Study Site Issues
There are several issues that a study site must address such as:
- Identification of trials
- Clinical Trial Agreement
- Clinical Trial Budget
- Subject Recruitment
- Site Marketing
Subject Recruitment: It has been reported that around 80% of clinical investigators fail to reach the anticipated recruitment rate and 30% do not recruit a single subject in industry-sponsored clinical trials. Those figures have not improved over the past two decades. Patient recruitment is the single most important issue that continuously fails in clinical trials.
Recommend documents and readings for study staff:
Study sites that have well-written, comprehensive and practical clinical research SOPs have a distinct advantage over those that do not. Well-written SOPs are the most efficient way to train new staff and to ensure that they continue to work autonomously. You can download a full set (n=55) of site SOPs developed in collaboration with an international group of clinical trial professionals from this page.
The industry evaluates a study site in terms of standard metrics in order to understand whether a site would be suitable to conduct the trial in question, by means of a feasibility study. This so-called feasibility study could be conducted by means of a standard questionnaire and/or by making a site visit. Based on the outcome of a feasibility study, a site may or may not be offered a role to participate in a trial.
A site feasibility study usually includes questions within six different domains, namely: (1) site clinical aspects, (2) site demographics and experience, (3) quality assurance, (4) subject recruitment and retention, (5) site infrastructure, and (6) research ethics. In the following text we will briefly describe with examples each of the six site feasibility study domains.
Site clinical aspects: Evaluation of the site’s standard care and patient population, and the investigator’s acceptance of study therapies and his/her familiarity of any trial-induced investigation.
Site demographics and experience: Evaluation of site’s type of clinical practice, experience in clinical trials, and availability of support staff, i.e. study coordinators, pharmacists and nurses.
Quality assurance: Evaluation of the site’s quality assurance program, such as written standard operating procedures, staff induction and continuing educational activities, previous sponsor or independent site audits.
Subject recruitment and retention: Evaluation of recruitment potential, presence of competitive studies, and prior experience in conducting similar studies. The industry sees this evaluation as the most important part of the feasibility study. However, the evaluation is difficult to conduct since all information is collected from the investigator who may not disclose the correct information, for instance, overestimating the number of potential trial subjects and over emphasizing the past experiences in conducting similar studies.
Research ethics: Evaluation of the operation of the local ethics committee, such as ethics committee guidelines, application requirements and overall process, including the timeline of ethics clearance.
Site infrastructure: Evaluation of administrative support (budget and contract), drug and biological sample storage, processing of biological samples, and the presence of expertise to conduct such activities. Evaluation of whether the site has capabilities to use electronic data capture and the familiarity with such tools.
A Clinical Trial Agreement (CTA) is a legally binding agreement that defines the relationship between the sponsor of the trial and the clinical investigator/institution conducting the trial. The CTA is important since it delineates the allocation of risk, responsibility, funds, obligations, and the protection of academic, legal, intellectual property and integrity.
However, any departure from a CTA seldom leads to legal actions from one of the two parties. The CTA should be seen as a fee-for-service contract whereby the clinical investigator is paid for the extra time that he/she performs as inducted by the study.
An industry-sponsored clinical trial agreement is usually a two-party agreement between the investigative site/institution and the trial sponsor. It can also be a three-party agreement that involves a clinical research organization (CRO).
There have been many efforts to develop a master or model CTA aimed to be suitable for all sponsors and investigators worldwide, but those initiatives have so far not been successful. The main reason for this is that each company has its own legal framework and each site must adjust the CTA to the requirements of its own jurisdiction.
It is advisable that a study site works with someone who has experiences in developing and negotiating a CTA. This person could be employed by an academic institution, be an experienced person at the study site, or an external consultant. However, it is not advisable to involve a legally qualified professional without previous experiences in executing CTAs; this will just delay the process and make the CTA too detailed to be acceptable by the sponsor.
Signing a CTA proposed by the sponsor without a full review of the agreement is also not advisable. Any contractual terms that are not reasonable or acceptable should be negotiated prior to accepting the terms of a CTA. It is quite common that the sponsor states that many other sites have already signed the sponsor’s CTA and that a negotiation process will not be fruitful and only delay the initiation of the study at the site. Please take your time to review the agreement and involve a person that is experienced in reviewing CTAs. It is, after, all a legally binding agreement between two parties.
Liabilities and Indemnity
This is a special note about liabilities and indemnity in clinical trials. A clinical trial aims to test a new medicinal product not yet accepted for use in everyday clinical practice. For this reason, the sponsor needs to take up the full responsibility for any adverse event related to the test product. Adverse events that occur as a result of a clinical trial cannot be covered by the clinics/hospital insurance related to normal clinical practice.
The sponsor must buy a clinical trial insurance, and a copy of the valid insurance should be given to the site. Many ethics committees will not review a clinical trial without a valid copy of the clinical trial assurance. The sponsor will often accept this arrangement and will provide a copy.
The common CTA headings are listed below; the headings given in bold are of specific interest and importance for the study site:
- Investigator and trial site team members
- Clinical trial governance
- Obligations of the parties and the investigator
- Liabilities and indemnity
- Confidentiality, data protection and freedom of information
- Intellectual property
- Financial arrangements
- Early termination
- Relationship between the parties
- Agreement and modification
- Force majeure
- Rights of third parties
- Dispute resolution
Budget Development and Negotiation
In deciding whether to conduct a clinical trial, three questions should be asked: (1) Does the protocol provide scientific value? (2) Can subjects be recruited? (3) Does the budget support the work to be performed? If your response is “No” to each of these questions – then decline trial participation.
Trial budget estimation: Request a draft budget and the full protocol from the sponsor as soon as you are approached to conduct the trial. You need the full final protocol in order to make an accurate budget estimation. You can roughly estimate the budget while waiting for the sponsor’s budget, but you need to have access to the final protocol. Always compare the amount provided by the sponsor with your own budget. The sponsor’s budget is usually as a flat rate per patient enrolled, such as US$8,000 per patient including indirect costs.
Itemize the costs: The per hour cost for study site staff, clinical examinations, laboratory test etc. varies between institutions and countries. The same is true for the administrative cost and the cost for the ethics committee review, and the start-up cost for the research pharmacy and clinical laboratory. However, the indirect fee on the direct cost should be the same across all sites regardless of the location. The first rule to remember is that a clinical trial budget should cover all trial-induced costs – both direct and hidden costs. The investigator should define the standard of care items in the study protocol against research-related items.
Budget cost sections
Fixed study site costs or start-up costs: These costs should be paid before the study begins. They are independent of the number of subjects recruited and are non-refundable.
Administrative cost: This includes both start-up costs and annual administrative costs for the development and negotiation of the trial agreement and budget; the initial ethics committee review fee and continuing review fee; and protocol amendment review fees; set-up costs and annual cost for the reach pharmacy; and set-up costs and annual cost for the clinical laboratory.
Costs related to subject visits: The investigator should identify all direct and hidden cost items that are induced by the trial at each subject study visit. Since each site visit commonly is different from other site visits, the cost of each visit should be defined. The sponsor is subsequently billed for each unique completed site visit according to the pre-defined cost for each study visit.
Indirect costs: Indirect costs or overhead is the cost that the study site/institution covers to maintain the building, the site space, electricity, cleaning, equipment, etc. An indirect fee of 25% is commonly adopted on all direct cost as listed above. An indirect fee above 25% is often subject to objections by the sponsor.
Specific budget considerations: Persons who are experienced in estimating clinical trial budgets are well aware of the cost items that less experienced persons may overlook. A few examples to illustrate this point: increased salaries and operating cost over time, unscheduled visits, site audits by the sponsor, data query resolutions and storage of research records. Another topic that is becoming increasingly important to determine is the site’s responsibility for electronic data capture of the study data and the sites’ involvement in the so-called risk-based monitoring.
Costs not included: Subject referral costs are not permitted for inclusion in the budget for another doctor who refers a subject to the study site and the trial. However, other doctors are allowed to refer potential subjects without a referral fee. A site should not be awarded a bonus payment for fulfilling a certain subject recruitment number. Doing so could increase the pressure on the subjects to participate and also increase the risk for violation of the inclusion/exclusion criteria.
Trial budget tips/considerations: Please note that if you have forgotten to include an item in the budget, the sponsor is not obliged to pay for this item. If a protocol amendment changes the work load or adds new clinical procedures, then the clinical trial budget should be re-negotiated. If the sponsor allows more patients to be enrolled in a study, the site should be prepared to make more payments for potential screening failures. When preparing your trial budget, you’ve asked for more money than you need, so you can reduce costs and satisfy the sponsor during the negotiation. You can consider increasing the cost of some items to be able to reduce the cost of other items during the budget negotiation. The sponsor should also allow other items to be invoiced, e.g. costs relating to advertising, travelling, and equipment, etc. For multi-year trials, consider adding an inflation rate of 2-3% per study year to the per-completed-subject cost.
Budget negotiation tips: When negotiation the trial budget use the words, “Our costs of participating in the trial” to be clear that you will not take part in the trial if the costs are not fully covered. Your internal trial budget will likely differ from sponsor offer. Do not allow any internal budget topics to be shared with the sponsor. Your internal costs may limit negotiation of future projects, since sponsors retain a database of previously negotiated budgets. Finally, do not be afraid to re-open the budget negotiation before the clinical trial agreement has been signed or at the protocol amendment stage.
Ideal payment schedule: The ideal payment schedule includes (1) non-refundable start-up payment; (2) regular payments with realistic milestones, and (3) final payments made at the sponsor’s close-out visit.
Payment tracking tips: Be clear about when and how the payment will be made, i.e. the billing calendar. The terms should be included in the clinical trial agreement. Many times the study site receives a payment late, meaning the site has to cover the trial cost before receiving the payment from the sponsor. A good practice is to request periodic payment reports from the sponsor to ensure that all information submitted by the site was received and that the payment has been directed to your site. Note that many sponsors miss payments to the study site. Some sponsors rely on the investigator or the study site to invoice all the visits, which means the sponsor will not have the responsibility for any outstanding payment.