European Union: Some Important Practical Points For ISO 14155 Compliant Clinical Trial Agreements In The EU, Part 2

Last Updated: 12 October 2011
Article by Erik Vollebregt

In a previous post I gave a number of practical tips for drafting ISO 14155 clinical trial agreements. In this post I will give another few. Additional points will surely come to mind and if so, I will devote a next post to those.

Agree on IP rights on the research data

If the clinical trial is to produce results in the form of data that the manufacturer of the investigational device wants to use to complete its technical file with a view to CE marking the device, it is critical for the manufacturer to own or at least have unfettered use of the data produced.

First of all, it is important to get the transfer of rights completely right. In the EU two types of rights come into play: copyrights on documentation created for the purpose of the trial and database rights under the EU databases directive on the databases used. Any assignment of rights must be broad enough or specific enough to encompass these rights.

Secondly, a problem with the database directive is that the sui generis database right accrues to the natural persons creating the database (i.e. the investigators) and only accrues to the legal entity the manufacturer is likely contracting with if national law of the EU member state concerned so permits. The same is true for copyright: it can differ from member state to member state whether employees' rights to creation automatically accrue to their employer and how it works with works for hire if the investigators are not employed by the clinical facility (e.g. because they are self-employed or employed by a CRO). A little due diligence into local copyright and database law is therefore required to decide if the investigators should co-sign the agreement for the purpose of the IP rights transfer. Keep in mind that the law governing this transfer is not necessarily the same as the law governing the agreement - you cannot choose the law under which copyright and database rights come into existence.

Manage termination and investigator replacement rights

With the entry into force of the EUDAMED database for the EU is has become important that disagreement with an investigator or CRO does not lead to termination or suspension of a clinical investigation, as this will be a reportable event that will go into the EUDAMED database and will be instantly available to the authorities in the whole EU. For that reason, it  is important to include replacement rights for the manufacturer that may provide for the replacement of certain investigators if they do not perform as agreed. Alternatively a sponsor could impose a 'key investigator' clause, requiring the key opinion leader important to the manufacturer to stay actively involved, possibly combined with a replacement clause.

In addition the agreement should provide for a hand-over clause that looks a lot like the termination assistance clause in IT implementation and outsourcing agreements without the termination: it concerns obligations relating to the phase-in of a new investigator or new CRO while the project continues with the least disruption.

Mind anti-kickback and other anti-corruption rules

A clinical investigation with a key opinion leader of a potentially big customer involved is a dream position for a manufacturer, but also very potential risk for anti-kickback and fraud allegations by competitors under e.g. the FCPA (US statute) and the UK anti-bribery act, both of which have an extra-territorial reach that companies often tend to completely overlook. Just ask other devices manufacturers that were fined millions and millions, for example just because of historical mistakes of a distributor in a far away country that they acquired at some point. Another problem could be insufficient separation of sales initiatives and clinical investigations with investigators that are employed at the intended customer, as basically most university hospital physicians in Europe are. Important universal principles that also apply to clinical investigation agreements are given in the Eucomed Guidelines on Interactions with Healthcare Professionals:

  • Consulting agreements must be entered into only where a legitimate purpose or the services is identified in advance.
  • Selection of consultants must be on the basis of the consultant's qualifications and expertise to address the identified purpose and should not be on the basis of volume or value of business generated by the consultant.
  • Consulting arrangements with Healthcare Professionals must be described in a written agreement, signed by the parties and must specify the services to be provided. Such arrangements must be consistent with the regulations of the country where the Healthcare Professional is licensed to practise.
  • The compensation paid to Healthcare Professionals engaged as consultants must be the fair market value for the services provided and must not be tied in any way to the value of medical devices which the consultants may use for their own practice. All payments made must comply with applicable tax and other legal requirements. I would add for clinical trials that the trial must not function as a means to provide the site with equipment and devices that have value for the site and can continued to be used (e.g. an MRI scanner or a large quantity of disposables).
  • Full compliance with national and local laws with regard to the disclosure or approval requirements associated with members engaging Healthcare Professionals as consultants must be ensured. Where no such national requirements are prescribed, members shall nevertheless maintain appropriate transparency by requiring prior written notification is made to the hospital administration, the Healthcare Professional's superior or other locally-designated competent authority, disclosing the purpose and scope of the consultancy arrangement.

If there is one thing that a company investing in clinical investigation really should not want it is a clinical investigation tainted with anti-corruption issues because it does not only lead to exposure to enormous fines, but also renders the data useless for future use.

Assure regulatory compliance with respect to the collection of patient data

A major issue with international clinical investigations are privacy rules and determining what exactly a sponsor should ask patient informed consent for. A typical mistake made by sponsors that have a US origin is that the forget to ask the patient's permission for export of the data to a jurisdiction outside the EU. The US, and many other countries, are not considered by the EU to have adequate protection in place for a data processor to send personal data to, especially sensitve data as patient records. The easiest way to deal with this is to ask the patient explicitly for his or her permission to transfer the data to a place outside the EU. In addition, the sponsor must take really good care to double check translations of the patient informed consent form, as sometimes the preciseness of the original document is lost in translation. And in the end, the statement that the patient signed of in his or her own language is decisive. I am just dealing with a case where this happened in a multi-trial situation. Outsourced translations of e.g. the label is also a critical process anyway that manufacturers must really have under control as part of their quality system.

Other ways to get the data outside the EU are more document intensive and require e.g. self certifiation under the US Safe Harbour programme or implementing binding corporate rules (which need to be approved by an EU data protection authority) or use standard contractual clauses approved by the EU. In the end, however, getting the scope of consent right from the start is the easiest solution.


Yet another batch of important points to take into account. And I have not finished yet - to be continued.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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