5. Investigator and Investigational Product

5.1 Does local regulation require PI/CI to be approved/registered by any health authority (e.g., RA/EC)?  

Although it is not 100% clear, it would appear necessary for the PI/CI to be approved/registered in accordance with national requirements (so as to be “entitled to practice the medical profession independently” – see Art. 6 of the Clinical Trials Ordinance (ClinO):

“1. The clinical trial investigator must:

1. be adequately trained in Good Clinical Practice and have the professional knowledge and experience required for the clinical trial; and
2. be conversant with the legal requirements for clinical trials or be able to ensure compliance by calling in appropriate expertise.

2. In addition, the investigator in a clinical trial of medicinal products…. must be entitled to practice the medical profession independently.”

Additionally, Swissethics published the statement “Professional qualifications of the investigators and project leaders of research projects”, which provides additional information on the qualification requirements and indicates that the EC can also make decisions on a case-by-case basis if they feel the investigator requires additional qualifications.

5.2 Does local regulation require any specific documents if PI/CI is based outside the country?

No, not that we have been able to determine, so long as the PI/CI meets the requirements of Art. 6 of the Clinical Trials Ordinance (ClinO):

“1. The clinical trial investigator must:

1. be adequately trained in Good Clinical Practice and have the professional knowledge and experience required for the clinical trial; and
2. be conversant with the legal requirements for clinical trials or be able to ensure compliance by calling in appropriate expertise.

2. In addition, the investigator in a clinical trial of medicinal products…. must be entitled to practice the medical profession independently.”

5.3 Does local authority allow electronic ICF administration, including electronic signatures?

There is some discrepancy on the guidance available.

The Swissethics’ Guidance on eConsent includes the statement that “Currently, in Switzerland, the eIC can make use of electronic media (e.g. video, podcasts, interactive Websites, applications for tablets and smart phones, etc.) to convey the information, while the subject’s consent must still be documented on paper with a hand-written signature of both the patient and the investigator. That is electronic and/or digital signatures are not yet permitted”.

However, the Swissmedic position paper on “Decentralized clinical trials (DCTs) with medicinal products in Swirzerland” indicates the following: 

“To date, a handwritten signature (“wet-ink”) is required in Switzerland, unless the trial participant can provide a qualified electronic signature that meets the legal requirements of the Federal law on electronic signatures (ZertES, SR 943.03). The original handwritten signed informed consent form or the certified proof of the e-signature signed by the trial participant must be archived in the “investigator site file” (ICH-GCP E6 (R2) 8.3.12). Whether electronic signature of informed consent forms will be acceptable in Switzerland in the future is currently being clarified. The position paper will be updated accordingly as new information becomes available.”

5.4 Does local regulation require ICF to be administered as audio/visual and do these need to be recorded?

Yes, where the person cannot read or write and where witnesses confirm the consent in writing, or a recording is made.

Arts. 7 & 8 of the Clinical Trials Ordinance (ClinO) provide that, on an exceptional basis, the ICF may be administered in a “non-textual” form. The exceptions to the requirement are if the person “concerned, for physical or cognitive reasons, cannot read or cannot write and the investigator furnishes proof of the provision of information and consent, specifically by means of written confirmation by witnesses, or by a recording of verbal consent”.

5.5 Is there any specific information/requirement on data capture/management (e.g., privacy regulations, etc.)?

Yes - see the position paper by Swissmedic and Swissethics on “Decentralized clinical trials (DCTs) with medicinal products” where section 2.4 - Data Capture outside the trial site using mobile technologies - states the following:

“Where the intention is to use mobile technologies to record data outside the trial site, it must be ensured that the trial subjects have been informed and agreed (consented) to data being recorded by the device (e.g. wearables) or entered by the trial subjects, e.g. electronic patient reported outcome (ePRO). This information is included in the written study informed consent form, i.e. a separate specific inform consent form is not required. The trial subjects must also be trained in the correct use of the mobile technologies. If source data are recorded directly in the CRF, this must be identified as such in the protocol. If data are recorded automatically, e.g. by wearables, it should be ensured that only trial-specific data are recorded by the mobile technology being used. The data which are considered to be source data must be stated in writing before the clinical trial begins, e.g. if data are only stored for a short time on the mobile technology.

The mobile technologies must be demonstrably validated and comply with the relevant standards for accuracy, precision, reproducibility, reliability and responsiveness (sensitivity to technological changes over time, ICH GCP E6 (R2) 5.5.3). Furthermore, the equivalence of the mobile technology used across various data-collection platforms or methods must be ensured. It must be possible to trace data entry and data changes by means of an audit trail. If the data generated this way are source data, the sponsor must ensure that they are documented in compliance with the legislation and that the statutory archiving obligation is observed. Continued access to this documentation must be guaranteed (ICH GCP E6 (R2) 8.1 Addendum).

The sponsor must define measures in order to ensure that the recorded data actually originate from the trial subjects or were generated by the trial subjects (and not, for example, by a third person). Here it must be ensured that the sponsor has no access to personal or identifiable information relating to the trial subjects. 

To ensure the protection of personal data from unauthorised or accidental disclosure, the sponsor must protect these data from any form of intervention from outside, whether accidental or intentional. This protection applies to all personal, identifiable information, to all personal health-related data and to devices and mobile technologies used to collect, store or transmit data. Compliance with the Swiss Data Protection Act must be guaranteed.”

5.6 If a clinical study involves the study product as OTC and this is provided via pharmacy/amazon, etc., are there any specific regulations for IP management that need to be followed?

Fulfillment via DTP is addressed in a joint paper published by Swissmedic and Swissethics entitled “Decentralized clinical trials (DCTs) with medicinal products in Switzerland”. Section 2.3 provides that:

“If the IMP is dispensed outside the trial site, the requirements of Good Manufacturing Practice (GMP) must be fulfilled (Annex 1 of the Ordinance on Licensing in the Medicinal Products Sector, MPLO [812.212.1]; Art. 32 para. 1 let. d ClinO). Moreover, the requirements of the Good Distribution Practice (GDP) for the IMP and the applicable cantonal provisions in Switzerland must be fulfilled. It is furthermore recommended that the details of a planned implementation in Switzerland be discussed in advance with Swissmedic and the competent Ethics Committee and, if applicable, the competent cantonal authorities.”

5.7 For a marketed study product/OTC, can a participant be compensated after confirmation of the purchased study product, or upfront prior to product acquisition? Does compensation in any way impact how the study is viewed (i.e., RWE vs. Interventional Study)?

No, not so far as we can determine, although it may be possible. Annex 3 of Clinical Trials Ordinance (ClinO), which deals with the submission of documents to the ethics committee, requires that applicants submit “information on the type and amount of remuneration for participants” – it may be that remuneration is dealt with on a case-by-case basis.

5.8 Is it permitted to pay participant stipends (i.e., is it permitted to pay the patients for their participation in the clinical trial)? If so, what is the average range?

Payments are only possible where no direct benefit is expected - see Art. 14 of the Health Research Act (HRA):

“i. No person may receive payment or any other non-cash advantage for participation in a research project with an expected direct benefit. Participation in a research project with no expected direct benefit may be appropriately remunerated.

ii. No person may demand or accept payment or any other non-cash advantage from another in return for the latter’s participation in a research project.”

Swissmedic clarifies the “participant reimbursement” further in their position paper “Monetary contributions to patients participating in research projects_09 Mar 2016” (only available in French and German). Section 3 - “The perspective of the cantonal ethics committees” - indicates the following:

“General principles

• When assessing a research project, the decisive factor is and remains whether the potential benefit of the research is considered to be higher than the risk associated with it - regardless of any financial contributions.
• Research with a direct benefit may not be associated with remuneration or a monetary benefit.
• The Human Research Act generally allows appropriate remuneration for participants in research without direct benefit, i.e. in principle also for patients, if the project as such or individual elements of the project (e.g. additional diagnostics that are not individually necessary or blood samples for pharmacokinetic studies) do not have a direct benefit expect benefit.
• A payment to patients (or the granting of a monetary benefit) can be made, but it does not have to be (“can” provision).
• Financial donations to test subjects and patients must be disclosed to the ethics committee (and, if necessary, justified upon request) and clearly stated in the test subject/patient information.
• The ethics committees make decisions on a case-by-case basis as to whether a financial contribution or its amount is appropriate or not.
• The ethics committees do not consider it their task to counteract the current heterogeneous practice by standardizing financial donations.”

5.9 Specific labeling requirements for clinical study product

Section 08 from the Clinical Trial Dossier provides the following:

For clinical trials of Category B and C, examples of the IMP labels to be used for the final product must be provided.

1. The identification labels for the trial products must comply with the requirements of Annex 13 of the "EUDRALEX Volume 4 - Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice". The following elements are essential: 

1. IMP name (incl. placebo, if applicable), dose form, and strength of the product
2. "For clinical trial use only"
3. Number or name of the clinical trial
4. Batch number
5. Expiry date or retest date
6. Patient number or randomization number
7. "Keep out of reach of children" (if IMP is administered by the patient himself)
8. Name of Sponsor or principal investigator or CRO (global Sponsor is acceptable) 
9. Storage conditions

These parameters have to be clearly identifiable. Parameters which are not self-explaining, or which are not depicted on the label, but are compiled in a unique identifier because Interactive Randomization Technology is involved, have to be presented by listing them and providing the missing information. The following must be obvious for the assessor: 

• Which number or sign is the unique identifier
• Which of the mandatory parameter are connected with the unique identifier
• Which is the Sponsor Study code 2

2. The identification labels for the IMP purchased directly from the market must comply with the requirements of Annex 13 of the "EUDRALEX Volume 4 - Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice". The following elements are essential:

1. Number or name of the clinical trial
2. Patient number or randomization number
3. Name of sponsor or principal investigator or CRO 

3. The identification labels must be available in the appropriate Swiss national language. The identification labels may be provided in English if the trial product is administered directly by the investigator to the trial subject at the trial center.

4. For IMPs emitting ionizing radiation, labels must also comply with Art. 46 of the Radiological Protection Ordinance (SR 814.501).

5. A copy of the identification labels must be submitted for both primary and secondary packaging (outer and inner packaging). 

6. For auxiliary medicinal products (AxMPs**) authorized in Switzerland or in a GMP-equivalent country* with packaging in the appropriate Swiss national language, no study-specific labels have to be submitted. Otherwise, labels must be submitted according to points 1 and 3-6 of section 07Q (4) of the “Swissmedic - Working Instructions Clinical Trial Application Dossier”. 

7. If an IMP, after it has been shipped to the study site, only has to be reconstituted or only has to be reconstituted and subsequently blinded for administration – i.e. no further manufacturing step according to the Therapeutic Product Act (HMG/LPTh/LATer°) and the Medicinal Products Authorization Ordinance (AMBV/OAMéd/OAMed°°) is performed at the study site – and the IMP is thereafter transferred to a final container which is different from the one labeled according to the example submitted in the CTA, then the following applies: 

It is in the responsibility of the sponsor to instruct the personnel designated to perform this reconstitution / preparation to label the final container in order to provide the following information: 

1. Number or name of the clinical trial 
2. IMP name/identifier and strength/potency and or placebo
3. Patient number or randomisation number 
4. If needed: Date/time of reconstitution 
5. Use-up date/time
6. Storage requirements

Swissmedic also provides the additional clarification on labels within the “FAQ on clinical trials with medicinal products”: 

Must labels be provided in several national languages? 

Depending on the Canton and the geographical location of the trial centre in Switzerland, the labels must be provided in one or several of the official national languages. 

Exception: For clinical trials in which the IMP is exclusively administered directly at the clinic or hospital by the investigator, and is not dispensed to the trial subjects, Swissmedic also accepts texts on the labels in English. 

Information to be provided on the label:

In order to be used within the framework of a clinical trial, all IMPs must have a trial-specific label. Samples of the labels of all IMPs must be submitted as part of the application dossier. 

The compulsory elements of the labels for IMPs are laid down in Annex 13, "Manufacturing of investigational medicinal products" to Volume IV of the EU guideline to Good Manufacturing Practice. 

If a commercially available medicinal product is used as test product or comparator product, a considerable amount of information such as batch number, expiry date and storage conditions is already included on the normal commercial label. In these cases, it is possible to use only an additional label with the following elements: 

• Trial number or Trial ID; 
• Trial subject number / Patient ID; 
• Name of the sponsor, investigator or CRO, and contact details of the main contact for information. It is acceptable to indicate the global sponsor’s name and phone number, as appropriate.

5.10 What documents need to be submitted (including relevant fee if any), and to whom, if a permit is needed for an investigational/study product being shipped from outside the country? Are there any specific requirements for biologics?

Swissmedic’s CTA approval also includes an import authorization, valid for the duration of the clinical trial.

See Section 10 of Swissmedic’s Clinical Trial Application Dossier Guideline:

“In case the IMP(s) is/are imported from a foreign country and intended to be sent directly to the Swiss centre(s) involved in the clinical trial, Swissmedic will grant an authorisation of import based on the information provided in the CTA Form. This authorisation concerns exclusively the IMP(s) used in the clinical trial concerned and is valid only for the duration of the clinical trial. This authorisation of import is given in the authorisation letter for the clinical trial. The same applies for import of auxiliary medicinal products…. used in the clinical trial, based on the information provided in the cover letter.”

“In case of import of the IMP(s) by a distributor located in Switzerland (for example a hospital pharmacy or packaging company), this distributor must have the appropriate licences from Swissmedic to import, store and distribute the IMP(s). In case such a company is not in possession of the licences required, the licence(s) need to be applied for. The instructions and forms for such application are available on www.swissmedic.ch (Section Licensing; “Authorisations - > Forms - > Authorisation“ - Swiss Medic - Authorisation Forms)..... Meanwhile, this company can pursue its activities until the decision with regard to licences has been taken. The same applies for import of auxiliary medicinal products used in the clinical trial, based on the information provided in the cover letter.

If substances which are under the control of the narcotics law (narcotics like opioids or psychotropics like benzodiazepines) must be imported, an import authorisation according to the narcotics law is required for each import. This authorisation can only be issued by the Narcotics Division of Swissmedic.

If substances capable of emitting ionising radiation must be imported, the import for this substance must be covered by the handling licence of the Federal Office of Public Health (FOPH).

5.11 What is the turn-around time to get an import permit?

Generally, the authorization to import product is given by Swissmedic in the letter of authorization to conduct the clinical trial – see Section 5.10 above.

5.12 Does local authority allow the destruction of clinical supplies at an off-site location (e.g. third-party vendor in or outside the country) after study completion? Are certificates of destruction required?

Whilst return of IMP to the sponsor or destruction on site is specifically referred to, there is no mention of destruction outside of Switzerland, but neither is prohibition mentioned.

Swissmedic’s “FAQ on clinical trials with medicinal products” indicates the following:

“What is drug accountability and to which medicinal products does it apply?

Drug accountability means maintaining documentation that accounts for the whereabouts of IMPs used in a clinical trial up to the level of the individual trial subject (volunteer, patient) and medication units. This involves the following steps:

• Receipt and storage by the trial center
• Dispensing to the patient or administration at the trial center
• Return of unused units and empty containers
• Return to the sponsor or destruction of remaining product on site

Note: Drug accountability is a GCP aspect but is not part of the CTA review by Swissmedic. It may, however, be assessed during a GCP inspection.”