Spain is a strategic and attractive country to conduct phase 1 clinical trials in oncology. In fact, Spain is one of the top 4 countries with more clinical trials run in Europe, along with France, Germany, and Italy.
Many sponsors from all over the world choose Spain to perform their early phase clinical studies due to its many advantages, some of which are the quality of healthcare, the high rates of patient recruitment, and the relatively low costs of executing clinical trials in Spanish hospitals.
Are you a biotech company dedicated to cancer drug development interested in conducting a phase 1 oncology clinical trial in Spain?
In this article, you will be able to understand the different costs involved in performing this kind of study in Spanish sites.
A Phase 1 Cancer Trial Example: A Classic 3+3 Dose Escalation Design with 4 Sites in Spain
We are going to consider the costs of a phase 1 cancer clinical trial example with a 3+3 dose escalation design, conducted in 4 Spanish hospitals.
The proposed clinical trial consists of a study in solid tumors and it is an accurate estimate for any solid tumor type (e.g. sarcomas, ovarian cancer, breast cancer), and even for hematological cancer trials (i.e. leukemia).
Assuming a classic 3+3 dose escalation design with 4 dose levels, we calculated a total sample size of 15 enrolled patients.
In terms of duration, the following timelines are set:
- Start-up: 4 months
- Recruitment: 9 months
- Treatment (per patient): 6 months
- Survival follow-up: 6 months
- Study close-out: 3 months
- Total study time: 28 months
This phase 1 cancer clinical trial example would be conducted in 4 Spanish hospitals, which could be located in Madrid, Barcelona, Valencia, and Málaga.
CRO Costs vs. Pass-through Costs
One of the first useful budget aspects to be understood is the difference between direct Clinical Research Organization (CRO) costs versus pass-through costs.
CRO costs are the services directly provided by the CRO staff managing the study, while pass-through expenses are all those services performed by third parties (e.g. hospital costs, courier services, and drug management vendors).
CROs normally divide their clinical trial quotations in these two main cost sections, and we are also going to do that in this article.
CRO Cost Sections
The quotation described in this article includes the following CRO cost sections:
- Ethics and regulatory affairs
- Site identification and selection
- Site contracting and payments
- Site initiation and activation
- Site management
- Onsite monitoring
- Drug safety management
- Drug logistics support
- Biological sample logistics
- Clinical supplies logistics
- Medical writing
- Site close-out
- Project management
- Study files and document management
- Clinical data management
- Statistical programming
- Quality control
In the following lines, we are going to explain each of these cost items in more detail.
Ethics and Regulatory Affairs
Firstly, in order to conduct a clinical trial in Spain —and in any European country— the trial Sponsor needs to hire an insurance policy. The study CRO can do this on behalf of the Sponsor. Please note that this section includes the effort made by the CRO personnel to obtain the insurance policy from the insurance company, but the actual policy price is included below as a pass-through cost.
The next step is to prepare the site documentation required for the submission of the study application to the ethics committee (EC) and the regulatory authority (RA). In Spain, even regarding multicenter studies, only one central EC is needed, and the Spanish RA is called Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), which charges a fee for initial evaluation (see pass-through costs).
The CRO will help the trial Sponsor in the preparation and submission of the study to the EC and RA, including preparing and sending the responses to the evaluation questions made by these institutions.
During the development of the trial, study amendments may be needed, which are submitted to the EC and RA for approval (i.e. protocol and informed consent form amendments, among others).
In addition, the CRO will provide support for EC and RA reporting (study initiation, annual progress reports, and close-out communications), EC/RA communication for any issues during the study, and the actual development and distribution of the annual progress report by using the AEMPS document template for this purpose.
Ethics and Regulatory Affairs Total Cost: 9,900 €
Site Identification and Selection
Identifying and selecting the right clinical sites to recruit well during the trial is of utmost importance. Without doubt, this is a key element to ensure study success.
Clinical trial sponsors may use different tools to identify and select sites. In any case, they often rely on the existing knowledge and relationships established by local CROs. Oncology-focused CROs, like Sofpromed, already have contacts with sites recruiting cancer patients in other studies; therefore, this existing knowledge is very valuable to save time.
In this budget, we propose CRO support for the preparation and collection of site feasibility questionnaires, in which the clinical sites specify their operational resources and recruitment potential.
Site Identification and Selection Total Cost: 880 €
Site Contracting and Payments
Another important task in which the CRO support becomes essential is that of site contracting and site payment management.
For the trial to be conducted at sites, a trial contract is needed between each site and the Sponsor. In the case of Spain, as in most EU countries, these contracts can be negotiated in English, but many sites will ask that the Spanish version prevail. In the specific case of Spanish hospitals, sites are the ones proposing the contract template (templates cannot be provided by the Sponsor).
Moreover, the Sponsor will have to make payments to the sites for the different hospital-related expenses related to the study (e.g. clinical tests, site fees, etc.). The cost indicated in this section only refers to the CRO work for these tasks, and not the value of the payments themselves.
Site Contracting and Payments Total Cost: 4,070 €
Site Initiation and Activation
After the contracts with sites have been signed, and before patient enrollment begins, a number of site initiation and activation procedures are necessary.
First of all, the CRO staff (normally Clinical Research Associates —CRAs— and Clinical Project Managers) will arrange and conduct initiation visits with the hospital teams. These visits can be either onsite or remote (via teleconference). The goal of these visits is to train site personnel in the procedures of the study and solve any questions or doubts.
Furthermore, once the site initiation visits have been completed, a number of local documents have to be signed (such as the Delegation Log) and the CRO has to provide site personnel with access to the various electronic systems (e.g. EDC and IWRS). After this, the sites can be fully activated and enrollment can start.
Site Initiation and Activation Total Cost: 2,860 €
When patient enrollment begins, the CRAs of the CRO will provide site management support.
CRAs keep daily communication with sites to provide assistance and clarify doubts, responding to all site inquiries, and acting as a recruitment “helpdesk” for site staff. They also review site performance and escalate any infringements to the Sponsor, thus ensuring that the trial is conducted according to the protocol and good clinical practice (GCP) principles. The CRO will also notify sites about any updated documents.
Site Management Total Cost: 27,060 €
Onsite monitoring focuses on the review and verification of source data available at clinical sites. Among other things, one of its goals is to check that the clinical data entered in the trial database (Electronic Data Capture —EDC— system) of the Sponsor matches with the patient data contained in medical records.
Typically, the CRO or the Sponsor will prepare a monitoring plan specifying the frequency of monitoring visits and the specific data to be verified. In oncology phase 1 clinical trials, safety data have to be monitored very closely, so the hospitals will usually be visited at least every 2 months.
Monitoring visits are performed by CRAs and it is an effort that includes scheduling, preparation, traveling, the visit itself, a post-visit report, and follow-up until issues are resolved.
Onsite Monitoring Total Cost: 44,770 €
Drug Safety Management
Drug safety is fundamental in phase 1 clinical trials since the very primary objective of phase 1 studies is to ensure that a drug is safe for patients while determining the best dose to be given in phase 2 trials.
Drug safety management —also known as pharmacovigilance— entails developing a drug safety plan, managing and reporting serious adverse events (SAEs), as well as writing and distributing annual safety reports, among other tasks.
Drug Safety Management Total Cost: 5,720 €
Drug Logistics Support
Drug logistics procedures seek to ensure that the study drug is adequately supplied by the Sponsor, stored at sites, and well documented in the event of audits or inspections.
CROs usually help in developing a drug logistics plan and coordinating drug shipments to sites in communication with the drug depot. This work may include the supervision of drug destructions and returns. The CRO also communicates with hospital pharmacies to verify drug stock availability.
Drug Logistics Support Total Cost: 4,565 €
Biological Sample Logistics
Biological sample management is very important in cancer clinical trials, but even more critical in phase 1 studies that include blood sample collections for pharmacokinetics (PK) analyses.
The study CRO can contribute to the development of biological sample management manuals, and tumor and/or blood sample shipment coordination from hospitals to central laboratories.
Biological Sample Logistics Total Cost: 2,530 €
Clinical Supplies Logistics
In close relation to biological sample management, CROs also help with clinical supply management tasks.
This can involve developing a clinical supply plan, the initial preparation and shipment of clinical supplies to sites (biological sample containers, lab kits, equipment), and the ongoing tracking and resupply of containers, kits, and equipment for sites.
This section does not include the actual cost of the containers, kits, and equipment as such, as this is included in the pass-through costs below.
Clinical Supplies Logistics Total Cost: 2,970 €
CROs help sponsors with the writing of important documents used in clinical trials. Three essential documents are the study protocol, the patient information sheet / informed consent form (PIS/ICF), and the final clinical study report (CSR). The CRO will provide specialized medical writers to produce these documents.
Medical Writing Total Cost: 8,160 €
When the clinical trial is finished, the CRAs appointed by the Sponsor must perform onsite close-out visits, consisting of hospital visits to ensure that all the information and files of the study are in place and adequately completed and signed.
Conducting a close-out visit implies scheduling, preparation, traveling, the visit itself, a post-visit report, and visit follow-up. All the work involved in a close-out visit may require around 21 hours, at a cost of nearly 1,155 € per visit.
Site Close-Out Total Cost: 4,620 €
The role of a Clinical Project Manager is essential for the correct development of a phase 1 oncology trial. The Project Manager is in charge of coordinating and supervising the clinical study, making sure the milestones are completed within the agreed timelines and budget.
Project Managers develop the global project plan, including timelines, milestones, and work structure. They have weekly internal meetings with the CRO team and regular update meetings with the Sponsor.
Additionally, the Clinical Project Manager directs the clinical study from a financial point of view, supervising study costs, while escalating and solving operational issues, and responding to all Sponsor’s inquiries within a reasonable period of time.
Finally, Clinical Project Managers may write and distribute study newsletters, review site initiation, conduct regular monitoring visits, and produce close-out visit reports.
Project Management Total Cost: 69,300 €
Study Files and Document Management
Every clinical trial requires substantial file and document management. Clinical Trial Assistants (CTAs) are the CRO staff in charge of managing documentation.
For example, they prepare the Investigator Site File (ISF) and the Pharmacy Site File (PSF), which will then be shipped to sites. They also maintain the electronic Trial Master File (eTMF) throughout the entire study, and perform a final eTMF reconciliation to ensure document completion and quality at the end of the trial.
Study Files and Document Management Total Cost: 10,560 €
Clinical Data Management
Many CROs have data management capabilities to help trial Sponsors in handling clinical data.
Clinical data management tasks include the development of a Data Management Plan (DMP), a Data Validation Plan (DVP), writing the Electronic Data Capture (EDC) specifications, the development of the EDC completion guidelines, and the implementation of the EDC system, including testing and validation.
In addition, Clinical Data Managers will train site personnel in the EDC, develop customized data status reports, and perform data reviews and cleaning (including queries to sites and follow-up until resolution).
Clinical Data Management Total Cost: 22,500 €
Statistical Programmers play a key role in the handling, processing, and analysis of the clinical trial data.
They take care of the Statistical Analysis Plan (SAP) and, using programming languages like SAS, they produce a series of tables, figures, and listings (TFLs) to show the results of the study.
The work of Statistical Programmers also includes the use of SDTM (Study Data Tabulation Model) and ADaM (Analysis Data Model) standards to prepare, analyze, and submit clinical data according to FDA requirements.
Statistical Programming Total Cost: 66,840 €
The execution of clinical trials requires quality control tasks to ensure that the study is conducted according to the specifications of the protocol and Good Clinical Practice (GCP). Quality Managers will perform protocol deviation review and management, and they will attend Sponsor’s audits and regulatory inspections.
Quality Control Total Cost: 4,920 €
Adding up all the CRO services described above, the total amount for the CRO budget is 292,225 €.
Pass-Through Cost Section
In addition to the direct CRO services, the quotation described in this article includes the following pass-through cost items (products and services provided by third parties):
- Trial insurance policy: 6,000 €
- Shipping of physical files to sites: 120 €
- Shipping of physical contract documents to/from sites: 60 €
- Shipping tumor samples from sites to central laboratories: 225 €
- Shipping of frozen blood samples to central laboratories: 2,400 €
- Blood tubes and shipping packages: 900 €
- Office supplies: 500 €
- Payments of the Sponsor to clinical sites (to cover medical tests): 120,000 € (8,000 € per patient)
- Ethics committee evaluation fee (initial submission): 2,500 €
- Ethics committee evaluation fee (amendments): 2,000 €
- Site contract fees: 6,000 €
- Regulatory authority evaluation fee: 4,400 €
- Onsite routine monitoring visits (travel costs): 6,840 €
- Onsite close-out visits (travel costs): 720 €
- EDC system (license and hosting): 16,800 €
- IRT system for drug management (license and hosting). 9,600 €
- Electronic Trial Master File (eTMF) (license and hosting): 9,600 €
- Pharmacovigilance platform (license and hosting): 7,200 €
- Drug depot for drug labeling, storage, and distribution: 22,500 €
The total sum of pass-through costs is 218,365 €.
Total Budget Summary
The grand total for the CRO quote described in this article, for a phase 1 oncology clinical trial in Spain, is 510,590 €.
Contact Sofpromed to Get a Personalized Quote for Your Oncology Trial
Sofpromed is an oncology-focused CRO specialized in managing phase 1 cancer clinical trials in Europe, and more particularly in Spain.