The impact of the new European CTR on academic clinical research: A survey by the Italian Sarcoma Group Federated Trial Centre

Introduction

The Clinical Trials Directive 2001/20/EC (CTD), implemented in 2001, marked an initial attempt to standardize the conduct of clinical trials (CTs) across European Union (EU) Member States (MSs). However, due to its decentralized nature, each MS adopted varying submission methods and timelines, ¹ resulting in increased costs, delays in study initiation, ² and an increase in administrative burden. ³

To improve this situation, the EU adopted the Clinical Trials Regulation (CTR) EU No. 536/2014. ⁴ The CTR introduces innovative elements: centralised submission and faster assessment of CTs, improved information sharing and decision making between and within EU member states, stringent safety standards and transparency in CT information. ⁵ CTR implementation attempted to overcome country-specific requirements and push clinical research into a new global perspective transition. ⁶ The CTR core is the Clinical Trials Information System (CTIS), a single-entry portal, for sponsors and companies, facilitating trial submissions and evaluations across EU and European Economic Area (EEA) countries. Moreover, CTIS has a public open-access website for healthcare professionals and the general public. As of 31 January 2023, all new Clinical Trial Applications (CTAs) must be submitted via CTIS, with full transition required by 31 January 2025. ⁷

In Italy, the implementation of the CTR required regulatory steps, culminating in the “Lorenzin Law” of 11 January 2018 ⁸ and subsequent six implementing decrees regulating various aspects of clinical trials^9-14 These changes required significant procedural adjustments at the site level, ¹⁵ posing challenges for academic research institutions, which often lack robust management support ¹⁶ and limited financial resources. ¹⁷ Additionally, Italian research staff consist of legislatively unrecognized professional roles that lead to a high personnel turnover. ¹⁸

The Italian Sarcoma Group (ISG), the non-profit Italian scientific society for research in sarcomas, has introduced the Federated Trial Centre (FTC) model to strengthen clinical research capabilities across sarcoma treatment centres. The FTC, implemented in 2023 based on a census of clinical research professionals, primarily Clinical Research Coordinators (CRCs) but also other professional figure involved in clinical research, aims to foster collaboration among the ISG’s network sites. This initiative addresses, among others, the evolving challenges posed by the implementation of CTR.

During the 2023 ISG Annual Meeting, FTC participants discussed facilities compliance and clinical research staff awareness of the changes brought by the CTR. A survey was conducted to assess CRC involvement in local feasibility processes and evaluate CTR implementation among ISG sites, with results and conclusions presented in this manuscript.

Methods

In April 2023, a freely accessible web survey was sent by email to 48 participants from 27 sites belonging to the ISG FTC. Each centre could have more than one participant representing their department or professional role (up to a maximum of five respondents per site). The link for filling out the questionnaire remained active for 15 days. All data were anonymous and participation was strictly voluntary. Each survey took about 10 minutes.

A semi-structured questionnaire was pilot tested by a representative group of participants (three CRCs, two project managers and two clinicians) coming from five different institutes, in order to verify the clarity of the questions and refine them.

Survey was designed with 33 closed-ended questions including nine with binary answers (yes/no) and 24 with a-single-choice-option list questions. The questionnaire also included seven Likert scale questions with open scale responses from 1 to 10, aiming to have participants rate their own knowledge or their facility's compliance, for a total of 40 questions. Questions were divided in five sections. The first part (10 questions) dealt with the current internal organization of the site. The second part (8 questions), aimed at evaluating the suitability of facilities involved in conducting clinical trials. The third part (10 questions), focused on new clinical trial submission management. The fourth section (nine questions) concerned the experience with CTIS portal use. The final part (three questions) pertained to future perspectives for academic research. Answers to questions were not set as mandatory. A copy of the survey is included in Online Supplementary Appendix 1.

All responses were analysed using descriptive statistical methods by calculating the frequency of each option. For Likert scale answers, the mode and median were also calculated, and the frequency of each response option was categorized as “insufficient” for responses equal to or less than 5, and sufficient for responses equal to or greater than 6. To evaluate the responses, a cross-tabulation analysis was used, allowing for a detailed examination of the relationships between different variables. Given the descriptive nature of the surveys, sample size was not formally estimated.

Results

The survey was sent to 48 participants of the ISG - FTC. Responses were received from 30/48 (62.5%) participants. Main characteristics of the respondents are described in Table 1.

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Table 1.

Institution type, feasibility process and training (sample: 30 respondents).

		Overall
		N	%
Type of institution
	Scientific Institute for Research, Hospitalization and Health Care	18	60,0
	University Hospitals	9	30,0
	Public Hospitals	3	10,0
Involvement of CRCs in feasibility process
	CRC directly involved	23	77,0
	CRC involved as supervisor	5	16,6
	Other	2	6,4
Training Modality
	Arranged independently	15	50,0
	Organized by Institution	8	26,6
	Suggested by Institution	5	16,6
	Training not received	2	6,8

CRC= Clinical Research Coordinator.

Most of the involved research staff taking part in the survey (n=18/30, 60.0%) came from IRCCS (Scientific Institutes for Research, Hospitalisation and Health Care), followed by University Hospitals (n=9/30, 30.0%) and Public Hospitals (n=3/30, 10.0%). They participated in study feasibility processes within their center in 77.0% of cases (23/30). Additionally, 16.6% (5/30) were tasked with supervising these activities, while 6.4% (2/30) selected 'other' without further specification.

In terms of training on European-and-Italian-regulations novelties, 50.0% (n=15/30) of participants found autonomously how to expand their knowledge. Institutions organized specific programs in only 26.6% of cases (n=8/30) and recommended participation in other courses in 16.6% of cases (n=5/30).

Regarding the innovations introduced by the CTR, 70.0% (n=21/30) of responders rated their level of knowledge ⩾ 6, overall indicating a satisfactory understanding with an average score of 6.5 (mode=7); 30.0% (n=21/30) of responders considered their knowledge insufficient. Regarding the Italian decrees, participants were split: 50.0% of CRCs (n=15/30) found their knowledge of national regulations insufficient, while the other 50.0% (n=15/30) considered it sufficient, with an average score of 5.5 (mode=5) (Figure 1).

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Figure 1.

Self-assessment of knowledge related to CTR innovation and Italian decrees innovation (sample: 30 respondents).

Table 2 shows respondents’ knowledge of CTR innovations regarding the new curriculum vitae (CV) template and declaration of interest (DOI), site suitability form, documents, transparency rules, and feasibility of process modification in the Institution. Most of the responders (93.3%; n=28/30) were aware that the investigator’s CV and the DOI statement must be drafted according to the templates provided by regulatory authorities and submitted to the sponsor, as part of the CTA. The CTR innovation, which involves the introduction of a list of documents and information to be provided for the CTA, was assimilated by 73.3% (n=22/30, with 26.6% not providing a response). Additionally, 60% (n=18/30, with 16.6% not providing a response) of participants were familiar with the new rules regarding personal data and commercially confidential information in response to the publicly accessible EU database.

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Table 2.

Respondents’ knowledge of CTR innovations regarding new CV template and DOI, site suitability form, documents, transparency rules, and feasibility process modification in the Institution.

Overall sample (N.30)	Are you aware that CVs and DOI will be prepared using new mandatory templates, and submitted as part be part of CTA?	Are you aware that the documents (e.g., protocol, letter of intent) will be prepared according to specific rules set by CTR?	Are you aware that many documents will need to be submitted in “redacted” and “not-redacted”' form to be also accessible for general public?	Are you aware that a site suitability form, signed by the site’s legal representative or delegate, will be part of CTA?	Have the procedures for managing local feasibility activities already been updated at your institution?
	N (%)	N (%)	N (%)	N (%)	N (%)
Yes	28 (93.3)	22 (73.3)	18 (60.0)	23 (76.6)	14 (46.6)
No	2 (6.6)	3 (10.0)	7 (23.4)	7 (23.3)	10 (33.3)
Not answered	0 (0)	5 (16.6)	5 (16.6)	0 (0)	6 (20.1)*

*

The answer was ‘not known’.

At the time when the survey was circulated, 76.6% (n=23/30) of participants had already been involved in studies submitted under the new regulations and had experience dealing with the site suitability form.

Time required to obtain the signature on site suitability form of clinical trial sites was less than 15 days for 87.0% (n=26/30), with only two cases taking between 15 and 28 days and two others more than 28 days (Figure 2A). Although 46.6% (n=14/30) of participants reported that their facilities had implemented changes for managing the CT start-up phase (Table 2), the average confidence in their institution’s ability to meet contractual agreement signing deadlines was 4.6 (mode=5; 63.3% of respondents gave a score ⩽5) (Figure 2B).

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Figure 2.

A. Time to obtain the site suitability form signed. B. Participants’ rating their site’s ability to provide a contractual agreement within the timeline (sample: 30 respondents).

Moreover, 60.0% (n=18/30, with 16.6% non-respondents) confirmed their research staff were already trained in CTIS use. In 13.4% (n=4/30) of cases, training was planned shortly, while in 10.0% (n=3/30), it was incomplete or unscheduled. By April 2023, 36.6% (n=11/30) had already submitted trials through CTIS (Table 3).

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Table 3.

CTIS training and experience.

		Overall
		N	%
Has anyone at your site received specific training to use the CTIS?
	Yes	18	60,0
	It is planned	4	13,4
	No	3	10,0
	Not Answered	5	16,6
Has your site already submitted any studies as a sponsor through the CTIS?
	Yes	11	36,6
	No	10	33,3
	Unknown	5	16,6
	Not Answered	4	13,5

Lastly, 16/30 (53.3%) answered that the new regulations do not support academic clinical research. Instead, 14/30 (46.7%) believed that the CTR will facilitate non-profit research (Figure 3).

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Figure 3.

Impact of new regulations in academic clinical research: a participant perspective (sample: 30 respondent).

Discussion

Our survey was conducted a few months after the full activation of CTR, and provides insights into the landscape of clinical academic research in Italy. Despite considerable strides in aligning with European standards and meeting CTR requirements within centres, obstacles persist, especially in handling bureaucratic hurdles and ensuring sufficient support for staff.

In more detail, almost a half (46.6%) of the respondents reported that their institutions had implemented internal procedures to meet the new required standards, confirming that progresses had been made to adhere to the new regulations, compared to what detected by the 2015 investigation by Cagnazzo et al. ¹⁶ within the Data Manager’s Italian Group (GIDM) institutions. With 93.3% of ISG-FTC-associated clinical research coordinators reporting that they had already dealt with the new documentation, we found that standardized procedures and documentation for the initiation of clinical trials, available on the AIFA and EMA website, have been already embraced by the clinical research community. The survey indicated that sites had found a solution for the processing of the site suitability form, a document signed by the institution as part of the CTA that attests to the suitability of the facilities, equipment, and personnel involved in a specific clinical trial. Based on our results, 86.6% of respondents were able to provide the sponsor with the statement within 15 days, potentially enabling the sponsor to promptly submit the CTA and reduce bureaucratic delays. The biggest challenge still lay on the contract negotiation process. Time for negotiation and finalization of the contract can range between 60 to 106 days. ⁴ Additionally, the decree of 27 January 2023, sets a seven-day deadline for both parties to sign the contract following AIFA approval. ¹¹ Despite this, many CRCs reported that meeting these deadlines was still challenging, with 63.3% of respondents rating their institution's ability to comply as insufficient.

The survey once again highlighted the importance of training research site staff with 60.0% reporting that personnel at their site had received specialized training for the use of the CTIS and 36.6% having already submitted a study through the new portal shortly after its full implementation.

Moreover, the survey suggested that, despite the effort made by the institutions to adapt internal procedures in compliance with this new scenario, there was not enough emphasis on providing adequate support and guidance to the data managers and study coordinators. A significant number of interviewees stated that they had acquired their knowledge about CTR and its innovations autonomously (50%). In contrast, only a minority (26.6%) had benefited from internal courses and a proper guidance within their institutions. These findings align with the previously published results. ¹⁶

Notably, opinions on the new regulations varied: 46.7% felt the CTR would streamline submissions and expedite trial approvals for non-profit research, while 53.3% believed it posed significant challenges for academic research.

Our findings reflect the circumstances and challenges faced by Italian sites only and at that particular moment in time. Therefore, the situation may have evolved since the data were collected. A new survey is planned in two years from the implementation of the CTR to provide a longer follow up.

CTR has effectively blurred the distinction between for-profit and non-profit sponsors. The high-quality standards needed for conducting studies have significantly increased and non-profit sponsors now need to allocate greater resources to meet higher demands.

Surely, academic research covers a key-role in addressing clinically relevant questions or diseases that can be of limited interest for pharmaceutical companies but are of major interest for patients and would otherwise remain unsolved, such as for instance, optimising the use of an already approved drug or developing a therapy in rare cancers, such as sarcomas. Unfortunately, the budget for conducting this type of research is often limited. It is still unclear whether these changes will strengthen enthusiasm or will lead to negative consequences for non-profit research. For the aforementioned reasons, it is necessary to raise greater awareness among trial sites and to find new approaches and strategies to make the submission and conduct of non-profit clinical studies more efficient, helping to overcome one of the major obstacles in non-profit research: financial sustainability.

To overcome at least some of these issues and barriers, the ISG, a society aimed at fostering academic non-for-profit clinical research, has decided to adopt an organizational model similar to that of the FTC to provide support on non-commercial research under the new CTR. This includes facilitating dialogue and sharing experience among study coordinators from different sites within and outside Italy and enhancing the role and the definition of the professional profile, as well as the specific training, of the study coordinator and research nurse. Initiatives like specialist meetings and collaborative projects aim to improve the quality and effectiveness of academic research, particularly in the sarcoma research field. FTC can raise awareness within the sarcoma research community, including clinicians and institutional staff.

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