Investigator Initiated Studies, what are they and how can they be of value to your company?

Investigator Initiated Studies (IIS) are clinical investigations that are started by physicians. As opposed to manufacturer-sponsored studies, IIS are conducted more or less independently from the industry.

Definitions are important here. The EU Medical Device Regulations (MDR) 2017/745 defines an investigator as an individual responsible for the conduct of a clinical investigation at an investigation site. The Sponsor is any individual, company, institution or organization which takes responsibility for the initiation, for the management and setting up of the financing of the clinical investigation. In IIS, the investigator assumes the role of both Sponsor and Investigator by initiating, implementing and taking full responsibility for the clinical investigation.

IIS may be funded directly by the healthcare institution or funding may be acquired by the investigator from governmental institutions, non-profits, foundations, etc. and thus the setup is in many cases entirely independent from the industry. As a manufacturer of medical devices, you may encounter the results of such studies when they have been published in the scientific literature. However, many investigators will seek industry funding. Why would a manufacturer (co-)fund an IIS?

In industry, IIS are perceived a relatively low-cost source of clinical data. Funding an IIS means a hands-off approach – which it should be for compliance reasons. Note that to prevent confusion in this context the use of the word “sponsoring” should be avoided when speaking about funding. In a true IIS, the process starts with an unsolicited, spontaneous request for funding of the Investigator to the manufacturer based on a research proposal. The manufacturer reviews the proposal and determines whether the proposed research meets the manufacturers clinical needs and company strategic goals. The manufacturer should also judge the scientific merit of the study and quality and compliance criteria. The manufacturer may then decide to support the research with funding and/or provision of devices free of charge. The Sponsor-Investigator remains responsible for the research. If all goes well the investigator publishes the results which can then be used by the manufacturer. Depending on how contracts are set up, the manufacturer may also obtain anonymized datasets, original study protocol and reports among other documents. The manufacturer may also audit parts of the study.

The main advantage of IIS over company-sponsored studies is that the manufacturer does not carry any of the sponsor responsibilities and uses less resources to generate new data on their device.

An IIS can produce data on the issues faced by medical practitioners in the real world and they can help answer questions based on day to day experience of device use by a clinician.

Such studies could also exploratively to look into unmet clinical needs and new uses of the device, however it is important to realise that in such cases additional regulatory approvals may be required. In addition, IIS typically have a different profile of potential sources of bias. These studies can be ideal for post-market clinical data collection purposes, marketing purposes and local projects such as support for reimbursement. The use of IIS data for regulatory purposes is probably limited to providing supporting evidence only, since pre-market studies (MDR Art. 62) as well as post-market clinical follow-up (PMCF) studies outside the scope of the intended purpose (MDR Art. 74) require approvals from competent authority and much more involvement from the manufacturer.

The challenges in IIS are controlling the deliverables, timelines, quality and compliance. The manufacturer should have a solid contract in place with the investigator detailing agreements on roles, adherence to regulations, availability of protocol and amendments, informed consent, Ethics and regulatory approvals, registration in trial registries, data ownership and processing, review of manuscripts and dissemination of results, reporting obligations to manufacturer and a payment schedule for successive payments per milestone. Intellectual property and inventions should be covered by the contract as well.

The manufacturer can reserve the right to audit certain elements of the study but source data verification (monitoring) or any other activities that require access to patient data will not be possible. In an IIS, the sponsor-investigator must ensure adequate monitoring of the study, whereby the monitor has to be independent from the research site (MDR Annex XV). In case of multicentre IIS, it may be challenging for the Principal Investigator to coordinate the study and to subcontract to other sites. Data collection is often demanding and can be improved using electronic data capture (EDC). Lastly the amount of resources required to conduct a study tend to get underestimated by the sites. Start-up, enrolment and execution times are often longer than expected, which can pose challenges in milestone completion and may result in requests for budget extensions.

How can a CRO help with IIS? Sponsor-investigators can subcontract several activities to a CRO. In our CRO we have provided monitoring, medical writing, training, data management, auditing and regulatory submission support to IIS. If you are a manufacturer who is funding an IIS, you may suggest to the research team to use a CRO for such activities. Involving a CRO can help comply with ISO14155/GCP and ensure the ethical conduct of the research and scientific validity of the data. Contact us if you want to know how we can support your IIS or if you have questions regarding your existing IIS program or IIS data.

Whether data from IITs, funded by a manufacturer, can be used for regulatory submissions is a matter of debate since these studies are generally not monitored by the company per its SOPs.

Funding an IIS involves the transfer of value to healthcare providers. The MedTech Europe Code of Ethical Business Practice contains valuable rules (binding to MedTech Europe corporate members) for compliance including agreements on research grants.