A contract is a “written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract” (EMEA, 2009).

More formal contracts are often necessary for research projects and are described below. Getting contracts agreed and signed is often considered quite late in the process of getting a study started. However, it can often take a long time, especially if several institutions are involved and even simple agreements that appear straightforward might become complex when set out in a terms of reference or a memorandum of understanding. Therefore it is strongly advised to attempt to get any agreements and contracts drafted, reviewed and signed-off as early as absolutely possible.

The planned research needs to be considered in terms of risk and complexity and the number and nature of any collaborative activities. These considerations will inform the study team about what agreements may, or indeed may not, be needed. Many organisations involved in research have administrative departments and research support services. These are usually the people tasked with advising on what sort of agreements and contracts are required and helping to get them put into place.

Template and example contracts are also available on Global Health Trials for download and adaptation for other studies, see the article in the resources section.

Confidentiality or Non-Disclosure Agreements (CDA or NDA)
A confidentiality agreement is a document that stipulates how confidential information, including Intellectual Property, results or know-how owned by one of the partners (which may be a trial sponsor, or the institution of the lead investigator) may be disclosed or used by the other parties, such as other investigators. The agreement sets out the terms of disclosure and whether information is returned to the sponsor or destroyed upon request.

Having agreed to collaborate in a research study, the other investigators might be required to sign a confidentiality agreement prior to being sent the full study protocol or other documentation, such as an investigator brochure or details on an intervention, such a vaccine specifications. This is often the first agreement put in place between research collaborators.

Clinical Trial Agreements (CTA)
These agreements are commonly used between sponsors and study sites, especially by pharmaceutical companies. However they can be very helpful for academic researchers to use if they are setting up a multi-centre study, whether it is a clinical trial or indeed an observational study.

There are key elements that should be included in a CTA such as:
- The parties signing the contract
- Detail of the work to be carried out
- Funds to be paid and when and how it is to be paid, procedures for delay in payment if contract terms are not observed.
- Minimum patients to enrol and trigger for first payment (if appropriate)
- Details about document retention, indemnity, compensation, insurance
- The terms of termination due to negligence or other reasons
- Publication rights and ownership of data generated during the study
- Circumstances under which the contract may be terminated with or without fault. Provide reasonable notice for termination where there is no fault.
- Identify the law of the state or country which is to govern the contract and where the disputes are to be heard.
- Whether or not the price is inclusive or exclusive of taxes?
- The obligations of each party regarding management of any adverse events
- Access to Source Documents and research documents by the sponsor (or their representatives), regulatory authorities and ethics Committee.
- Willingness to participate in an Audit either by the sponsor (or their representative) or the regulatory authorities or ethics committee.

Study Budget
The site budget needs to be agreed and incorporated into the CTA. There are a number of costs that add up to the overall site budget, they might include the following:

Pay Per Fees – Some agreements are set up to pay a fee for each patient enrolled, based on the average cost of each assessments to be performed at the visits. The per patient cost will vary from study to study as it is usually dependent on the protocol, the number of visits and the complexity of the assessments.
When reviewing the budget, it is important to read the protocol carefully to ensure that all visits and assessments have been captured in the cost.
Normally an amount is presented to sites by the sponsor to open negotiations. Sites will then need to justify any increase for sponsor consideration and agreement.
The cost will include pro rata payments for early withdrawal/termination as well as cost for screen fails (where applicable).

Fixed Fees are independent of study activities and are expected to be incurred irrespective of the type of study, e.g. staff costs, start-up payments, Archiving cost, Pharmacy fees, percentage overhead cost, IRB/IEC fees etc.

Pass-Through Costs are direct invoicable cost with little or no mark-up to account for cost incurred by sites. E.g. cost of hiring equipment, etc

Legal Differences and Impact on Clinical Trial Agreements
Increasingly, clinical trials involve global collaborations. This means that principal investigators and sponsors are governed by international laws and regulations, national, state, local or regional laws that often make negotiating contracts rather cumbersome.

For instance, in the European Union (EU) the EU Clinical Trial Directive was formed in 2004 to streamline much of the clinical trial processes across member states. The directive is now required to be incorporated into member state national law; whereas in the South American region where the “mercosur law” was formed among its members (Uruguay, Paraguay, Argentina and Brazil), only Uruguay enforces this law on its own.

Also in the EU, special consents are required before personal data is transferred outside of the EU except in those countries that have an equivalent privacy law. In Singapore and Australia the law requires that a local company provides sponsor indemnification whilst most countries in the EU or indeed in the US will be happy to have central insurance cover for indemnification.

ICH GCP states that the sponsor should retain essential documents until at least 2 years after the last approval of a marketing application in an ICH region. In Canada, the retention period is for 25 years whereas in the Mercosur states, retention is for 5 years after study final report.
Whilst these issues in themselves are obviously not insurmountable, they can add to the complexity of contract negotiations and need to be considered.
There are a number of ways in which the difficulty of contracts review and approval could be minimised.

Memorandum of Understanding
This is another type of documentation that is commonly set up between collaborators on a research study. An ‘MoU’ is a written agreement that sets out the expectations between both groups and what the terms are. MoUs are less formal than full legal contracts and are used when the situation does not merit the extent of a full legally binding document. For example MoUs are often used for sharing of samples or data, and are specifically appropriate when there are no funds being exchanged.

An MoU is very helpful to set out the details of a collaborative research project where two or more sites will be working together. The MoU might well include many of the aspects of a full clinical trial agreement, because it is important to set out very clearly what has been agreed in terms of publications, authorship, material transfer, roles and responsibilities, etc.

Terms of Reference
Terms of references (ToR) are very useful documents and are used to describe how a committee or panel will operate. They are essential to good governance of a research study or project.

In the context of clinical research, Terms of Reference should be drawn up to guide the study steering committee and the data safety board (if there is one). The ToR should set out the membership of the committee or panel, how often it will meet, and whether face to face or via telephone or video. The ToR should also explain what documentation and other information the committee will receive and when, how the committee with report and how they are organised. The ToR also sets out clearly the role and objective of the panel or committee, who they report to (or indeed who reports to them if it is a research project steering or executive committee).

Speeding up Contract and Agreement Review Processes
It is often a good idea to start the contract and agreement discussions as early as possible. Identifying who needs to be involved in the drafting and review process should be clarified from the onset and communicated to everyone involved.

Establishing a Time frame for Agreement and Contract Approval
One clear method of ensuring contracts are reviewed in a timely manner is by all the collaborators working closely with the institutional reviewers and approvers to establish a time frames for the review process. This might seem overly cautious, but it really can be time well spent. 

Conclusion
With all those involved in research being keen to shorten the time it takes to set up research studies, it is important that proper attention is given to the contract negotiation process as early on as possible so as to minimise delays.
Also, if some of the suggestions elucidated in this article are implemented it will ensure that one of the primary reasons for study start-up delays can be eliminated. 

References and Further Reading

• Laws, Regulations and Clinical Trial Agreements
• http://firstclinical.com/resources/articles/Laws.pdf
• Seila Mikhali and Giddings Robb “Clinical Contracting Efficiency” Applied Clinical Trials Aug 2011.
• European Medicine Agency - ICH Topic E 6 (R1) Guideline for Good Clinical Practice 
• http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf
• Universities and NHS Hospitals: The Model Agreement’s terms and its use in the Development of Contracts for Collaborative Studies
• http://www.nihr.ac.uk/files/mICRA%20Guidance.pdf
• Contracts overview - Clinical research administration 
• https://wiki.duke.edu/download/attachments/14723021/M7-+Effective+Budgeting+and+Contract+Negotiations+for+Clinical+Trials.pdf?version=1
• Advanced GCP for investigators
• http://whoindia.org/LinkFiles/Clinical_Trials_Advanced_GCP_for_Investigators_%E2%80%93_Training_Manual_.pdf

The Regulatory Requirements Database is a free and open-access database providing information on regulatory authorities around the world. http://regulatory.ghtcoalition.org/