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The organization of clinical trials for oncology at IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale” Napoli and the impact of the OECI accreditation process

Abstract

The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori “Fondazione G. Pascale” (INT-Pascale) is the largest Clinical Care and Research Cancer Center in Southern Italy. The mission is prevention, diagnosis, and care of cancer and innovative research in oncology. In 2013, INT-Pascale joined the Organisation of European Cancer Institutes (OECI) accreditation and classification project along with other Italian IRCCS cancer centers. One of the major OECI requirements that a cancer center must fulfill in order to achieve and maintain OECI certification is a strong emphasis in translational and clinical research: increasing the number of patients enrolled in clinical trials, establishing easily accessible databases for operators, and informing all possible stakeholders, including patients. A characterizing theme of INT-Pascale is a strong commitment to clinical experimental studies. In the 2007-2014 period, 440 clinical trials were activated at INT-Pascale; in this period, the number of clinical trials and observational studies has had an increment achieving in 2014, respectively, the share of 60 clinical trials and 35 observational studies activated. Optimization of clinical trials management and dissemination of the clinical research culture at INT-Pascale are main objectives to be achieved through several actions and procedures being implemented as a component of the OECI improvement plan. Participation in the OECI program has represented an important challenge to improve quality and processes related to promoting, prioritizing, and monitoring clinical trials at INT-Pascale.

Tumori 2015; 101(Suppl. 1): 33 - 37

Article Type: REVIEW

DOI:10.5301/tj.5000465

Authors

Gianfranco De Feo, Francesca D’Ambrosio, Giada Palmieri, Francesco Perrone, Gennaro Ciliberto

Article History

Disclosures

Financial support: this work was financially supported by the Ministry of Health-Italian Government within the Finalized Research Project Code: RF-2009-1532731. (Coord.: A. Paradiso, F. Belardelli).
Conflicts of interest: the authors declare no conflict of interest.

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Introduction

The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) National Cancer Institute of Naples-Fondazione “Giovanni Pascale” (INT-Pascale) is the largest Clinical Care and Research Cancer Center in southern Italy. The mission is prevention, diagnosis, and care of cancer and innovative research in oncology. The organizational model is based on that of US Comprehensive Cancer Centers in which multidisciplinary teams are dedicated in an integrated manner to tackle all aspects related to the care of cancer patients.

Founded in 1933, INT-Pascale received the first recognition as a research center in 1940. It is composed of 4 distinct buildings: 1) main hospital and surgery (187 beds); 2) day hospital and day surgery (42 day hospital beds); 3) research building; 4) administrative building. In addition, INT-Pascale owns an outstation dedicated to research located in Mercogliano. Currently, INT-Pascale has approximately 760 employees, including 208 medical doctors, 50 biologists, and 350 nurses.

Methods

The OECI model at INT-Pascale

In 2013, INT-Pascale joined the accreditation and classification project of the Organisation of European Cancer Institutes (OECI) with other Italian IRCCS. They activated the OECI startup phase in June 2013 and after the self-assessment phase and peer review visit, held on January 29 and 30, 2015, the OECI Accreditation and Designation Board approved the Improvement Action Plans and sent the certificate in June 2015. The certificate contains the following notification: “Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione ‘G. Pascale’, Napoli, Italy meets the quality standards for cancer care and research and it is therefore designated as a: Clinical Cancer Centre.”

The steps and timing of the project at INT-Pascale are detailed in Figure 1. One-year follow-up of the actions and deadlines set out in the action plan will take place in June 2016.

Steps of the project at INT-Pascale.

Based on the guidelines proposed by OECI, INT-Pascale is working on the implementation of improvement plans (1). In particular, we established an Accreditation and Quality Team (TAQ), a multidisciplinary team that includes different services/facilities. The primary goal of the TAQ is to implement a quality management system based on the integration of rules relating to multiple quality management and safety systems (International Organization for Standardization, international accreditation). In a relatively short time, TAQ, in collaboration with other professionals of the institute, generated several procedure operating standards (POS), including cases of misconduct POS, internal audit management POS, management documentation POS, management discharge patients POS, management planning POS, pain assessment POS, and management liquid biobank POS.

Figure 2 shows the activity flow of the quality management system at INT-Pascale.

Activities flow of the quality management system at INT-Pascale.

Results

An example of a best practice at INT-Pascale: ­implementation of a proper management system of clinical trials

One of the major OECI requirements that a cancer center must fulfill in order to achieve and maintain OECI certification is a strong emphasis on translational and clinical research: increasing the number of patients enrolled in clinical trials, establishing easily accessible databases for operators, and informing all possible stakeholders, including patients. A characterizing theme of INT-Pascale is represented by the strong commitment towards clinical experimental studies.

In the 2007-2014 period, 440 clinical trials were activated at INT-Pascale. As shown in Figure 3, the number of clinical trials (CT) and observational studies (OS) has had an increment achieving in 2014, respectively, the share of 60 clinical trials and 35 observational studies activated

Studies for activation year and type of sponsor. CT = Clinical Trial; OS = Observational studies.

Figure 4 reports the percentage of activated studies divided by type of study (CT and OS) and sponsor (profit and nonprofit). The large number of nonprofit institutional clinical trials is notable.

Activated studies for type of study and type of sponsor. CT = Clinical Trial; OS = Observational Studies.

Of 440 activated studies in the 2007-2014 period, 238 were still active, of which 157 (CT) and 81 (OS) were during 2014. At a later monitoring (December 31, 2014), 167 out of the 238 studies (110 CT and 57 OS) appeared to be still in progress, while 71 (47 CT and 24 SO) were shut down during 2014 and 1 study was suspended. Moreover, in 2014, 5 clinical trials activated before 2007 were found to be still active. Overall, in 2014, 3,100 patients were enrolled, 2,510 (81.0%) in nonprofit studies and 590 (19.0%) in for-profit studies.

Tables I and II show the number of patients enrolled in CT and in OS, respectively, in and out of INT-Pascale in 2014.

Patients enrolled in active clinical trials (n = 157) in 2014

Patients enrolled INT-Pascale Not at INT-Pascale Total
INT coordinator center
 Nonprofit (n = 29) 466 518 984
 Profit (n = 20) 50 - 50
INT participating center
 Nonprofit (n = 37) 117 - 117
 Profit (n = 71) 125 - 125
Total 758 518 1,276

Patients enrolled in active observational studies (n = 81) in 2014

Patients enrolled INT-Pascale Not at INT-Pascale Total
INT coordinator center
 Nonprofit (n = 31) 1,005 7 1,012
 Profit (n = 5) 131 - 131
INT participating center
 Nonprofit (n = 30) 397 - 397
 Profit (n = 15) 284 - 284
Total 1,817 7 1,824

Optimization of clinical trials management and dissemination of the clinical research culture conducted in accordance with good clinical practices at INT-Pascale are 2 objectives achieved through many actions at different levels, which will be described later in more detail:

Clinical Trial Unit

Clinical Trial Internal Committee (CISC)

Web-based centralized technology platform (StudyMon)

Annual Clinical Trials Monitoring Report

Internal audits

Dissemination of information about clinical trials to cancer patients

The Clinical Trial Unit is located within the Department of Research and its mission is to design, conduct, analyze, and finalize multicenter and single-center investigator-initiated clinical trials for the treatment and diagnosis of solid tumors, especially lung, gynecologic, gastrointestinal, and breast ­cancer. To date, 16 clinical trials and 5 translational projects, including molecular analyses on tissue and blood samples collected within 5 closed clinical trials, are ongoing (Pignata et al, JCO, 2011; Gridelli et al, JCO, 2012; Pignata et al, Lancet Oncol, 2014; Morabito et al, ASCO, 2015; Pignata et al, ASCO, 2015).

In detail, the main research projects concern the following:

Development of innovative therapeutic strategies for patients with lung cancer. A trial dedicated to non-small cell lung cancer (NSCLC) patients with EGFR mutated tumor (BEVERLY) was launched in the third quarter of 2015; it will test the efficacy of adding antiangiogenic treatment with bevacizumab to standard treatment with a TKI (erlotinib). The trial will be enriched by serial collection of blood samples for liquid biopsy testing a panel of mutations potentially actionable in second-line treatment of progressive disease, in collaboration with the Cellular Biology and Biotherapy Unit of the institute. In 2 ongoing trials (MILES3 and MILES4) testing the efficacy of adding cisplatin to standard monotherapy in elderly patients, evaluation of the prognostic and predictive value of potential biomarkers is included, such as ERCC1, RRM1, TS, BRCA1, and CCDC6, assessed on baseline tissue samples. Within the already published TORCH trial (Gridelli et al, JCO, 2012), showing that the chemotherapy-erlotinib sequence is better than the opposite one as first-/second-line treatment of NSCLC patients nonselected for EGFR mutations, additional analyses are ongoing for EGFR and RAS genes, as well as PTEN, MET, HER2, and HER3 expression and possible pharmacogenomics predictive factors (Liu et al and Tsao et al, ESMO, 2014). Finally, in a study with SCLC patients (the STAD-1 study, recently closed, which assesses the efficacy of a treatment strategy modulated according to the hematologic toxicity), an evaluation of the prognostic and/or predictive value of the circulating tumor cells assessed with the CellSearch, in collaboration with the Cellular Biology and Biotherapy Unit of the institute, is planned.

Optimization of treatment with biological drugs in ovarian cancer. The MITO 16 project aims to assess the efficacy of bevacizumab as both first-line treatment and beyond progression, which includes the serial collection of tumor tissue and blood samples during the course of the treatment and the disease, with the aim to evaluate the predictive and prognostic value of several biomarkers.

Optimization of treatment with biological drugs in colorectal cancer. The OBELICS study evaluates a first-line bevacizumab-based treatment schedule, optimized according to the mechanism of action of the drug, and the V-shoRT trial, a phase 1-2 study, evaluates the feasibility and activity of a combination of valproic acid with chemoradiotherapy as neoadjuvant treatment of low-risk rectal cancer, including the dynamic study of circulating cytokines and angiogenetic factors, circulating endothelial cells and miRNA, and pharmacogenomic studies, in collaboration with the Experimental Pharmacology Unit of the institute.

Identification of prognostic and/or predictive biomarkers in ovarian cancer. A translational project is ongoing taking advantage of 2 published trials of first-line chemotherapy (MITO2, JCO, 2011, and MITO7, Lancet Oncol, 2014). The project is supported by an AIRC grant, and is exploring or validating the value of several biomarkers, assessed in tumor tissue samples, before treatment and after progression.

Phase 1 clinical trials with new drugs. Currently a phase 1, open label, multicenter study to assess safety, tolerability, pharmacokinetics, and preliminary activity of ascending doses of AZD5363 under adaptable dosing schedules in patients with advanced solid malignancies is ongoing.

The clinical research is overseen by the Scientific Directorate in collaboration with the CISC. The CISC is an Advisory Body of the Scientific Directorate which has as its main objective to harmonize the use of internal resources and expertise to improve the performance of the institute in processes related to clinical trials and observational studies.

In this context, the CISC has the task to assess clinical trials before their submission to the independent ethics committee and to monitor the progress of those approved. Also, among its functions, CISC identifies strategic areas of interest for the institute and promotes initiatives for clinical trials in these areas.

The CISC is composed of the Scientific Director (coordinator), the Medical Director, and the Head of the Clinical Trials Unit.

The CISC meets monthly and CISC meetings are attended by the coordinator of clinical studies monitoring and by the coordinator of the ethics committee secretariat.

Recently, INT-Pascale established a collaboration agreement with an expert biostatistician from a local university in order to warrant on-site statistical support for the design and the analysis of clinical trials sponsored by the institute, supporting researchers in the development of clinical protocols.

Clinical research, from the writing of protocols to regulatory submission, to monitoring and closure of the study, and to evaluation of results, is based on a complex organization of professionals, objectives, and resources. For these reasons, the Scientific Directorate of INT-Pascale created a Web-based technology centralized platform (StudyMon-INT) for the integrated management of various activities related to clinical research in order to harmonize the procedures and to improve system efficiencies.

The StudyMon-INT platform has been designed and realized for the following purposes:

To create a centralized database containing information about all clinical trials and observational studies conducted at the institute, in order to assess the trend of quality and quantity of such studies in the institute;

To create a network between all actors involved in the conduct and management of clinical trials (external promoters, internal researchers, Scientific Directorate, ethics committee);

To support the harmonization and simplification of procedures, improving transparency and efficiency in the process of evaluation and monitoring of studies, through the dematerialization of document processes and standardization of information flows;

To perform descriptive analyses and produce periodic reports on studies conducted at the institute.

The Scientific Directorate publishes an Annual Clinical Trials Monitoring Report, which is shared with all researchers within the institute. Since 2014, the reports have been available on the institute’s Web site (2).

The OECI accreditation program underlined the importance of proper management of clinical research and, especially, the proper management of clinical trials (1). In addition to the above listed activities, the center has recently focused on 2 important aspects:

Research monitoring (1.5.4.1.2. A quality assurance program for clinical research: Qualitative Questionnaire OECI) (1)

Dissemination of information about clinical trials to cancer patients (6.4.1.1.4. The written information includes information about clinical trials: Qualitative Questionnaire OECI) (1)

Based on these aspects, INT-Pascale defined 2 improvement plans. A detailed description is provided in the following.

Research monitoring

In order to monitor the proper management of clinical trials, specific internal audits will be planned and conducted, which will be based on the following criteria:

Proper management of trial master file and/or investigator’s file

Correct data entry in the StudyMon-INT platform

Progress reports

Correct completion of informed consent

Management amendments

Management adverse events

The audit plan is subjected to the evaluation of the CISC and will also be sent to the independent ethics committee and to the various structures involved. At least 30 days before the audit, an e-mail is sent to the interested structure to confirm the dates of the audit and to establish the list of studies.

The audit team will use a checklist in which it will include observations, noncompliance, and corrective actions.

The internal audit team will assess 70% of the CT (75% closed [25% in progress]) and 50% of the OS (75% closed [25% in progress]). Results of the audit will be sent to the CISC and the outcome, observations, any nonconformities, corrective actions, and the general guidelines will be discussed with the principal investigators.

Dissemination of information about clinical trials to cancer patients

Clinical studies active at INT-Pascale are now published on the institutional Web site (2). Since June 2015, the list of active clinical trials at the institute, updated on the StudyMon platform, have been sent to the ICT office for publication on the institutional Web site monthly. Patients have access to lists of trials, broken down by disease, and can contact the Scientific Directorate to receive more ­information about the study or to make contact with the principal investigators.

Discussion

The OECI accreditation model takes into account relevant aspects such as the highly innovative nature and multidisciplinary of oncology institutes, and the improvement of professional and organization quality, and takes into consideration specific aspects such as activities in the field of prevention, screening, research, and treatment of pain, and training, innovation, and dissemination of knowledge (3).

The OECI accreditation program is dynamic, requiring ongoing communication between the OECI and the participating centers, which are called upon to demonstrate continuous quality improvement of care and processes.

The OECI model has been a useful and stimulating process for improving the management of many activities that are already taking place at INT-Pascale; for example, improvement of clinical trials management. A future challenge is to implement the quality management system by standardizing the procedures related to the multidisciplinary teams and clinical pathways. Furthermore, the implementation of an electronic medical record is fundamental.

In conclusion, the institute continues to be actively engaged in an intensive improvement plan towards the goal of receiving accreditation as a Comprehensive Cancer Center.

Acknowledgment

During the OECI process, there was involvement of a large number of people in the activities for improving quality and active participation by the leadership. The Scientific Directorate thanks the personnel for their participation.

Disclosures

Financial support: this work was financially supported by the Ministry of Health-Italian Government within the Finalized Research Project Code: RF-2009-1532731. (Coord.: A. Paradiso, F. Belardelli).
Conflicts of interest: the authors declare no conflict of interest.
References
  • 1. Boomsma F De Valeriola D Van Harten W Hummel H Otter R Saghatchian M Accreditation and designation user manual [Internet]. Brussels: Organisation of European Cancer Institutes, European Economic Interest Grouping; 2011 Available at: http://www.oeci.eu/Documents/OECI_accreditation.pdf. Accessed November 12, 2015. Google Scholar
  • 2. Quinto Rapporto Monitoraggio Studi Clinici INT. Pascale (2015). Available at: http://www.istitutotumori.na.it/RicercaScientifica/StudiClinici.html. Accessed November 27, 2015. Google Scholar
  • 3. Deriu PL La Pietra L Pierotti M et al. Accreditation for excellence of cancer research institutes: recommendations from the Italian Network of Comprehensive Cancer Centers. Tumori 2013 99 6 293e 298e Google Scholar

Authors

Affiliations

  • Scientific Directorate, “Fondazione G. Pascale” National Cancer Institute, Naples - Italy
  • Research Department, “Fondazione G. Pascale” National Cancer Institute, Naples - Italy

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