The new article clarifies the approach to be followed when introducing modifications to combination studies already approved by Swissmedic.
Table of content
Swissmedic, the country’s regulatory agency in the sphere of healthcare products, has published an information sheet dedicated to combination studies. The document provides an overview of the applicable regulatory requirements set forth under the existing legal framework, as well as additional clarifications and recommendations to be taken into consideration by medical device manufacturers, study sponsors, and other parties involved.
At the same time, the authority reserves the right to make changes to the document and information provided, should such changes be reasonably necessary to reflect corresponding amendments to the underlying legislation.
Modifications (Amendments): Basics
First of all, the authority mentions that modifications to combined studies can affect the MP/ATMP aspect, the MD/IVD aspect, or all study aspects. If changes are made to one aspect (e.g., MP/ATMP), corresponding changes may also be required for the other aspect (e.g., MD/IVD).
In accordance with the applicable regulatory requirements, all modifications, whether substantial (requiring authorization) or non-substantial (requiring notification), must be submitted as a single submission package (eDok) via the eGov Service eMessage portal.
According to the guidance, a party responsible for a combination study in question should proceed with the following steps:
- Folders 00.00 – 17.00: This section should contain any new or modified documentation for the MD/IVD aspect, presented in both clean and track-change modes, including form BW610_20_025e_FO. The form should indicate whether the modification is subject to authorization or notification, and specify which study aspects are affected. Modified protocols should be placed in sub-folder 04.00, and the reasons for the modifications should be explained in the cover letter.
- Folder 18.00: This section should contain any new or modified documentation for the MP/ATMP aspect, in clean and track-change modes, along with the FO submission form.
For non-substantial modifications, an automatic acknowledgment of receipt can be found in the eMessage portal. However, for substantial modifications, a decision letter from Swissmedic is required before implementation.
Special Case 1: Amendments Affecting Multiple Studies or Clinical Trials
Sometimes, the same investigational MP/ATMP is used in multiple combined studies or in both combined studies and clinical trials. In these cases, modifications or updates (e.g., to the Investigational Medicinal Product Dossier, IMPD) might impact several combined studies or clinical trials.
Scenario A: If the planned modifications affect multiple combined studies:
- Submit a single eDok using the eGov Service eMessage portal.
- Folders 00.00 – 17.00: Include form BW610_20_025e_FO, listing all reference numbers of the combined studies (1000xxxx) impacted by the amendment. Indicate whether the modifications are subject to authorization or notification. All modified protocols should be placed in sub-folder 04.00, and the situation should be explained in the cover letter.
- Folder 18.00: Place the modified MP/ATMP documentation in clean and track-change modes, along with the FO submission form.
Scenario B: If the planned modifications affect both combined studies and clinical trials, there are two options for submission:
- One Submission: Submit a single eDok.
- Folders 00.00 – 17.00: Include form BW610_20_025e_FO, listing the reference numbers for all combined studies and clinical trials (1000xxxx for combined studies, 70xxx for clinical trials). Indicate whether the modification is subject to authorization or notification.
- Folder 18.00: Include the modified documentation for the MP/ATMP aspect in clean and track-change modes with the FO submission form.
- Two Submissions: Submit separate eDoks for combined studies and clinical trials.
- For the combined studies eDok, Folders 00.00 – 17.00: Use form BW610_20_025e_FO and tick the box indicating that an identical amendment has been submitted for a clinical trial. All modified protocols should be placed in sub-folder 04.00, and the situation should be described in the cover letter.
- Folder 18.00: Include the modified documentation for the MP/ATMP aspect in clean and track-change modes, along with the FO submission form.
It is important to mention that Swissmedic will only charge one review fee for the submission, provided that the sponsor and representative are the same across all submissions. If this is not the case, each amendment will require an individual submission and will be invoiced separately.
Special Case 2: Re-categorization of a Study as a Combined Study
An existing clinical trial of an MP/ATMP can be re-categorized as a combined study under certain circumstances. For instance, if a medical device (MD) or in-vitro diagnostic device (IVD) used in the trial loses its conformity or a non-conforming MD/IVD is added, the trial may need to be reclassified.
The re-categorization process requires submission of a single submission package (eDok) using the eGov Service eMessage portal.
The document further explains how to populate the eDok for re-categorization:
- Folders 00.00 – 17.00: Include documentation for the new MD/IVD aspect, along with the form BW610_10_026e_FO (MD) or BW610_10_027e_FO (IVD). In the cover letter, mention that the trial was previously approved as a clinical trial for an MP/ATMP, include the Swissmedic identification number, and provide the reason for reclassification as a combined study.
- Folder 18.00: Include updated MP/ATMP documentation, along with the FO submission form for the amendment. Ensure the regulatory status of the MD/IVD is clearly described, and integrate reporting requirements for clinical investigations or performance studies appropriately.
Similarly, an existing MD/IVD investigation or performance study may be reclassified as a combined study if a non-licensed MP/ATMP is added to the study or if the authorization status of an MP/ATMP changes. The submission process is the same as for re-categorizing an MP/ATMP trial.
Required Documentation Updates
Reclassification to a combined study requires submission of new documentation related to any added or modified products. This also includes updating previously approved documents. The study protocol(s) must always be updated, and often changes are needed for other study materials, such as the Case Report Form (CRF), patient information, Investigator’s Brochure (IB), or Instructions for Use (IFU).
To ensure compliance with ethical standards, sponsors must contact the relevant ethics committee for instructions on how to submit the necessary documents to them.
Conclusion
In summary, amendments to combined studies must be submitted in a structured manner, with careful attention to both MP/ATMP and MD/IVD aspects. The process allows for handling modifications that affect multiple studies or clinical trials, as well as the re-categorization of existing studies. Sponsors must ensure that all documentation is up-to-date and accurately reflects the changes, including any impacts on protocols, patient information, and regulatory requirements. Swissmedic’s structured review process ensures that both substantial and non-substantial modifications are properly addressed before they can be implemented in the study.
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