Contracts in Global Clinical Trials
Rebecca Sergeant & Sarah Watts
Session chaired by: Jan Robinson MICR CSci
Reporter: Judit Varkonyi-Sepp MICR CSci
Keywords
Investigator contracts, Global clinical trials, Model contracts, Multi-partite contracts, Site contracts
According to ICH-GCP, “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”.
Specifically, in relation to an investigator (site) contract, the main topic of this session, it is a binding agreement documenting the relationship between the sponsor, CRO (if applicable), and the site and/or principal investigator. It has to detail all provisions on how the parties co-operate for the given services and has to be in place before such services start. It is therefore one of the most important legal documents in a clinical trial, alongside the study protocol and investigators’ brochure. Bizarrely, not so long ago, this was one of the most neglected parts of the trial set-up, often arranged at the last minute. Luckily, times are changing and players in the clinical research field have increasingly realised this. The ICR conference this year devoted a whole session to this important topic.
The speakers, Rebecca Sergeant and Sarah Watts, each have a CRO background with several years’ experience in contracting. Rebecca has been working in contract management since 2005 and in the past 2 years she has led site contracting on a number of global studies. She has experience in working with some of the largest pharmaceutical companies. Sarah has been in clinical research for over 10 years and, as a clinical project manager, she has been involved in contracting.
Sponsor-CRO contracts
The speakers started by listing the types of contract typically used in clinical research, such as contract between sponsor and CRO, vendor contracts, sub-contractor contracts and site contracts, to which I will return later. There was no discussion on the difference between vendor and sub-contractor contracts, so I hereby take the lead and give one possible distinction from a CRO aspect: vendors are other, non-clinical service providers contracted by the CRO for ancillary services within the scope of services provided to the sponsor (such as printers or couriers, for example) whilst sub-contractors are clinical service providers who are contracted and managed by the CRO on behalf of the sponsor. Rebecca and Sarah might have a different categorisation, though, and some use the terms interchangeably.
Only a limited part of the presentation was devoted to this type of contract with brief mention of the two main types:
- Fixed price or fixed unit price contracts, wherein the buyer (ie, the sponsor) pays a set fee for service items (eg, one monitoring visit costs £400)
- Time and materials contracts, wherein the buyer pays for the CRO’s time spent on each activity (eg, nurses’ hours in a phase I unit)
From the moment a contract is awarded to a CRO, the sponsor wants the service provider to start acting immediately. ‘Contract award’, however, rarely means having the contract fully signed and lengthy negotiations might still lie ahead before work can start .Not having a written agreement in place leaves both contracting parties vulnerable and vendors increasingly demand some sort of document fully signed before actions commence. A Letter of Intent (LOI) is an agreement often used in these situations, covering imminent activities and usually referring to a main contract as a future comprehensive agreement. The main provisions of the two agreements are typically harmonised. Rebecca highlighted that LOI has its limitations, eg, in terms of sub-contracting with clinical sites because these cannot be fully executed without a fully signed sponsor-CRO agreement in place. It was not entirely clear from the presentation whether this is a regulatory requirement, guidance or standard business practice.
In order to speed up the contracting process, another option for sponsors is to have a Master Services Agreement (MSA), which is a form of umbrella contract giving general terms and conditions between contracting parties and which aims to cover the main aspects of individual trial agreements. This is practical when the parties aim to conduct several trials in co-operation. The individual contracts will still have to be negotiated, including study-specific aspects, but the work can start before individual agreements are finalised because the legal framework for agreement is covered in the MSA.
Site contracts
The major part of the talk was about site contracting, as a shared presentation by both speakers. Site contracting is at least as complex as sponsor-CRO contracting, albeit in a different way. Having as many variations of requirements as there are countries sours the life of the brave clinical trials professional setting out to conduct studies across Europe (or, in fact, across any group of countries).
Firstly, there are countries where CROs have to contract with an institution, with the sponsor also having to be a signatory on the contract. The UK works in this (relatively simple) way, and the situation is further aided by a series of model contracts, developed and agreed jointly by the Association of British Pharmaceutical Industry (ABPI) and the Department of Health which are now widely accepted by NHS institutions for clinical trials. Australia has recently developed a similar tool but it is still suffering from teething problems.
Then there are other, more complicated countries, such as the Czech Republic, where the Principal Investigator (PI) also has to be a signatory, making the contract quadri-partite.
In some countries where the PI has a separate agreement with the sponsor or CRO, the institution will have to be fully informed about the contract terms, sometimes including financial aspects. In Poland, for example, the finances are handled in a separate addendum but both the PI and the institution are signatories.
In some instances, the site agreement is even more complex as it might be required that sponsors-CROs contract with each ancillary department or site member separately, in individual contracts. One such country is Hungary. This requirement makes contracting extremely complex and lengthy.
Whatever the requirement regarding the identity of the contracted party or signatory, the contract has to contain standard provisions on:
- Patient protection
- Data protection
- Inspections/audits
- Intellectual property
- Publication
- Trial specifics
- Liabilities
- Financial disclosure (increasingly also required outside the USA)
- Payment terms, which also have to include patient travel, screen failure, payment for equipment, exchange rate agreements and where the money is to be paid (including country)
Rate-limiting step
The speakers emphasised the rate-limiting nature of the contracting process in the set-up of a clinical trial. The best practice therefore is to start contract negotiations as soon as possible, involve key parties in negotiation very early, even aiming to have the budget finalised by the time the protocol is finalised. In some countries (eg, Poland, Romania, Bulgaria, Croatia or Ukraine) a fully signed contract is required before ethics committee (EC) submissions can be made. Other countries are different. EC and/or institution approvals may have to be in place before contracts can be signed (eg, Italy, Belarus, India, Serbia etc.).
Some countries require the contract in local language (which must be factored in during/after negotiations). In addition, where a CRO negotiates the contract on behalf of the sponsor, the sponsor should review and approve the contracts before sign-off, which also extends the timelines. Apart from the few fortunate cases when there is a country-wide model contract template which parties accept without changes, all signatories would probably involve legal review to assure their interests are protected, adding further to the time taken to finalise the contract. Add to this a scenario where the contract is negotiated through multiple countries (eg, a US sponsor, a UK CRO and an Eastern European site where, before contracting, you might also need a hospital director’s approval, who might be on holiday for several weeks) and you have the one of the most testing study set-up challenges of your clinical research professional life, equal to white-water rafting in adrenalin rise!
Things can go wrong in several areas: even when parties negotiate within the same country, lawyers are usually employed for the review of terms. If the negotiations are between countries where the language is different, then translations might be faulty, negotiations (queries/replies) might be misunderstood, changes in the law might occur which need to be informed, understood and interpreted. All of these add to the difficulty and ultimately the length of achieving agreement.
A good tool to overcome at least some of these set-backs is for sponsors/CROs to develop country-specific contract templates and review them periodically (eg, bi-annually) to make sure adherence to regulatory/statutory changes. There might be changes in requirements in one country, which could also be considered across all contracts. Sarah and Rebecca advised that some countries or sites be dropped from the sponsor’s shortlist if the set-up is very lengthy.
The speakers then showed a summary slide of the ‘usual suspects’, (which groups several countries according to the ease/speed of site contract set-up).
Quick starters
- Belgium
- Denmark
- Sweden
- Netherlands
- India
- Romania
Slow starters
- Poland
- Czech Republic
- Hungary
- Latin America
- Spain
- Italy
Improvers
- Italy – CRO templates
- UK – Introduction of DOH/CRO template
- Australia
- Russia
Summary
The message from the speakers is clear: plan and consider contracts carefully, allow plenty of time to set them up, make sure parties observe the terms and be vigilant in case changes are needed.
The session was very informative. Rebecca and Sarah were keen to share their vast experience, including case studies and practical suggestions and I took many pages of notes on how we can contract better in my own organisation.
I would have liked to learn more about the vendor contract, but that probably would have required a whole session itself, so I am looking forward to next year’s conference where it might be on the programme on its own merit!
It would have been good to hear about site contract execution as well. This is another intriguing topic, eg, how does a company act when investigators/sites are in breach of contract. I suspect that many of us involved with site contracts have many other practical questions.
I hope that contracting will stay firmly on the agenda of future ICR events and that there will continue to be many occasions to share experience with colleagues from different fields of clinical research.
Rebecca Sergeant is a Contracts Associate with i3 Research.
Sarah Watts is a Project Manager with PAREXEL.
Judit Varkonyi-Sepp MICR CSci is a Clinical Trials Manager.
