Jaana Hynynen

Participating in clinical trials offers opportunities for doctors to learn more about novel medications and how to use drugs after launch. Investigators and investigative sites are important in the drug development process because they may have input into study design, have access to trial participants, and are a critical source for clinical practice experiences.

Though there is an increase in the use of contract research organizations (CROs) by sponsors, surveys and research that examine the relationship between the sponsor and CRO find that there is a lack of research on relationships between investigators and CROs. Turnover rate among investigators conducting clinical trials is significant. Worldwide, in 2006, 35%-55% of the investigators stopped doing clinical studies after conducting one trial. These high turnover rates have increased the discussion and interest about investigators’ experiences in clinical trials.

	We designed a study to increase knowledge about cooperation between investigators and CROs. The aim of the study was to describe how investigators in Finland are experiencing cooperation with CROs, with the objective of finding out answers to following research questions:

		What kind of positive experiences investigators have in cooperation with CROs?

		What kind of negative experiences investigators have in cooperation with CROs?

	The results of the study will help CROs to identify development needs and improve procedures related to cooperation and clinical trials.

	In order to study investigators’ experiences in cooperation with CROs, in-depth, face-to-face interviews were conducted with six experienced investigators in Finland. In order to get experiences from investigators with expertise and knowledge in research, the investigators selected for the study were to have experience in collaboration with CROs, and had at least five years experience as an investigator. The six participants were selected among the authors’ contacts, colleague references, and investigators recommendations. Prior to the interviews, investigators signed their consent.

	All six interviewees were specialist physicians representing five different therapeutic areas. One interviewee was a female and five were males. Interviews were conducted in five different towns in Finland. Five interviews were conducted in private clinics and one in a public hospital. Four out of six investigators had experience in clinical trials in both private and public healthcare sectors, and two had experience only in private clinics. Working experience in clinical trials varied from eight to 35 years, and all interviewees had worked as principal investigators in clinical trials operated by CROs.

	In the interviews, investigators were requested to talk freely, openly, and honestly about what kind of positive and negative experiences they had in cooperation with CROs. During the interviews, specifying questions were made by the interviewer.

	This study used a qualitative approach by transcribing interviews and analyzing that data using conventional inductive content analysis. After several readings, the meaning units, which were answers to questions, were collected from the interviews and reduced to include only the material relevant to this study. Condensed meanings (n = 304) were clustered into themes. Condensed meanings in theme clusters were classified to subcategories according to research questions. Subcategories (n = 44) were clustered into categories (n = 9). Finally, three themes were abstracted from categories to describe research subject:

		Positive experiences related to cooperation with clinical research associate (CRA).

		Negative experiences related to cooperation with CRA.

		Experiences related to CRO's position and operational environment.

Positive experiences related to cooperation with CRA

	Cooperation with the CRAs was understandably the most discussed topic during the interviews. CRAs are the main contacts between investigators and sponsors, and they may be the only sponsor representatives having face-to-face contact with site personnel. There were 88 condensed meanings describing positive experiences related to cooperation with CRAs. The number of condensed meanings reported per investigator varied from 10 to 21. Condensed meanings were clustered to three categories: CRA is working together with site personnel; CRA is qualified; and CRA is working in a business-like manner.

	All the interviewed investigators had the most positive experiences in cooperation with CRAs who were helpful, assisted site personnel and resolved issues. The investigators wanted to see clinical trials as a cooperative effort where CRAs and site personnel share goals, plan, and execute trials together. Good collaboration motivated the investigators to do their best in patient recruitment and data generation. It also motivated the investigators to participate in future trials with that CRO. The investigators experienced that CRAs were available for communication, and the contacts with CRAs were generally satisfying. In the situations where CRAs were changed, information from the previous CRA was transferred to the new CRA-at least in situations where the change had been planned and the CRAs had the possibility to work together before the trial handover.

	The investigators were appreciative of CRAs’ competence in clinical trial management, and working with an experienced CRA made cooperation easier and motivated investigators for better performance. They felt that experience helped avoid misunderstandings and false interpretations of source data. To achieve proper competence, the investigators believe a CRA should be “inside” a pharmaceutical company. This insider position would enable a CRA to have more information about the therapeutic area and the molecule being studied.

	In the interviews, four out of six investigators expressed their satisfaction toward monitoring visits. The investigators felt that a decrease in the amount of on-site visits was not affecting cooperation, because they were familiar with trial processes and CRAs were available for technologically mediated communication. Even though personal characteristics have an influence on cooperation and willingness to cooperate, investigators appreciated that duties and tasks were performed in a business-like manner and that work was done properly.

Negative experiences related to cooperation with CRA

	Even though the attitudes of investigators towards CRAs were largely appreciative and positive, interviewees also shared negative experiences related to CRAs. There were 82 condensed meanings describing negative experiences. The number of condensed meanings in this theme varied from three to 36 per investigator. Experiences were clustered in two categories: CRA’s working method was not satisfactory, and site left alone with increased workload.

	The investigators were disappointed and frustrated in situations where a CRA was not committed to resolve trial-related problems. There were differences between CRAs in the level of engagement and commitment. Investigators experienced that CRO monitors were not committed and did not have time or motivation to resolve issues as much as a sponsor’s own monitors. CRAs did not take responsibility and ownership of the trials they were involved in. The investigators had experienced unfulfilled promises when a CRA had left tasks uncompleted or refused to complete tasks. Investigators reported a lack of service attitude and lack of interest. Some of the monitors did not understand unintended mistakes made by site personnel, and provided only negative feedback to a trial site. When reminding investigators about uncompleted tasks, CRAs’ commanding and dictating communication style had a negative influence on investigators’ motivation.

	Five out of six interviewed investigators had noticed that the workload of site personnel has increased. They did not necessarily feel the trend as deterioration, but thought it was unfair if in the budget negotiation phase of a trial that they were not aware of all the duties and tasks they were responsible for. The tasks transferred from CRAs to sites included printing documents, ordering supplies, shipping materials, and resolving technical problems with helpdesks. Investigators felt that they were left alone with increasing usage of technical devices and lack of local help. Resolving technical problems took time and increased technologically mediated communication and pressure in cooperation with CRAs. Lack of local guidance was also experienced with other new tasks. The investigators felt that they needed to learn by trial and error and were concerned about inadequate trial data due to lack of guidance.

Experiences related to CRO's position and operational environment

	The third theme abstracted from the data was experiences related to the CRO’s position between investigators and sponsors as well as the operational environment in general. There were 132 condensed meanings in this theme, the variation being between six and 49 per investigator. They were clustered in four categories: CRO is using site to get profit; CRO-sponsor contract causes difficulties; CRO’s working method is not satisfactory; and operational environment influences on cooperation.

	Four out of six interviewed investigators experienced that the CROs were not treating them as equal or cooperative partners. They felt the CROs were using sites as resources that provided materials that the CROs then sold to sponsors for profit and income. The investigators understood the willingness to make profit but felt it was done at the expense of the trial site. The investigators indicated that maximizing profit made financial agreement negotiations more complicated, and it was difficult to get compensation for working hours spent on trial preparations and for extra work needed during the trial.

	The contract between a sponsor and a CRO had an affect on cooperation between the CRO and the investigator. All investigators felt that it was complicated to discuss or negotiate the issues for which the CRO had no authority. Unclear duty delegation between the CRO and the sponsor also complicated cooperation. The investigators were frustrated when they needed to convey and clarify the same information to both collaborators. Uncertainty also caused delays in making final decisions and increased bureaucracy. The contract between the sponsor and the CRO also affected CRAs’ work. Due to the contract, the CRAs were not able to visit site and were only doing tasks they were paid for by the sponsor.

	Based on experiences of the investigators, there are differences in working methods and in the quality of monitoring activities between CROs. The investigators reported that insufficient and inflexible processes and lack of local knowledge prevented usage of meaningful and site-specific solutions, which caused extra work. For example, they cited numerous emails that made it difficult for investigators to prioritize relevant and important messages. If a site had a negative experience with a CRO, it affected its willingness to work with the organization in the future. In general, the turnover rate of CRAs was quite high and some investigators thought that was due to poor working climate and lack of team spirit inside the CRO. However, some of the trials run by CROs had interesting study designs or molecules under development, which were deemed more important for investigator than the negative experiences.

	A CRO is representing a sponsor, and the sponsor´s working methods and guidance had an influence on CRO operations. Strategic decisions made by the sponsor also had an impact. The investigators noticed that outsourced trials, which were strategically unimportant, may influence a sponsor’s motivation to invest in the trial. At the site level, this is seen in poor technical solutions, incomplete process planning, and in uncertainty in carrying on the project as planned. Increasing challenges and changes are also occurring in the daily practice of doctors in hospitals and clinics.

	Even though the results of this study increase knowledge about cooperation between investigators and CROs, there are some limitations. Results are based on experiences of very experienced investigators, and, thus, generalization to all investigators is not appropriate. Some of the trends in the clinical trial field, such as a decreased number of on-site visits or face-to-face trainings, did not cause problems for the experienced investigators, but might do so for inexperienced investigators. During the interviews, investigators were asked to share their experiences in cooperation with CROs at any point of their career. All experiences reported in the results may not describe the present situation.

	The interviews comprised a very small number of investigators conducting clinical trials in Finland. Although there are differences between nations, clinical trials are global, so the results might be relevant and reflect the experiences in wider scale. 

Investigators’ experiences in cooperation with CRAs and CROs

	All interviewed investigators reported both positive and negative experiences. Negative experiences were expressed spontaneously, but the interviewer needed specifically to ask for positive experiences as well. Even though negative experiences were first recalled by most of the interviewees, it was in investigators’ interest to develop cooperation toward a more positive direction.

	The interviews revealed that the investigators appreciated and valued cooperation with CRAs who had time to resolve issues, were available, and viewed the trial as teamwork. The investigators described positive cooperation experiences when CRAs visited sites more frequently in the beginning of the project and site personnel were able to familiarize themselves with trial procedures. Thus it was confirmed that they all were conducting procedures correctly. A similar approach was previously suggested by Cascade et al, in reducing burdensomeness of clinical trials among investigators.

	Even though it is ICH-GCP requirement for the trial monitor to be familiar with the investigational product and trial protocol, investigators experienced that some CRAs were lacking in knowledge of clinical trial project management, medical aspects of the trial, or not willing to share their knowledge and focusing only on their own tasks. The same thing was also pointed out in the study of Azoulay et al.

 Task orientation may arise from the sponsor-CRO contract. If the CRAs are trained and appointed to complete only certain tasks but not involved in and implemented to the whole trial process, it is difficult for the CRAs to see their personal influence on the project.

	The investigators reported that mutual understanding was gained by sharing expectations and goals and by understanding the challenges of each collaborator. It was more important for investigators to have tasks handled properly and in a business-like manner than to have a close, friend-like relationship with the trial monitor. Attitude and cooperation skills of CRAs influenced the motivation of the investigator to conduct clinical trials. According to this study, qualification of CRAs seemed to be one factor influencing investigators’ interest in participating in clinical trials in the future.

	Business orientations of sponsor organizations and CROs are different. For the sponsors, clinical trials are cost items, and profit is only gained from the investigational drug if it reaches the market. CROs are getting their income from clinical trials. The investigators experienced that this difference in orientation led to situations where a CRO was using trial sites as a resource for generating profit, and were ignoring investigators’ needs, interests, and opinions. For pharmaceutical companies, investigators can be valuable, long-time partners, as the cooperation still continues after a drug is on the market. It should be remembered that for sponsor companies, a CRO is representing them at clinical trial sites, and both positive and negative cooperation may have an affect on associations for the sponsors.

	Results of this study showed that difficulties in sponsor-CRO relationships reflected on CRO- investigator relationships. Contractual stipulations limit a CRO’s and CRA’s work and complicate communication, especially if duty delegation is not clearly stated. Difficulties may decrease when sponsors are contracting CROs as strategic partners and are able to build up committed and long-term relationships. In this strategy, CRAs are able to boost their knowledge in the sponsor company’s operations, and, thus, are better able to engage the sponsor, benefit from closer teamwork with sponsor representatives, and utilize knowledge from the sponsor’s prior experiences and projects.

	Five out of six investigators were concerned and annoyed about the enormous amount of email communication that hindered their ability to focus on the relevant information and to notice important messages. Based on the results of this study, improving email etiquette is an essential aspect of cooperation and reliable clinical trial data. In the initiation phase of the trial, discussion about proper email procedures tailored for the site could improve cooperation and ensure acknowledgement of important and relevant messages at the clinical trial site.

	The investigators indicated that feedback was not collected regularly; this finding supported previous research findings.

 This prevents development of processes based on lessons learned during previous projects. Investigators reported failures in internal and interorganizational communication flow in and between CROs and sponsors. There is a great number of simple, easy-to-use feedback collection tools available, and implementation of these tools should be taken into consideration in clinical trial operations.

	The purpose of this study was to increase knowledge and understanding concerning cooperation between investigators and CROs. The objective was to find out what kind of positive and negative experiences investigators have in cooperation with CROs. The results showed that investigators appreciated and valued cooperation with qualified and committed CRAs. It was evident they wanted a clinical trial project to be a cooperative effort, where everyone has their own roles and responsibilities, but work is done in mutual understanding.

	The results of this study supported the concept that fostering more strategic-oriented partnerships improves sponsor-CRO relationships. To improve cooperation with investigators, CROs should treat investigators as equal partners, rather than just a resource that can be utilized for a CRO’s own needs. Regular feedback collection might help in building up more streamlined and flexible processes. Proper processes save money and can provide a competitive advantage for companies involved in the high-cost and long-lasting drug development processes. 

Jaana Hynynen is a Senior Clinical Research Associate, PRA Health Sciences*, email: 

 Eija Metsälä, PhD, with Metropolia University of Applied Science, Helsinki, Finland

 To whom all correspondence should be addressed

	1. Smeds M, and Getz KA. “Unfulfilled Translation Opportunities in Industry Sponsored Clinical Trials.” 

	2. Cascade E, Sears C, and Nixon M. “Key Strategies in Sustaining the Investigator Pool.” 

http://www.appliedclinicaltrialsonline.com/key-strategies-sustaining-investigator-pool

	3. Azoulay P, Repenning NP, and Zuckerman EW. “Nasty, Brutish and Short: Embeddedness Failure in the Pharmaceutical Industry.” 

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While several studies and surveys have examined the relationship between sponsors and CROs, there has been little analysis of CRO-investigative site relationships. This study uncovers useful learnings on the positive and negative experiences of investigators in their direct dealings with CROs.

Jaana Hynynen

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Investigators’ Experiences in Cooperation with CROs in Clinical Trials in Finland