Perfecting the Clinical Trial Agreement Template: An In-Depth Guide

Clinical trial agreements explained

A clinical trial agreement (CTA) is a legally binding contract that governs the relationship of a sponsor and a clinical trial site or sites. CTAs serve multiple purposes. In general, they facilitate cooperation and communication between parties and help manage the complex issues that arise in clinical research, such as intellectual property, confidentiality, liability and publications. Specifically, CTAs govern various issues including the scope of the work to be performed by the sites, their rights to reimbursement for the work performed, how much sponsors will pay the sites , what happens to the study data at the end of the study, insurance and indemnification obligations, and how long sites must keep study materials following the study.
In addition to sponsors and sites, the key stakeholders in the creation and management of CTAs include the principal investigators, the institutions and/or companies that sponsor clinical trials, institutional review boards, ethics review committees, regulatory authorities and independent contractors providing specialized services, such as data safety monitoring services or independent monitors.

Essential Components of a Clinical Trial Agreement Template

For the clinical trial itself to be successful, the clinical trial agreement must allude to the information necessary to complete the trial in a pivotal manner. The template for the clinical trial agreement, therefore, has to include the following components: timelines, responsibilities, sponsorship, financial agreements, confidentiality obligations and additional terms that detail each party’s expectations. It is imperative that this scope of information be expressly stated in the agreement to avoid a misunderstanding of the parties’ respective obligations under the agreement.
The template must contain a "Project Schedule" fluently estimating each party’s anticipated timeframes for completing their designated tasks. This section of the template is the perfect opportunity to regulate the future course of the trial, as well as control the schedule of the Clinical Research Associate ("CRA") and all of its designated Clinical Research Coordinators ("CRCs"). Inclusion of this section will provide the opportunity for the trial to be brought to a close in an orderly fashion with deliberate closure of the study lead-in and summary meetings. The CRA and the CRC have thousands of trials in which they partake—prioritizing them will ensure that the trial is brought to an orderly conclusion prior to the end of the term of the study.
The template must also include a provision addressing who will sponsor the trial—typically, this section will read that there is no financial compensation from the sponsor towards the site unless the parties come to a direct financial agreement. Parties, however, should ensure that they specify who pays for any reasonable expenses of the CRCs/CACs, such as travel to the site, lodging, etc. A reasonable rate per hour will also need to be established—though this number will vary by market, the range will often lie between $50-$80. Also, if the CRCs/CACs will receive bonuses or non-cash rewards for their work, the parties will need to address that as well, as there is an industry standard of providing bonuses when CRCs exceed site enrollment targets. Finally, if the CRA is a clinical service organization rather than an individual, the CRAs hourly rate must also be included.

Creating a clinical trial agreement template

A well-drafted clinical trial agreement template is a fundamental aspect of medical research that includes all of the assurances listed in the introduction as well as many others. The process for drafting a clinical trial agreement template is very simplified because it was already drafted to consider these issues and did not omit any important assurances. However, the drafting of a template involves many other considerations to arrive at a product that is acceptable to many institutional review boards ("IRBs"), sponsors, and other potential users of the template. There is no universally accepted template model. These groups differ in their particular policies and procedures. This is partially based upon the risk involved in the research proposed and the adequacy of the brochures, consent forms and other supporting documents provided. Unfortunately, the brochures, consent forms, and other supporting documents required to be distributed in accordance with the FDA, ICH GCP, and state regulations are not uniform to the extent that each institutional IRB would accept another institution’s templates of this type without modification.
The deviation from normal in any of these documents will likely result in deviations, which can complicate the process of negotiating a clinical trial agreement template to resolve the differences between the template and the clinical trial agreement to be used by the sponsor. In addition, the frequently imperfect match, between IRB templates, and the form of IRB approval issued by one institution, and the sponsor’s IRB approval template can result in some confusion and negotiation. Some IRBs do not have a standardized approval form. This can be very difficult for a sponsor when it is attempting to finalize a clinical trial agreement template. When this occurs, it can be difficult or impossible to determine if the language in a clinical trial agreement template is adequate to meet IRB approval requirements. In these situations, the writer must refer to the sponsoring organization’s IRB guidelines and guidance. The writer may have to contact the institution with a call or email for additional information about the clinical trial agreement template approval. If there is any doubt, the writer will need to insist that the clinical trial agreement template not be used until the institution clears the modifications made to the clinical trial agreement template.
Most institutions require that all clinical trial agreements be reviewed and approved on behalf of the institution by a legal advisor familiar with the clinical trial regulations and university and teaching hospital structure. In fact, some institutions will insist on the approval of their general counsel before they will approve the clinical trial agreement template for use. For this reason, at least one of the person’s drafting a clinical trial agreement template should be a lawyer familiar with IRB and clinical trial agreement template issues involving these types of institutions and the regulations controlling their actions.
The provisions of FDA 21 C.F.R., Part 50, ICH GCP Guidelines, and other applicable regulatory requirements should be incorporated into clinical trial agreements signed by investigators, research subjects, and institutional sites.

Template pitfalls and how to avoid them

The number one pitfall I see in the creation of clinical trial agreements is poorly constructed language. Let’s face it, these documents have very specific uses and a set terminology. A poorly written CTA often reads like a corporate NDA. I have seen projects that were delayed or that resulted in wrongful termination and consequently litigation, because the CTA had poorly constructed language creating an ambiguity in the terms of the study. When you are drafting the language for your CTAs, be sure that you haven’t omitted completely new terms that should be defined and included. Be sure to include a list of defined terms at the end of the document, so there is no ambiguity as to what that means.
Most of the time, ambiguity in the contract will be resolved by the intent of the parties as it can be inferred from their actions. When there is ambiguity in a CTA, it is a good idea to go back to the protocol and see whether the intent can be inferred from the underlying protocol or the parties’ actions. (for example, was there implied consent based on the manner of conduct).
Another common pitfall I see is generic Language. Oftentimes companies will use a standard CTA template, basically a copy and paste document, without review or redacting of template provisions and terms which have been incorporated but are inapplicable either to the type of study that’s being undertaken or to the jurisdiction where the trial is being done. One is also left to wonder why some of the provisions have been left in when they are clearly redactable. Template language can cause more confusion than clarity, if its not appropriately reviewed for applicability for each specific situation.

Why It’s Helpful to Use a Pre-Built Template

A pre-structured template can reduce the time it takes to develop a new clinical trial a number of hours by making sure that you have all of the paragraphs that you need; that those paragraphs are consistent; that you will not forget to add pay to a subject budget; that you will not forget a "fees and payment" section because of the unique circumstances of that trial. In addition, templates improve compliance because you will include all of the provisions that you have already vetted and approved. Less frequent mistakes mean less re-work and less need to re-train. At the same time , it is too easy to treat the template as a pro forma document with no thinking or customization. Reviewing and adjusting even templates is a continuous learning effort that can help you craft even better agreements in the future that are more effective in achieving your objectives – as well as become even more efficient. Templates can be a very effective tool – but only if you are willing to see them as starting points for further, critical thinking.

Legal and regulatory issues

The creation of a clinical trial agreement is not only a commercial matter; there are a host of legal considerations that must be taken into account when drafting the terms of a CTA. Key legislation governing the conduct of clinical trials include the UK Medicines Damages Act 1971, the UK NHS Research Governance Framework, the EU Clinical Trials Directive (2001/20/EC), and the US Federal Food, Drug, and Cosmetic Act (the "FDCA"), together with guidance issued by government bodies and industry associations. All CTAs need to be aligned with national and international regulations as well as recognised conventions on ethical standards.
Membership of the International Conference on Harmonisation ("ICH") and its adoption of Good Clinical Practice Guidelines will also affect the negotiation of a CTA. The ICH is dedicated to developing scientifically sound and compatible rules and regulations for the conduct of drug clinical trials in the three major areas of drug development: good clinical practices, good manufacturing practices, and good laboratory practices. The adoption of the ICH Good Clinical Practice Guidelines (which are broadly similar to UK regulations) by the FDA means that clinical data received in support of approved drugs may be considered sufficient for studies submitted to regulatory authorities in other ICH member countries.
There are also a number of governing codes of practice that are invoked when clinical trials are conducted in accordance with the law and guidance. These codes relate to the pharmaceutical and bio-pharma industry which generally includes the Association of the British Pharmaceutical Industry’s Code of Practice (the "ABPI Code") in the UK, and the Pharmaceutical Research and Manufacturers of America Code of Practice in the USA (the "PhRMA Code"). In many areas, these governing codes are similar to one another. For instance, both the ABPI and PhRMA Codes contain rules governing the relationship with clinical investigators and certain limitations on promotional activities.

Clinical trial agreements in practice

Real-world examples of successfully negotiating a CTA are limited, and certainly fewer than the discontented examples. The difference in the cases is remarkable. Successful CTAs seem to be based on effective planning, communication and open-minded negotiation.
The success of the study as a whole should be the goal, and the CTA effective in making that happen.
The case study: A Sponsor was able to negotiate an agreeable contractual arrangement with a single site and set the stage for additional sites that were recruited months later.
As in many cases, at least one of the parties sees the value of a study very differently than the other. In this case, a clinical trial was scientifically valuable, but sub-studies were significantly underrepresented in the budget and were not contingent upon the availability of funding from a grant.
Finding a way to include the additional sites with specific language that addressed the unique issues, made this study an excellent example of how a sponsor was able to turn the situation to its advantage. All of the sub-studies were then funded from grants. If the CTA had not been properly and completely negotiated, the study may have failed to find the additional funding.
Another example of how a study was saved by effective negotiation comes from a complex agreement involving multiple investigational sites, a competitor sponsor and a CRO. Similar to the study above, this study was important, but the budget was short. Each of the sites had different requirements. With multiple layers of contracting, the basic, bare-bones agreement was negotiated first. After that , the study-specific agreements were handled individually with the sites. This effectively limited the dialogue and negotiations to only one level. By the time the sites received their agreements, the main negotiations were complete so there was no incentive to continue to negotiate at the site level. A uniform approach to the process was key to keeping the timeline in line with the patient recruitment goals.
In both examples, the initial agreements were modular and did not become entrenched in the specific situation. By starting with a template and processing the CTAs separately, these sponsors avoided extensive re-negotiation of terms that were acceptable to all.
Some specific lessons learned include:
If a study is being sponsored by multiple sponsors, take the lead to negotiate the umbrella agreement. Otherwise, if there are differing terms between the individual sponsors and the lead sponsor, the lead sponsor becomes liable for the others.
Next, look at the entire budget for a study. Even if one component or site is being funded by a grant, it may be possible to consolidate the project budget so the sub-studies are paid from the study budget. This can reduce the overall spend.
Consider adding study-specific modifications or appendices to an agreement. This gives both parties the necessary flexibility to deal with new information or unforeseen contingencies or develop studies as they become apparent. If the umbrella agreement can be negotiated first, the ability to detail out the various components is not as time-consuming and is less likely to derail the process.