Determine Health Authority (HA) and Ethics Committee (EC) requirements early for a smooth submission.
Submitting the dossier to the HA and EC is an accomplishment and milestone within the clinical investigation process. For many, this can be a chaotic undertaking accompanied by uncertainty, but it doesn’t have to be. While the core essential documents for submission are not negotiable, be aware that different countries and ECs will have additional required documents, response periods, and submission methods. The good news is that the information you need to ease uncertainty is available on HA and EC websites. It is merely a matter of organising the process as soon as possible during the initiation of the project or, even better, maintaining it as a knowledge management project where the information is collected and updated.
For regulations regarding HA requirements, the first reference is the MDR or IVDR; for EC requirements, the first reference is ISO 14155 or ISO 20916. However, each country has individual regulations and laws that must be followed. Stricter regulations will take precedence when rules diverge between international and local laws.
Alright, so where should we start?
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What type and class of device needs to be investigated? |
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How many sites will be included and where? Which will be the lead country? |
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What are the HA requirements? If the device is not CE-marked or is used for a new purpose, one can be quite certain that a complete submission to each HA is needed. If the device bears the CE marking, things become less straightforward. |
If the study involves submitting subjects to procedures other than those performed under the normal conditions of use of the device and those additional procedures are invasive or burdensome, Article 74 of the MDR will apply. This means that notification to the HA is required. Additionally, in some countries, notification to the HA is required even for CE-marked devices that do NOT include burdensome procedures.
What is meant by invasive or burdensome? This can vary by local laws and regulations. For example, randomising a patient to one treatment or another can be considered burdensome as it is not part of a standard of care – requiring notification in one country but perhaps not in another.
When planning an IVD clinical performance study – pay particular attention to the sampling method. For example, drawing blood may be considered invasive in one country but not in another.
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How do the ECs work within each country? |
What to submit…
Now that it is clear to whom the documents need to be submitted, we need to know which documents are required. As stated in the beginning, all the essential documents will be identical. For an overview of the documents, refer to Chapter II of Annex XV of the MDR and to section 5.6.2 of ISO 14155 plus Annexes A – D for more details on specific documents.
Some documents are country and/or site-specific. The most obvious of these is the Informed Consent Form (ICF), which is given to the subjects and must be in their native language. Therefore, it is necessary to consider how many translations are needed to cover each country. Keep in mind that multiple languages may be needed in certain countries depending on the regional requirements. Are vulnerable subjects going to be included or those admitted in an emergency? Situational ICFs will be required, and those allowed to sign may differ per country, i.e., legal representative, spouse, or perhaps a trusted person.
The contracts will also vary per site. It is possible that a sponsor could enforce the use of their template; however, sites often require their own templates to be used. Site-preferred templates can also apply to ICFs, data privacy documentation, and financial disclosures. Sites often require additional, unexpected documents that may only be provided in the regional language. Determine these documents for each site early in the process.
Finally, many sites now use electronic online portals for submissions, but some still require paper submissions or even both. Be informed about how best to prepare each dossier.
… and move on
Allow enough time to prepare all the documents when planning the timelines of the projects. Always plan for at least one round of re-submission with either changes requested to the documents or the need to provide further documentation or justification to the HA and/or EC. When submitting to both organisations, ensure that the submissions are aligned. Confirm that the same document versions have been prepared and submitted on the same day to both the HA and the EC.
At some point in the future this process will become slightly easier, at least for European sites, when a central European submission entry point (EUDAMED) becomes available. Until then, manage the process with awareness of all site HA/EC requirements, sufficient time allowance, and thorough preparation of documentation.
