Everyone involved in clinical research must follow Good Clinical Practice (GCP) as specified in ICH GCP and the international ISO standard 14155:2020, the EU MDR 2017/745, the EU IVDR 2017/746, the EU Clinical Trials Regulation 536/2014 (as of 31 January 2022) and other relevant scientific MDCG guidelines provided by the European Commission.
With these regulations, the scientific and medical community has been presented with a safer and more stringent regulatory scenery to protect society and European patients. Moreover, to ensure that the clinical investigation is scientifically and ethically sound, each Member State may have specific requirements to approve the research ultimately.
Collaboration between medical device – and drug companies, and hospital research organizations is essential for getting new devices and drugs to market. Clinical investigations and trials are subject to a high degree of regulation, with multiple stakeholders being involved to ensure successful execution.
What is a clinical trial agreement?
A clinical trial agreement (“CTA”) is the legally binding agreement between a sponsor, usually a medical device or pharmaceutical company which provides the study device or drug and financial support, and the clinical institution, which provides the patients and the clinical data.
Other parties may also be involved in the execution of the clinical investigations, such as a contract research organization (CRO), clinicians, manufacturers, suppliers, and, of course, patient volunteers. Each party’s roles and responsibilities, and perhaps most importantly, liabilities, must be clearly defined before any investigation or trial is undertaken. Here we provide an overview of some of the critical issues that must be addressed in any CTA.
Elements of a CTA include:
- The terms of the collaboration.
- The responsibilities of each party.
- Payment and reimbursement procedures and requirements.
- Intellectual property and publication terms.
- Insurance and indemnification.
- Coverage for subject injury.
- Dispute resolution guidelines.
- The procedure for amending contract terms.
- The guidelines to terminate the contract.
I. Form of agreement CTAs differ from standard commercial services agreements because they focus on the clinical investigation plan (protocol) and looks at risk, rather than commercial benefits or financial gain. Clearly, there may be a direct risk of harm to human volunteers who are the subjects in any investigation or trial. Furthermore, one of the parties to the agreement is likely to be an hospital, i.e. not a commercial entity, and the considerations are therefore different.
In most countries, approved model templates are endorsed by the Government and are, generally speaking, preferred by the hospital. The room for negotiation is often, therefore, different from everyday commercial practices. It is still essential for sponsors to ensure that their interests are best protected. The CTA itself is the main agreement that governs the investigation or trial. Still, given the complexities of clinical studies and the number of parties involved in bringing them to fruition. For example, you often need to set up consultancy agreements with medical practitioners. If a sponsor is outside the European Union, they must have appropriate representation (an agent) within the Union to interface with the regulatory authorities.
II. Regulatory framework The management of clinical investigation for medical devices in the EU is governed by the “Medical Device Regulation” 2017/745 and the “Clinical Trials Directive” (expected to change to the “Clinical Trials Regulation” 536/2014 on 31 January 2022). As sponsor and manufacturer you have to make sure the CTA templates comply with the current and correct regulatory framework. Practitioners should therefore ensure that the templates are updated with the new legislation when it comes into force.
III. Liabilities and ethical considerations Clinical investigations and trials involve human volunteers. The consequences if anything goes wrong can be catastrophic. It is therefore essential that any agreement deals with liabilities and determines who will be responsible should anything go wrong, and adequate insurance provisions put into place. In general, there little to gain from sponsors to negotiate such provisions than there might otherwise be in a standard commercial transaction – it is more important that the sponsor can properly test its drugs or device by having access to a large pool of patients and the infrastructure of the the clinical research center. In addition to the standard indemnities, CTAs must contain adequate insurance provisions to to cover the liability of the investigator or sponsor. As many sponsors are US based and consequently have in place US insurance policies, practitioners would be best advised to ensure that such policies are EU compliant.
IV. Intellectual property rights CTAs differ from most commercial agreements in that the IP generated is usually data that can be submitted to a regulatory authority in order to obtain approval for the device or drug in question. In most cases, they are unlikely to give rise to potentially patentable subject matter, but IP is still of paramount importance in such agreements. As with most commercial transactions, the key consideration is who owns the IP? Background IP should be owned by the party who brings it to the investigation, and consideration should be given to the licences required to enable the parties to the agreement to exploit this in relation to the trial. In contrast, in respect of any IP generated by the investigation (the “foreground IP”), the standard position is that such IP will be owned by the sponsor. However, it is worth remembering that the position may not be that straightforward and should be considered on a case by case basis, and even issue by issue basis. This is because there may, in reality, be several categories of IP – that which relates to the product which is subject to the investigation, that which relates to clinical procedure and any improvements to existing IP. Again, the parties should consider what licences may be necessary to deal with the exploitation of any such foreground IP.
In investigations where new IP is generated, such IP is most likely to relate to a potential application for a second medical use patent, i.e. an application for a patent in respect of a new use of a known compound. However, whether any application will result in patentable subject matter is questionable: filing a patent application prior to the commencement of the trial, without any supporting data, may lead to a lack of plausibility (on the grounds of insufficiency or lack of inventive step); alternatively, fling the patent application after completion of the trial once the data is generated, the lack of confidentiality may result in the patent application being rejected as it lacks novelty. This is an area of law which has not yet been fully tested, but the ownership of any rights generated by a clinical investigation should be addressed in the CTA.
V. Personal data
Clinical trials necessarily result in the collection and subsequent use of large amounts of sensitive personal data, and the voluntary consent of the patients is necessary for participation in such trials. Readers will be aware that the introduction of the General Data Protection Regulation 2016/679 (“GDPR”) has required that organisations have robust processes in place in respect of the use of personal data. This means that participants in a clinical investigation should have access to their data, and are provided with information about how it will be used and stored. In reality, data relating to participants in clinical investigation is likely to be anonymised, in which case the GDPR will not apply. Nevertheless, there are ethical considerations that must be met, and consequently the treatment of personal data is pretty much the same: the participants should be informed about how their data is used even if technically speaking it is not classed as “personal data”. Such matters will already be familiar to practitioners advising on CTAs, where ethical considerations and the protection of patient volunteers has always been paramount.
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