Contracts provided to study sites by industry sponsors contain legal language that is often confusing and not well understood by the study site representatives. This article reviews risk areas and contract language that sites should be familiar with when reviewing and negotiating a clinical trial agreement. To adequately protect the site, those who review the contract should clearly understand what they are agreeing to before approving a contract.
Overview
Clinical trials that are conducted under the U.S. Food and Drug Administration (FDA) regulations require a contract between the site and the study sponsor or clinical research organization (CRO). This contract is generally referred as a Clinical Trial Agreement (CTA). Contracts are written in a legal language that might be at a reading level as high as 35th grade. (Pfeiffer & Windschiegl, 2016). Not understanding the language or what the site is agreeing to can lead to an accidental breach of contract and serious legal and financial ramifications for the site and the investigator.
There is no requirement that a contract be written in legalese. A contract using plain language, understandable to all parties, is still a legal and binding agreement. Sites should work towards a contract that is written using less legal jargon, is clear to all parties, and provides clear definitions of legal terms. Site tasks, responsibilities and deliverables should be spelled out in detail to ensure that the site knows exactly what is required in conducting the study.
Both the sponsor/CRO and the site have goals related to the conduct of clinical trials. The primary goals of a sponsor include, (1) collecting complete and accurate data to support their application for marketing approval, (2) protecting confidential information and intellectual property, and (3) complying with current applicable laws and regulations. The goals of the site, in addition to compliance with the protocol and regulations include, (1) to be fairly compensated for their work, (2) indemnification, (3) the ability to publish study results, (4) payment for subject injury related to the study, and (5) to protect the site. The language in the contract can assure that the goals of both parties are met.
Be Aware…
When reviewing a contract be aware of words that are limiting, capitalized terms, and words that you do not understand. If the contract does not contain a definitions section, ask for one. Make sure that words you do not understand are defined in this section. Be aware of terms that are used in a unique way in the contract, they may not be used in the same manner in which you are familiar. These should be defined in the definitions section. Words are capitalized in the contract because they are important. Ask what these words mean. These terms should be included in the definitions section.
Limiting language to look for includes:
“Any” and “All” or “Without Limitations” – these words can commit the site to dropping everything and doing whatever is needed when an event occurs or a sponsor has an issue, query, or question. Request that these words be replaced with specific expectations and details. For example, a contract may state that in the event of a reported unexpected adverse event the site will notify the sponsor/CRO immediately and utilize resources available to investigate and adjudicate the event. Regardless of what is occurring, the site is expected to drop everything until the event has been completely investigated with a report to the sponsor/CRO. The site should request that the verbiage include promptly reporting the event upon notification of the event. It is acceptable to have a time period associated with reporting such as 24 hours upon notification of the event. In addition the contract should allow a reasonable amount of time to complete an investigation and provide a report. Use words such as in a prompt and timely fashion and using reasonable efforts. If a time period is included make sure that it is reasonable for the site, for example within 7 – 10 business days.
“Immediately” – this term indicates that the site will take immediate action. Replace this term with “promptly” or in a “reasonable period of time.”
“Best Efforts” – unless the site has the luxury of devoting the efforts of all site resources, this term should be changed to “reasonable efforts.”
“Sole Discretion” generally means at the discretion of the sponsor/CRO. “Reasonable discretion” of the parties to the contract is much more acceptable and protects the site.
When reviewing the CTA make sure that the terms of the contract are clear and the site is able to perform the responsibilities as described in the contract. The site should add preferred language and provisions to protect the site. A good way to do this is to redline the contract. To do this turn on the track changes feature under the review tab on your computer. This allows the site to easily track changes and the sponsor/ CRO the ability to identify the site’s requested changes. It is important to incorporate version control to ensure that the current version of the contract is being used and to use a consistent naming convention. An example of this might be “CTA_study_name_your initials_date_version.”
Ensure Reasonable Protection of the Site
What are reasonable changes a site can request and expect from a sponsor/CRO in a CTA? While the site should review the entire contract carefully, there are key sections that require special attention to protect the study site. When reviewing these sections check carefully for the terms and words presented earlier in this article.
Debarment
The use of an investigator, sub-investigator, vendor, or other study staff that have been debarred by the FDA from conducting investigational studies is prohibited. The site must, to the best of its ability ensure that no one used in the conduct of the study has been debarred or comes under investigation for possible debarment during the study. Some sponsors/CROs may want the site to report any person working in any capacity on any study at the site. This would include site staff that are not necessarily related to the study. A study site may not be aware of debarment or possible proceedings of a person not working directly on the study. An example of debarment contract language may state that “the site shall immediately notify the sponsor of any proceedings that could result in the investigator or their respective employees or agents being disbarred, disqualified or excluded.” Protect the site by suggesting the following verbiage, “the site will promptly notify the sponsor upon learning of proceedings that might result in…” In addition, ask to replace “respective employees or agents” with “respective employees or agents involved in the performance of the study…” (Pfeiffer, J. and Windschiegl, M. 2016, page 67)
Publication
Publication of study data has long been an issue between investigators/ sites and sponsors. (Pfeiffer and Richmond, 2015). Language in the CTA should not give the sponsor editorial rights or control over publications by an investigator. The sponsor should have a right to review the manuscript for the removal of confidential information only. There should be a set timeline for review by the sponsor, for example 60 days after receipt. The contract should clearly define when an investigator is able to publish or present study data.
Record Retention
Limit the number of years the site is required to maintain study records. The FDA requires that study records be maintained by the site for two years post approval of the investigational product or termination of the study. Sponsors often request that the site keep the records much longer. Unless, the sponsor can provide reasonable justification for maintaining the records for longer than the required two years, the site should seek to maintain them for only the required duration.
Site Payment
When a CRO has been assigned responsibility for conducting the clinical trial for a sponsor, it is important to include language in the CTA that the sponsor is responsible for payment due to the site, even if the CRO fails to provide payments due. A CRO may insert that payment to the site will depend on the CRO receiving money from the sponsor. This language should be removed if possible. The site should not be impacted by a contract between the CRO and sponsor as they are not party to that contract.
Payment Plan
When reviewing the payment plan be aware of payments tied to the review of case report forms (CRFs) by the sponsor/CRO. Depending on the occurrence of monitoring, it could be weeks or many months before a monitor reviews CRFs, delaying payments to the site for lengthy periods. Once the site has completed its assigned task of completing and submitting the CRF it should be eligible for compensation. This should not be delayed by the ability of a monitor to review forms. The payment plan should clearly identify how and when the site will be paid, as well as what is required from the site to trigger payment.
Confidential Information
Information that is defined as confidential by the sponsor should be clearly defined and identified. While this section of the contract might include general language that benefits the sponsor/CRO, the site should seek specifics and document identification to minimize the possibility of accidently sharing confidential information with unauthorized parties. The contract should list documents that are confidential and that the sponsor will clearly mark these documents as confidential. Occasionally confidential information may be shared verbally. The contract should address that when shared verbally the speaker will identify the information as confidential. A process for how and when the verbally shared confidential information will be put in writing and marked as confidential should be included in the CTA.
Subject Injury
Ensuring subject safety is the primary responsibility of the investigator. This includes making sure that the costs for diagnosis and treatment for injuries, illness or death related to the subject’s participation in the study are paid by the sponsor/CRO. It is best for the site if the investigator makes the determination that an injury has occurred and it is related to the subject’s participation in the study. A sponsor should not be permitted to make the sole determination. While less preferred, the sponsor/CRO may require joint-determination that injury has occurred. Be wary of sponsors that want to exclude payment of injuries that are covered by the subject’s insurance. This could get the site in trouble with Medicare as a violation of Medicare’s Second Payer law for subjects with Medicare insurance. Patients with private insurance could be responsible for copayments and deductibles. This also creates burden for the site ensuring that the correct party is billed and double-billing does not occur. It is best to obtain verbiage that treats all subjects the same, regardless of type of insurance or no coverage. (Pfeiffer, J. and Windschiegl, M. 2016, page 84)
Indemnification
In the indemnification clause the site should seek to be indemnified for the following:
- Subject illness, injury or death due to participation in the study or as a result of the investigational product.
- The sponsor’s/CRO’s failure to comply with current applicable regulations.
- The sponsor’s/CRO’s negligence, omissions, recklessness, warranties, or obligations.
- The sponsor’s/CRO’s breach of contract.
- The sponsor’s use of study results. (Windschiegl, M. 2016.)
Vice versa, the sponsor will require indemnification for negligence, omissions, recklessness or failure to comply with the protocol and applicable regulations by the site.
Contract Term and Termination
When reviewing the contract term and termination clause look for the following:
- How long is the contract? Does it cover the study period? Is a process outlined to extend the contract if necessary?
- What is the effective date of the contract? This is generally the date that the contract has been officially signed by all authorized parties. Make sure the effective date is clear.
- Early termination of the contract should be defined. This includes, who can terminate the contract and for what reasons; notification required (e.g. 30 days); and how the other party is to be notified. Each party should have termination rights and reasons should be spelled out for both the sponsor and the site.
The termination clause should also include full payment to the site for any services performed prior to the termination and costs incurred by the site as a result of the termination.
Negotiating the Contract
When reviewing and negotiating the terms and verbiage of a contract look for language and words that are troubling as well as language and terms that are acceptable and protect the site. Keep a list of both of these. These lists will help in the efficient review of future contracts and the negotiation of language and terms.
When working with sponsors/CROs keep in mind that the terms of the contract must be acceptable to both parties. Communication is a twoway street and clear and prompt communication with the sponsor/CRO during the review and negotiation process can go a long way. As a site, know the site’s priorities when conducting a study. What must the site have to properly conduct the study and what can the site live without? Sometimes the best action by the site is to walk away. Make a list of site priorities. Prioritize the list according to needs and wants. Needs are those terms that the site must have to conduct the study. Wants would be nice to have, but are not a deal breaker.
Preparation is critical for successful negotiation with the sponsor/CRO. Provide justification for the items and changes that are requested. Justification might include leveraging site metrics to demonstrate the quality of the site. These might include, a history of meeting enrollment goals, conducting studies with few deviations or violations, completing studies on time, and providing complete and accurate data. Use data from similar studies to prepare for negotiation. Be reasonable, but ensure that the site and the study staff are protected and that the contract is fair and balanced.
References
- Pfeiffer, J. and Windschiegl, M. (2016) Managing Clinical Trial Budgets and Contracts. LAD Publishers. Georgia.
- Windschiegl, M. (2016). Contract Review and Negotiation. Webinar Wednesday Series. Clinical Research Management Program, Arizona State University.
- Pfeiffer, J.P. and Richmond, F.J. (2015). Clinical Trial Agreements: Current Practices of Investigators in the United States. Therapeutic Innovation and Regulatory Science. Vol 49: 1, 139-145.