In this article you can read a comprehensive explanation of a cost breakdown for a first-in-human (FIH) phase 1 clinical trial with drugs in healthy volunteers, to be run in Europe (Spain will be used as an example).
- $Ethics & Regulatory
- $Site Contracting & Payments
- $Site Selection
- $Site Initiation & Activation
- $Site Management
- $Drug Logistics
- $Clinical Supplies Logistics
- $Files & Document Management
- $Medical Writing
- $Quality Control
- $Data Management
- $Statistical Programming
- $Pass-Through Costs
- $Grand Total & Conclusion
FIH phase 1 trials are very important to test the safety, tolerability, and pharmacokinetics (PK) of a new drug under development. Europe is a quite interesting territory to conduct such studies with an affordable budget.
We hope this information will be useful for biotech companies that are planning the funding and resources needed in their drug development programs.
You can view here the full budget grid that will be discussed, including each of the cost items:
Our clinical trial has the following specifications: one single site in Spain (phase 1 unit located in Madrid), total recruitment of 40 healthy subjects, 4 months for start-up, 2 months of recruitment, 1 month of treatment per subject, 1 month of follow-up for the last subject enrolled, and 1 month for study close-out.
Then, the total duration of the project is 9 months.
Before examining in depth each of the cost elements, I would like to give an overview of the general structure of our quote.
We are going to split our budget into two general parts. This is how CROs usually structure their quotations.
First, we have the direct CRO services and, secondly, the pass-through costs, which include any expenditures derived from third party vendors (these are services not directly provided by the CRO).
In this budget example, the direct CRO services are broken down into the following blocks: Ethics and regulatory, site contracting and payments, site selection, site initiation and activation, site management, monitoring, close-out, safety, drug logistics, clinical supplies logistics, files and document management, medical writing, project management, quality control, administration, data management, and finally statistical programming.
Ethics & Regulatory
So, let’s begin with cost section number 1, “Ethics and Regulatory”.
This item includes the gathering and preparation of site documents needed for initial ethics and regulatory submissions, the issuance of the initial insurance policy, the ethics committee initial application submission, and the regulatory authority initial application submission.
Moreover, the CRO can take care of ethics and regulatory reporting (including the communication of study initiation, first subject enrolled, the annual progress report, the annual safety report, and the close-out). These same communications must be sent to the clinical sites as well.
Finally, the CRO can also write and review the annual progress report (which is required by the regulatory authority and the ethics committee).
The total amount for this first cost section is 12,150 euros.
Site Contracting & Payments
Secondly, we have “Site Contracting and Payments”.
This section has to do with the negotiation and execution of site contracts (including budgets) and the payment of start-up fees required by clinical sites.
Site payments are also needed during the course of the trial to pay the visit costs.
The contract between the site and the sponsor stipulates the technical, financial, and legal conditions for the execution of the clinical trial.
Then, this section 2 adds up to 1,335 euros.
Number 3 (“Site Selection”).
Site feasibility is a very important task to determine whether the clinical sites will be able to recruit the expected number of subjects. The feasibility assessment also examines the capabilities of a clinical site (e.g., personnel, facilities, equipment).
Then, the preparation of a feasibility questionnaire shall be needed, which will be sent to the participating hospitals, and then returned to the CRO for review and discussion with the sponsor (to select the most suitable sites).
We will also need to perform site qualification visits (SQVs) that may be either onsite or remote. In this case we would conduct one onsite SQV.
Thus, the site selection block will have a cost of 2,160 euros.
Site Initiation & Activation
Once the site has been qualified, we will proceed with “Site Initiation and Activation” (section 4).
In this quote we propose one onsite site initiation visit (SIV). Onsite SIVs are highly recommended but remote SIVs have become an option too, particularly after the COVID-19 pandemic period.
After the SIV has been completed, the site must be activated by signing some documents and having the Electronic Data Capture (EDC) system access enabled.
Site initiation and activation total is 1,440 euros.
After trial recruitment has started, CROs provide site management services (this is our section number 5).
Site management involves communication with hospital personnel to provide support and solve doubts, reviewing site performance, and escalating infringements. This task seeks to ensure that the study is carried out according to good clinical practice (GCP).
Site management is typically quoted by proposing a certain number of hours per site per month (during the recruitment and treatment periods, and then during the follow-up stage). Sites with higher recruitment will require more attention.
Site management total for this study is 22,400 euros.
Section number 6 (“Monitoring”).
Firstly, before onsite monitoring begins, the Clinical Research Associates (CRAs, also called monitors) have to review the study documents and get familiar with the trial systems and procedures.
Then, during the execution of the clinical trial, they will perform onsite monitoring visits, which include time dedicated to preparation, traveling, the visit itself, the report and visit follow-up.
In this clinical study a total of 9 onsite monitoring visits are proposed for one site (phase 1 unit). In a FIH trial close monitoring is important because several patients will be enrolled in a short period of time.
The CRAs will also work on remote reviews of EDC data and query management. They will ensure (in collaboration with the CRO’s data management team) that the collected data is complete and consistent.
In our study, monitoring costs add up to 31,760 euros.
Once the trial is over, the clinical site needs to be closed. The close-out visit (COV) seeks to ensure that all the documents at the site are complete and ready to be archived.
Signatures of the research team will also be needed to certify the end of the study.
Then, we have budgeted one COV to be performed by the CRA for a total of 1,840 euros.
CROs can also take care of drug safety management, depending on their internal capabilities. Some CROs have full pharmacovigilance teams providing specialized safety services, while others may just handle essential safety reporting tasks.
This “Safety” section includes the initial configuration and setup of the safety software, serious adverse event and SUSAR management, and also the writing and review of the annual safety report (also known as DSUR).
The total for safety services is 11,520 euros.
Section 9 is “Drug Logistics”.
In a clinical trial the sponsor or CRO may subcontract a drug depot, which will receive, label, store, and distribute the study drug. Having this depot near the clinical sites is recommended to save costs and ensure quick drug delivery.
In this example the CRO gives support for depot contracting, shipping the drug from the manufacturer to the depot, and then coordinating drug shipments from the depot to the pharmacy of the clinical site.
Drug logistics total is 1,900 euros.
Clinical Supplies Logistics
In phase 1 first-in-human clinical trials there is a necessity to collect and ship blood samples for pharmacokinetics (PK) and/or pharmacodynamics (PD) studies.
CROs can help with the clinical supplies’ logistics, which includes the purchasing of kit components (tubes, bags, etc.) and the preparation of lab kits (including their shipment to sites).
The CRO will send these kits to the sites, so that the site staff can use them to collect the blood samples, which are usually processed and stored frozen at the site, until they are sent to a central laboratory for analysis.
The CRO personnel will also track the availability of clinical supplies at the hospital, resupplying them if needed.
Clinical supplies logistics total: 2,475 euros.
Files & Document Management
Section 11 (“Files and Document Management”).
Clinical trials generate a large number of documents, which are stored in a Trial Master File (or TMF). The CRO personnel will work on TMF setup, maintenance, and reconciliation. They have to guarantee that all the required documents are correctly kept.
The study sites will also require an investigator site file (ISF) containing the key study documents. At least in Europe, ISFs have been traditionally handled as physical, paper folders. However, this is changing as electronic ISFs come into play.
Additional documents will be managed by the CRO team as needed.
The total amount for files and document management is 5,775 euros.
With respect to “Medical Writing”, clinical trial sponsors may need more or less support depending on their own internal resources. Some sponsors might have internal staff capable of producing many of the study documents.
The following medical writing services may be outsourced to the CRO:
- Protocol writing
- Protocol synopsis translation (into local language)
- Informed consent form writing
- Study publications (abstract, poster, and scientific manuscript)
- Final clinical study report (CSR)
Medical writing total: 28,080 euros.
Section 13 (“Project Management”).
Clinical project managers organize and oversee all the tasks and processes of a clinical trial. They ensure that key milestones are achieved within the expected timelines and budget.
The CRO quote will include the project manager trainings (initial and subsequent), the development of study plans and manuals, internal and sponsor meeting costs, and study management work (such as financial management, vendor management, escalation and resolution of study issues and deviations, and constant communication with the sponsor).
Furthermore, project managers revise SIV, monitoring, and close-out visit reports, and they will organize and participate in kick-off meetings.
Project management is one of the highest cost items in a trial budget, 80,875 euros in this example.
Section 14 is “Quality Control”.
In this instance, the study budget includes the support of a quality manager to handle protocol deviations and to help with sponsor audits and potential regulatory inspections at the sites or at the CRO facilities.
Quality control total: 7,200 euros.
A clinical trial requires administrative support to manage travel logistics and invoice control. The CRO administrative department, in collaboration with the project managers, will help tracking the various expenses generated during the study.
Then, an administrative person is proposed with a budget of 1,100 euros.
Many CROs have data management capabilities, to manage the collection, cleaning, and reporting of clinical trial data.
These are the main elements required in clinical data management: the development of a data management plan and a data validation plan, the writing of the EDC specifications, the creation of the EDC completion guideline, the implementation of the EDC forms (including automatic queries and edit checks), the EDC testing and validation, EDC trainings for sites, EDC modifications during the study (if needed), data cleaning (through manual queries), EDC system technical support, and medical coding.
Data management total for this phase 1 FIH trial is 49,490 euros.
Lastly, another key CRO service is statistical programming.
In this quotation we are including the development of the statistical analysis plan (SAP), the SAS programming work (to produce tables, figures, and listings), SDTM tasks (annotated CRF, mapping specifications, programming, data transfers, data validation, the study data review guide, and the Define.xml), and the same set of items for the ADaM standard.
A total of 71,820 euros has been quoted for statistical programming.
Therefore, the global amount for the direct CRO services is 333,320 euros.
But we are not finished yet. The second general part in a clinical trial quotation involves the pass-through costs (PTCs).
These are services and resources provided by third-party vendors. The study CRO will normally subcontract these services and then these expenses will be invoiced by the CRO to the sponsor (or the sponsor may be directly invoiced by the vendor).
So, let’s look at the typical PTCs required in a phase 1 trial with healthy volunteers:
- The shipment of physical files to sites
- The costs of electronic signature systems (for contracts and other documents)
- The shipment of frozen blood samples to central labs (for PK or PD studies)
- Blood tubes and shipping packages
- Office supplies and communication costs
- The phase 1 unit costs, which involve the medical procedures and visit costs (3,000 euros per subject), the site contract management fees, and the site pharmacy setup costs
- Compensations to healthy volunteers (700 euros per subject)
- The trial insurance policy (16,000 euros for 40 subjects)
- Ethics committee evaluation fees (2,500 euros for initial submission and then 500 euros for each amendment)
- Regulatory authority evaluation fee (4,500 euros) in the case of Spain
- Traveling costs for onsite qualification, initiation, monitoring, and close-out visits
- Drug distribution services (this is the central depot) (25,000 euros)
- The central lab for PK and PD analysis (40,000 euros)
- And finally, the license and hosting fees for the EDC system, the electronic TMF, and the drug safety platform
In summary, the pass-through costs for this study are 265,995 euros.
Grand Total & Conclusion
Let’s finish with the global cost summary: the grand total is 599,315 euros (this is the sum of the CRO services and the PTCs).
I hope this article has been useful for biotech companies planning a phase 1, first-in-human study in Europe with healthy volunteers.
We should note that conducting clinical trials in Europe is generally cheaper than doing them in the United States. This can be an advantage if funding is a factor.