Some important practical points for ISO 14155 compliant clinical trial agreements in the EU, part 2

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 en entered  into  only  where  a  legitimate  purpose  for  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.

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