Oncology clinical trials are complex and sponsors should know in advance the key elements and local procedures that will be required to undertake such large, intricate, and demanding venture.
This knowledge becomes particularly critical if the study is to be conducted in a country with local procedures and singularities that may be unknown to the sponsor.
Thus, this article provides highly valuable practical information regarding the requirements and local processes involved in the preparation and execution of a cancer clinical trial in Spain.
Considering that the sponsor has a drug candidate ready to be tested in cancer patients (i.e. preclinical development and compound manufacturing already in place), conducting a clinical trial involves the following aspects:
1. Clinical trial design
A fundamental initial step in the clinical trial process is the design of the study, which is specified in detail in the trial protocol.
The study protocol is an extensive document (in the 70-120 page range) that includes the trial synopsis, scientific rationale, study objectives, sample size calculation (i.e. how many patients are needed), patient inclusion/exclusion criteria, treatment description, and a calendar of clinical, efficacy, and safety assessments, among several other sections.
The protocol can be considered as the “heart” of the trial, since it contains and in-depth description of the scientific, clinical, and operational aspects of the research to be performed.
Protocol development in oncology is a challenging task since it may require the inputs and reviews of a multidisciplinary team (i.e. medical oncologists, pathologists, radiologists, molecular biologists, biostatisticians, regulatory affairs and clinical project managers).
In Spain, the full trial protocol can be written and used during the study in English language. However, a translation of the trial synopsis into Spanish will be necessary for initial submission to the ethics committee.
2. Document writing: Protocol, Patient Information Sheet (PIS), and Informed Consent Form (ICF)
In addition to the study protocol, a clinical trial involves writing multiple technical documents.
Particular attention deserves the patient information sheet / informed consent form (PIS/ICF), which is a critical document to be signed by all the patients who will participate in the study.
The PIS/ICF explains to the patient (in simple language) what the trial is about, its duration, and which tests/assessments will be performed, among other aspects.
An experienced medical writer plays a crucial role to generate a good PIS/ICF as well as the texts required in the different study documents.
In Spain, the PIS/ICF must be written in Spanish and, depending on the sites taking part in the trial, translations into Catalan and Galician could be requested.
3. Regulatory affairs: Ethics committee, competent authority, and insurance policy
Clinical trials imply managing numerous regulatory aspects from the beginning until the end of the study.
Initially, in Spain, clinical trial applications must be prepared and submitted to an ethics committee (EC) and to the national competent authority (CA) (namely the Agencia Española de Medicamentos y Productos Sanitarios, AEMPS: www.aemps.gob.es), in order to obtain official authorizations from both institutions. These two approvals are essential and mandatory for trial initiation.
Only one central EC evaluation is needed in Spain (just a single EC of reference is required), even in the case of a multicenter trial. The preparation of this application involves the collection of diverse documents, including signatures of local staff belonging to the sites participating in the study.
The AEMPS application is very similar to that required by the EC, but the documentation is not exactly the same.
To obtain a full checklist of the actual documents required for clinical trial applications in Spain (to EC and CA), you can contact Sofpromed’s Regulatory Affairs Department.
The trial applications to the EC and the CA are normally submitted simultaneously by using the same web portal (ecm.aemps.es).
ECs evaluate new applications once or twice per month and the AEMPS reviews applications continuously without specific submission deadlines.
The EC and the CA assess trial applications in a coordinated manner (they communicate with each other internally during the evaluation process) and the sponsor receives a detailed calendar with the key timelines after submitting the applications.
ECs issue their approval certificates, as average, in 60 days after the application submission date, and the AEMPS may authorize the study one or two weeks after the EC approval. These timelines can be longer if the review process requires additional clarification requests.
Spanish EC initial evaluation fees are in the range of 1,500-2,500 € per trial application. The AEMPS evaluation fees depend on the type of study (see Table 1 below).
Fee for the evaluation of a first clinical trial with medicines that are not authorised in a country that belongs to the International Conference on Harmonisation (ICH) with active substances or combinations of active substances that are not authorised in Spain
Fee for the evaluation of: a) A clinical trial with a medicine that is authorised in a country other than Spain that belongs to the International Conference on Harmonisation (ICH). b) Clinical trials with medicines that are not authorised in any country belonging to the International Conference on Harmonisation (ICH), following a first clinical trial included in the category 5.1. c) Clinical trials with the characteristics outlined in 5.1 in the event of resubmission when the outcome of the first application was a withdrawal of the application or was refused. d) Clinical trials with a medicine that is not authorised in a country belonging to the International Conference on Harmonisation (ICH), with active substances that are authorised in Spain.
Fee for the evaluation of: a) Clinical trials with medicines authorised in Spain, irrespective of their specific labelling for the trial. b) Clinical trials whose sponsor is a researcher or group of researchers and in which a Pharmacy Service is responsible for preparing or blinding the medicines under investigation
Table 1: AEMPS clinical trial evaluation fees (source: https://www.aemps.gob.es/en/industria/tasas.do?id=5)
The initial stage of the study also requires the issuance of an insurance policy to cover the liabilities in relation to the clinical trial.
Several vendors provide trial insurance policies in Spain (e.g: HDI Global, Chubb).
Insurance companies normally ask for a summary of the trial and the PIS/ICF to evaluate the risks of the research and offer a policy quote, which depends on the number of patients.
Trial insurance policy costs in Spain usually range between 7,000 and 15,000 € depending on the size of the study.
Once patient recruitment has begun, the management of regulatory aspects continue through the reporting of trial progress and drug safety data (the EC and the CA require annual reports).
Regulatory processes involve specialized knowledge so sponsors must count on the support of regulatory experts capable of performing these tasks and comply with local legislation.
4. Site selection and activation
One of the main keys to clinical trial success is the selection of adequate hospitals that can ensure patient enrollment in terms of quantity and quality.
Oncology trials recruit patients affected by cancer, who are normally diagnosed and treated in large hospitals or cancer centers providing specialized care.
The selection of the most suitable sites requires local verification of hospital facilities, staff capabilities, and patient recruitment potential so that site qualification visits and feasibility reports become essential.
These suitability confirmation tasks are typically performed by clinical research associates (CRAs) and project managers (PM) hired by the sponsor.
Site selection can be quite difficult when a clinical trial needs to enroll patients with extremely rare tumors. In these situations, and especially when the sponsor plans to open a study overseas, collaborating with national cancer research groups can be very helpful, as these groups are specialized in investigating specific tumor types, have the local knowledge and can quickly provide the top recruiting hospitals in the country.
In Spain, there are various well organized cooperative research groups (networks of doctors and hospitals) focused on rare cancers. These groups collaborate with pharma and biotech companies to conduct multicenter trials with higher speed and efficiency.
Sofpromed CRO has close relationships with Spanish cancer research groups to help sponsors in this regard.
Once site selection is completed (and the regulatory approvals have been obtained) hospitals must be activated for recruitment and this involves the negotiation and signature of a contract with each hospital, as well as a site initiation visit to explain the trial objectives and procedures to the local research team (this visit involves the presence of the principal investigators -medical oncologists-, study coordinators, nurses, and pharmacists, among other personnel).
Each site contract negotiation involves a hospital fee in the range of 1,000-2,000 € per agreement.
5. Site management
Following administrative authorizations and site activations, clinical sites can start enrolling patients into the study.
In oncology, patients are recruited through hospitals visits and interviews with their oncologists, in which they are invited to take part in the trial.
During the recruitment period of a clinical trial, the sponsor must provide enrollment support to sites.
Constant communication must be kept between the sponsor (through its Clinical Research Associates and Project Managers) and the local research team (principal investigators and study coordinators working in the hospital), in order to solve clinical/technical doubts, supervise overall site activity and ensure quality in procedures and reporting tasks.
The recruitment period is the most intensive stage of a cancer trial, since patients receive the experimental treatment during this time, and the sponsor must ensure adequate onsite and remote monitoring visits.
When cancer patients finish their trial treatments, they continue to be monitored for follow-up to obtain survival data. Therefore, as general rule, patients remain in the study until death or until they withdraw consent or get lost to follow-up.
6. Data management: Electronic case report form (eCRF)
Managing clinical data is a crucial part of a clinical trial and data management tasks begin in a very early stage.
Along with the writing of the trial protocol, the scientific leaders of the study get involved in the specification of the case report form (CRF), which contains the data forms and fields that will be used to collect the clinical information.
Nowadays, most CRFs are web-based tools that facilitate online data entry by study coordinators located at clinical sites. These digital systems are known as electronic case report forms (eCRFs) and have several advantages over paper-based CRFs. The term EDC (electronic data capture) is also used to refer to eCRFs.
CRFs used in cancer trials include specific forms to collect tumor-related data (i.e. tumor assessments by RECIST/Choi). Other forms collect information about physical exams, medical history, ECOG status, concomitant medications, adverse events, hematology, biochemistry, coagulation tests, vital signs, pregnancy tests, ECG, quality of life, and biological samples, among other parameters.
In addition to the clinical knowledge of the scientific leaders (typically medical oncologists), building an eCRF requires specialized services in software design, programming, testing, validation, and training. There are many eCRF vendors in the market. Sofpromed recommends Omnicomm’s TrialMaster EDC Suite.
After sites start entering data in the CRF, data managers associated to the sponsor initiate data cleaning tasks, which consist of reviewing the CRFs and issuing queries to sites in order to correct erroneous data and solve inconsistencies. The aim of this labor is to attain precise and consistent data to assure reliable results.
Once datasets are cleaned, they are analyzed by the scientific leaders (in collaboration with statisticians) in order to obtain the final results and conclusions, which will then be published in the form of abstracts, posters, and/or scientific articles.
Oncology trial results are communicated in congresses like ASCO (American Society of Clinical Oncology) and ESMO (European Society for Medical Oncology).
7. Monitoring: Source data verification (SDV)
Clinical monitoring constitutes a major set of activities in a clinical trial, being an important part of the total study budget.
Monitoring tasks are performed by clinical research associates (CRAs), also known as “monitors”, linked to the sponsor, and one of their goals is to conduct onsite and remote visits to review data (i.e. hospital documents, test reports, etc.).
The verification process of clinical data contained in hospital documents (compared to the information entered in the CRF) is known as source data verification (SDV).
Clinical trials must be monitored with enough frequency to ascertain the following:
- Drug storage conditions and sufficiency of drug supply for the trial.
- Compliance with the approved protocol and all approved amendments, if any.
- That the investigator receives all documents and all trial supplies needed to conduct the trial properly and to comply with the applicable regulations.
- That the investigator and trial staff is adequately informed about the trial.
- Integrity and accuracy of data (source data verification as per monitoring plan): Informed consent (version, signature and date), eligibility criteria, baseline tests, adverse event collection, SAE reporting, biological sample collection and storage, and drug stock reconciliation in pharmacy.
- eCRF completion.
- Reporting of protocol deviations according to good clinical practice (GCP) and the applicable regulatory local requirements. Taking appropriate action to prevent recurrence of the detected deviations.
The CRO appointed to the study must review the eCRFs for compliance with the protocol, and for inconsistent or missing data.
Should any missing data or data anomalies be found, queries must be sent to the relevant center for resolution. Any systematic inconsistencies identified may trigger monitoring visits to sites.
Following the required reviews, the eCRF data items are exported into the clinical study database for analysis.
The frequency of monitoring visits depend on the characteristics of the study, the amount of data to be verified, and the number of participating sites.
A detailed monitoring plan must be written to describe monitoring staff, goals, and procedures.
8. Pharmacovigilance: SAE, SUSAR, and DSUR
The supervision of patient safety and the analysis of experimental drug toxicities are of utmost importance in oncology clinical trials and particularly in phase I studies (in which safety is a main endpoint).
The sponsor must have pharmacovigilance experts assigned to oversee adverse events caused by study drugs and report this safety data according to national legislations.
A development safety update report (DSUR) must be elaborated and sent to authorities and sites annually.
The drug safety supervision work also includes the review of biochemistry, hematology, and other laboratory test values to detect and classify abnormalities.
Serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) are critical and require strict assessments, follow-up and expedited reporting by qualified personnel.
9. Material, sample, and drug logistics
Clinical trial processes require a set of logistics services related to trial materials, biological sample management, and drug distribution.
At the beginning of the study, a set of materials (trial files, blood tubes, biological sample packages) must be prepared and shipped to each clinical site for use during the trial.
During patient recruitment and treatment, oncology trials frequently involve the collection of tumor and blood samples, which are sent to central laboratories for diagnosis confirmation and translational experiments performed by molecular biologists.
In addition, distribution processes are required to ship the study drugs to the hospital pharmacies. Some sponsors have the capability to prepare and ship the drugs from their own facilities, while others may subcontract a drug distribution company to receive, label, store and ship the drugs to local pharmacies.
Clinical trial logistics must be defined and organized in an early stage so that the supply chain is ready when enrollment starts.
10. Project management
As we have seen, clinical trials are composed of many related parts and involve multiple processes and services that must be well coordinated and managed.
Clinical project managers guarantee that trials are well organized and executed on time and within the approved budget, working on planning, supervision, quality control and financial management tasks.
Cancer clinical trials are challenging projects involving a substantial number of highly specialized tasks, including trial design, document writing, regulatory affairs, site selection and activation, site management, data management, monitoring, pharmacovigilance, logistics, and project management.
These activities require qualified professionals in diverse scientific and technical areas that are commonly out of the scope of the trial sponsor’s main business.
This fact justifies and recommends the use of knowledgeable contract research organizations (CROs) focused on providing these services as a single vendor, guaranteeing thus the operational development of the study and the success of the venture.