clinical research—study design and planning—can be improved using patient-centered development approaches. While a growing number of sponsor companies solicit patient feedback for study designs and are piloting approaches to reduce the burden of study participation, fewer than half of investigators gave the average sponsor “excellent” marks for these attributes, suggesting a key area for improvement.
“We always take the time to ask and listen,” said Kate Owen, vice president of Clinical Trial Management at Novo Nordisk, which ranked among the three top-performing sponsors for patient-centric attributes. “By taking the time to ask and listen, you are always going to find something you can use to make a difference.”
Other areas suggested for sponsor improvement included providing protocols that require fewer amendments, supporting initiatives to help sites build stronger relationships with study volunteers and being more flexible in modifying protocols and budgets. These attributes received some of the lowest “excellent” scores from investigators.
The 2017 CenterWatch Global Investigative Site Survey, conducted online from October 2016 through January 2017, asked principal investigators and study coordinators to rate the sponsors they worked with during the past two years on 40 project attributes. Key changes this year included new attributes that addressed issues related to patient-centric protocol design and risk-based monitoring. Sites provided feedback on the importance of these attributes to their success in conducting clinical trials.
Clinical research professionals representing 1,376 sites across 15 countries completed the survey. The highest concentration (49%) of respondents was from Europe, followed by North America (35%), South America (9%) Asia Pacific (6%) and Africa (1%). Representation from North America increased from 24% in 2015. Even with the strong geographic diversity represented in the survey this year, the overall results haven’t changed significantly from prior CenterWatch global site surveys, which helps to validate the data previously collected.
A total of 25 sponsors with sufficient sample size were included in the analysis, compared to 24 in the 2015 survey. Sponsor rankings were an overall relationship quality rating based on the percentage of “excellent” scores from sites; the frequency with which companies placed among the top-three rated sponsors across the 40 relationship attributes was used as a tiebreaker for companies with the same scores.
Gaps widen in top attributes
Overall sponsor performance remained the same or showed slight improvement, compared to 2015, for the nine attributes investigators rated as most important to running a successful study. Yet the gap between the importance of relationship attributes and the ability of sponsors to deliver them widened by an average of 5.3 percentage points across those top areas largely because of investigators giving them higher importance ratings. In contrast, analysis for the 2015 survey found importance/excellence gaps for the nine most important attributes narrowed an average of 4.4 percentage points in comparison to the 2013 survey.
The most notable gap increases in 2017 were in areas previous CenterWatch surveys have identified as most critically in need of change: having staff easily accessible, for which the gap increased from 11% in 2015 to 16% in 2017; and providing good overall protocol design, for which the gap increased from 15% to 18% between the two surveys. Performance gaps increased four percentage points for three other attributes investigators ranked as most important for study success: being organized and prepared; maintaining open communications; and being responsive to inquiries. Gaps increased two percentage points for sponsors having knowledgeable/well-trained monitors and effectively working with CROs.
Throughout the survey, when comparing importance/excellent gap changes and aggregated sponsor ratings from 2015 to 2017, an approximate two percentage point difference between values is statistically significant.
The analysis suggests that investigators have higher demands for sponsor performance in attributes they consider most important for study success and that sponsors could strengthen their relationships with sites by prioritizing improvements in these areas, which could lead to more efficient clinical trial operations.
“Investigators find it easier to work with companies that have expertise and can make it easier for them to execute the protocol. That is one of their expectations. Companies need to have content knowledge as well as operational knowledge about how to work with investigators,” said Christopher Corsico, M.D., senior vice president, Corporate Division Medicine, and chief medical officer, Boehringer Ingelheim. “You are seeing an increase across the globe in terms of expectations from regulatory authorities about quality, about how investigators engage patients and about how studies are conducted. Investigators want to work with sponsors that will work with them to meet quality standards and that have an excellent track record in terms of demonstrating quality studies.”
Performance gaps also widened in areas related to sponsors’ financial relationships with sites. A total of 57% of investigators rated attributes in the contracts and budget category as “very important,” yet only 43% gave sponsors an “excellent” rating for performance, representing a 14 percentage point gap. This compares to a 10 percentage point gap for the category in 2015. The broadest importance/excellence gaps in 2017 were for being flexible about modifying protocols/budgets and providing overall fair grant payment amounts, which each had 15 percentage point gaps. Two other attributes, offering realistic grant payment schedules and providing prompt grant payments, both had 13 percentage point gaps.
Need for patient-centric study design
Investigators identified patient-centered study design and planning approaches, which can result in more feasible clinical trials and minimize the burden of study participation, as a critical way to improve working relationships between sponsors and investigative sites.
Although there isn’t comparative data, since this was the first year the question was asked, a majority of investigators (59%) said that designing patient-friendly protocols was among the top 15 most important elements of a successful study. Almost two-fifths of respondents (39%) viewed actively involving patients or patient groups into protocol design, which was another new attribute in 2017, as “very important.” Survey results, however, suggested room for improvement for both attributes. Sponsor performance fell 14 percentage points below expectations for designing patient-friendly protocols and the attribute for actively engaging patient groups in protocol design received one of the five lowest scores in the survey (42%).
Many of the top-ranking sponsor companies have begun to solicit patient input into study designs through patient advisory boards or one-on-one interviews and are piloting initiatives designed to make study participation more convenient, including the use of telemedicine and wearable technologies.
Boehringer Ingelheim, which was among the first companies to form internal protocol review processes, consults with patient advocacy groups for insights not only about the burden of their disease and what would be important for them in a new therapeutic, but also for recommendations about potential barriers to participation in a particular study, including inclusion/exclusion criteria, number of visits or types of procedures. For example, before the protocol was finalized for a scleroderma clinical trial, patients consulted about study requirements suggested that only small-bore needles be used to collect blood samples, since the rare disease results in hardening of the skin, and that investigators be required to use pediatric mouthpieces to measure lung function since scleroderma patients can’t open their mouths widely.
“By getting that critical information, we have designed a more patient-friendly protocol, which will make it more likely for the patients to come back and continue through the entire sequence of the study. It helped us avoid mistakes that could have led to protocol amendments,” said Corsico. “That type of proactive dialogue is helping to turn the tide in collaboration and creating a feeling that there is important input that patients can provide.”
At Janssen Research & Development (R&D), a dedicated department called Investigator and Patient Engagement was created a year ago within global clinical development operations to advance both patient and investigator involvement in clinical trials. A process has been implemented across the portfolio to solicit both investigator and patient viewpoints on a regular basis through different methodologies, including focus groups, clinical trial simulations and advisory boards, to inform both clinical and compound development strategies as well as protocol and operational designs.
“If we just designed within the four walls of our sponsor company, we could miss something that is critical. Patients and investigators often see things that we are not seeing. It’s important for us to get their insights early because it saves everybody a lot of headache in the long term,” said Katie Mazuk, head of Investigator and Patient Engagement, Global Clinical Development Operations, Janssen R&D, the pharmaceutical companies of Johnson & Johnson. “We take patient and investigator engagement very seriously and put it into our goals and objectives. It’s not a special project. It’s in everybody’s way of working.”
Sponsors also increasingly look for new ways to improve the study volunteer experience and reduce the burden of participation, which makes it easier for sites to recruit and retain patients in clinical trials.
Novo Nordisk has partnered with a vendor that provides a concierge service that arranges travel plans for clinical trial patients and their caregivers, which reduces logistical burdens and stress for both patients and sites. In another example, GSK has a dedicated innovation group that focuses on making clinical trial participation easier for study volunteers and reducing burdens on sites. Initiatives include implementing electronic informed consent for a majority of GSK clinical trials. GSK also has begun pilot programs testing the use of wearable devices in clinical trials, video technology for remote visits and the ability for patients to have blood samples taken at home or a local laboratory rather than at the study site.
“If we can reduce the burden of cumbersome visits to the site, it’s going to help with protocol compliance and reduces rates of study withdrawal,” said Valérie Reynaert, head of In-Country Clinical Operations for the Americas, GSK.
Sponsor performance since 2013
Sponsor performance has remained on par or showed modest improvements, compared to 2015, on all but four of the individual relationship attributes measured. Overall, sponsors received an average “excellent” rating of 48% across all attributes, which represents a one percentage point increase from 2015, and compares to an average rating of 44% in 2013. Companies that experienced a 5% or more improvement in their performance from 2015 to 2017 included Teva, Otsuka, Novo Nordisk, AbbVie and Pfizer.
While importance/excellence gaps have widened since 2015, sponsor performance overall has steadily improved during the past three surveys in several key areas, including study monitoring support, where “excellent” scores have increased since 2013 for being organized and prepared and being responsive to inquiries. As investigators have consistently ranked having professional, knowledgeable well-trained monitors/contract research associates (CRAs) as the most important area for a successful study and a critical area for improvement, “excellent” scores increased by four percentage points since 2013. Many top-ranking companies have changed monitoring outsourcing practices or strengthened in-house teams in recent years, which can lead to stronger relationships with investigative sites.
GSK, which was among the top-performing sponsors in the past two CenterWatch site surveys, has reduced the number of CROs it uses for study monitoring functions during the past two years for both in-house and fully outsourced studies to promote greater continuity and consistency of CRA staff. For studies conducted in-house, GSK maintains an internal staff of CRAs—many of whom have worked at GSK for more than 10 years—and has reduced the number of outside providers contracted for supplemental monitoring from 50 to one. For fully outsourced studies, the company has reduced the number of CROs that provide monitoring support from 50 to two.
“This has helped us build close relationships where we can truly work together as partners. When one study is over, the CRAs will switch to another GSK study. We feel this has helped us provide better oversight, harmonize the way we work, establish clear escalation pathways and provide a lot more consistency in how trials are executed at the site,” said GSK’s Reynaert. “We consider this a core competency at GSK. The CRAs are our eyes and ears on sites.”
Novo Nordisk, which has maintained strong overall performance across the past four CenterWatch site surveys and ranked among the top three companies this year for being organized and prepared (71%), having easily accessible staff (67%) and maintaining open communication (65%), uses a sourcing model that relies almost entirely on in-house CRAs, along with long-established practices that ask sites for feedback on ways to improve.
At Novo Nordisk, 80% of U.S. sites and 100% of sites in the rest of the world are supported by in-house monitors. Insource staff, who are put through Novo Nordisk’s training program and held to company expectations, are employed in areas where the workload doesn’t justify a full-time employee. Each investigative site is assigned a field CRA for monitoring visits and dedicated in-house staff are available at any time to address protocol questions and other needs. In addition, study coordinators are brought together for panels each year to discuss their perceptions on industry changes or difficulties and site staff are asked to complete anonymous surveys annually to rate both CRAs and other in-house staff on their professionalism, protocol knowledge, timeliness of response and overall satisfaction.
“All of our communications to patients funnel through the investigator or study coordinator,” said Novo Nordisk’s Owen. “We have to have a strong partnership and open communication with those people to ensure not only that they understand why we are doing a study and the way we are doing it, but also so that they can convey that message to patients and the value that patient commitment means to us.”
Other relationship areas that have steadily improved during the past four years include being responsive to inquiries; overall project support attributes that include accessibility of staff and timely drug availability; and maintaining open communication.
Servier ranked among the top three companies this year for the quality of its monitors (76%), being organized and prepared (77%), having staff easily accessible for escalation of issues (71%) and maintaining open communication (72%). Christoph Manz, M.D., director of Worldwide Clinical Operations at Servier, credits an organizational model that invests in a network of local clinical research centers, called International Centers for Therapeutic Research (ICTR), as a key to the company’s ability to maintain strong investigator relationships and ensure a high-level of responsiveness to site concerns.
The ICTR sites are staffed by experienced, in-house clinical operations teams that oversee Servier’s phase I-III studies, including feasibility processes and study execution, and remain the primary point of contact for investigators in the region. Operational processes are standardized across the company and local ICTR teams work in close collaboration with clinical operations and therapeutic areas in the company’s R&D headquarters in France. Yet local teams are in charge of negotiations, ensure investigators understand the protocol and any potential difficulties that may arise, alert sites to potential problems, solicit investigator feedback in feasibility and study design processes and ensure protocols meet local cultural needs. Investigators can contact local ICTR teams both for studies Servier conducts in-house and those outsourced to CROs.
“Local proximity to investigators is an important strength we have,” said Manz. “Since we have low turnover of our people in clinical operations, we are able to build long-term partnerships with investigators. There is open dialogue in the process and we can give feedback to sites quite fast, both during the feasibility process and during the run of the study. Even when we must stop a trial, which can happen for different reasons, we have an open communication with the site to explain the rationale. We can be quite transparent because of our local proximity.”
Janssen R&D engages investigators and their teams on a regular basis through market research, surveys, advisory boards and in-person discussions to understand their experience in working with Janssen on clinical trials and to incorporate that feedback into efforts such as simplifying feasibility and start-up processes. Janssen also uses the feedback to develop both local and global action plans that look at specific areas of improvement based on regional or country needs. Johnson & Johnson maintains 31 local clinical operations offices around the world, where staff work directly with investigational sites in their local countries, run studies and serve as the main point of contact for investigators.
“We want to co-create with them a better clinical trial experience based on what is important to them,” said Janssen R&D’s Mazuk. “We try to understand the needs regionally and locally within the countries and to be flexible enough to adapt for what works for the individual country’s needs. It’s never a one-size-fits-all situation. I think that is a key to our success.”
Many companies have also begun implementing risk-based monitoring programs that could improve working relationships with sites by focusing attention on outliers and potential issues rather than on monitoring every document at the site. In a new question this year, 47% of investigators gave the average sponsors an “excellent” mark for providing an effective risk-based monitoring process.
“Last year, we implemented risk-based assessment and a risk-based approach to monitoring that focuses more specifically on the needs of investigators and patients and more specifically on the core questions and critical aspects of the trial. This may ease a bit of the hard work for investigators, such as reducing logistical burdens and trivial questions,” said Servier’s Manz.
Many companies that received the highest ratings in previous years remained in the top tier as leading companies have gotten better at creating continuity in their R&D practices, both within their companies and through industry-wide collaborations, and the initiatives they have implemented in recent years are beginning to positively affect the quality of their site relationships.
Novo Nordisk has consistently ranked among the top performing companies in CenterWatch global site surveys since 2011. Novo Nordisk and Servier both showed strong performance on the top five most important attributes in the past two surveys. Boehringer Ingelheim was rated highly in the 2013, 2015 and 2017 global surveys. AstraZeneca, GSK and Janssen also received high ratings for direct working relationship quality in both 2015 and 2017.
Corsico attributed Boehringer Ingelheim’s consistently strong performance to harmonizing its processes globally and establishing a strong centralized clinical operations organization that uses a standard set of processes and expectations that everyone participating in clinical research for the company are expected to follow. The company, which ranked among the top-three sponsors this year for having professional and efficient staff, couples its processes with continuous training programs and ensures staff assigned to support investigators understand both operations and the disease area.
“Developing our talent and raising the expectations internally has allowed us to set these new standards and has created consistency in the way we engage,” said Corsico.
Sponsor companies also ascribe stronger overall ratings to cross-industry collaborations, such as the one created by TransCelerate BioPharma to help standardize drug development processes and reduce inefficiencies for both sponsors and investigative sites. TransCelerate’s initiatives include streamlining documentation, avoiding duplicative training and standardizing protocol templates.
“The things that we can do together to make it simpler and easier for people to participate in clinical trials and for sites to implement them is a win for everyone,” said Janssen’s Mazuk.
Although companies have put a premium on improving relationships with sites and have dedicated significant resources to creating new site engagement initiatives, the widening importance/excellent gaps in several key areas raises the question of whether execution at companies supports these activities.
Sponsors need to continue looking for opportunities to address site concerns and incorporate their viewpoints into improving operational processes, particularly as the industry moves toward a patient-centric R&D approach that relies on strong relationships with sites for its success.
“During development of a clinical trial, investigators really are at the heart of what we do. They are our connection to the patient. Therefore, we see that it’s really critical to have a strong relationship with our investigational site,” said GSK’s Reynaert.
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 of Science degree from the Columbia University Graduate School of Journalism. Email firstname.lastname@example.org.
Annick Anderson has been conducting market research since 1998 in both the health care and consumer packaged goods industries. Annick holds a Master’s of Business Administration from the Boston University Graduate School of Management. Email email@example.com.
This article was reprinted from Volume 24, Issue 03, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>