On the tails of the EMA’s Guidance on the Management of Clinical Trials during the COVID-19 pandemic, the Hungarian National Institute of Pharmacy and Nutrition (NIPN) has issued its guidance on how local regulations are to be applied to mitigate the negative effects of the COVID-19 pandemic on the continuity of clinical trials. It also provides divergence from general rules for clinical trials relating to COVID-19.
The NIPN points out that in the course of any decision making and risk assessment relating to adjustments to clinical trials and protocols, the provisions of the ICH GCP, the applicable European and Hungarian legal provisions, including in particular the GPDR, must be observed.
The guidance touches upon general regulatory aspects, as well as data protection issues. Below we highlight some of the key adjustments and safeguards to consider.
Prudent documentation to ensure patient safety
Patient safety is top priority for the NIPN. This means that a thorough risk assessment of ongoing trials should be carried out considering restrictions already applied and expected – such as quarantine, visitation bans in healthcare institutions, increased burden of the healthcare system, etc.– and measures should be put in place to prioritise patient safety and data validation. In the event of conflict between these two objectives, patient safety should be prioritised.
Any change should be proportionate and based on an appropriate risk assessment. Depending on the evolution of the COVID-19 situation, risk assessments should be revisited, repeated and properly documented (following ICH GCP 5.0.4).
Changes to ongoing trials should be agreed with and communicated clearly to study sites. To support implementation by the study sites, it is important that changes and local implications are made clear, including marking amended documents with track changes.
As a significant ease, in cases when obtaining wet ink signature is difficult, agreements may be documented with alternative methods, e.g. e-mail exchange.
The NIPN expects an increased number of deviations from protocol. In case of divergence, clear documentation is a must (following ICH GCP 4.5.3). The NIPN reassures that it will follow a fair approach when reviewing deviations provided they are in the interests of patients and do not expose them to undue risk.
When substantial modifications of the study are required in order to ensure the patient’s continued participation, as an ease, sponsor may do so as an “urgent safety measure” (USM). This means the change will take effect immediately. The USM, however, should be sent to the NIPN and the amendment should be subsequently, officially authorised in accordance with the general procedure.
If the continuation of the study is not possible due to COVID-19 at the study site and the relocation of the site also is met with difficulties, patients may be informed in the simplest way, even via telephone. Again, this must be properly documented, and – following an appropriate risk assessment – a decision is to be made whether the sponsor puts the study on hold or terminates that. Such decision may be provided to the NIPN subsequently with providing the reasons and the exact timing.
Obtaining Informed Consents
In Hungary, the patient’s informed consents must be obtained as a two-piece set of documents, consisting of: (i) a patient information sheet and (ii) a separate informed consent form. As a general rule, these must be in hard copy, furnished with the patient’s wet-ink signature.
From a data protection perspective it should be noted that, according to the current legislative framework in Hungary, the sole appropriate legal basis for processing health data in the context of clinical trials is explicit consent of the patient. Therefore, the sponsor and the study site should always consider that the patient information sheets and the informed consent form mentioned above should not only comply with the regulatory requirements, but also with the requirements of the applicable data protection law. In particular, the patient information sheet should include the information listed in Article 13 GDPR, and the consent forms should comply with the threshold of explicit consent of GDPR.
Considering the current situation with its restrictions, in case of ongoing trials, a new informed consent form may be necessary and patients may have to be re-informed. The NIPN informs that alternative opportunities for this re-information may be considered, such as contacting the enrolled patient via telephone or video-call, and obtaining oral verbal consent followed by confirmation via e-mail.
It is important to note that in this case every information sheet provided and consent obtained in this way must be documented, and confirmed by the patients with wet-ink signatures as soon as possible, when attendance at the study site is possible again. This presumably applies to the GDPR compliant privacy notice as well, when annexed to the patient information sheet, since in such case it should be signed on a separate signature line, according to general rules.
The principle rule thus remains in effect that, in Hungary, electronic patient information sheets and informed consent forms are not permitted, and this must be observed in the current extraordinary situation as well.
In case of COVID-19 related trials
Special rules apply to COVID-19 related clinical trials, according to the Ministerial Decree 63/2020 (III.24.), namely
- patients may be informed of the information set to be included in the patient information sheets via telecommunication means;
- informed consents may be granted as well as withdrawn via telecommunication means.
These are only applicable for non-invasive medical research in connection with COVID-19, during the state of emergency declared by Ministerial Decree 40/2020 (III.11.) due to COVID-19 and only for patients having full legal capacity.
Telecommunication means for these purposes are all devices that allow post-factum retrieval and review of such provision of information and consent, in particular ones capable of recording sound. The specific content of such information and consent nevertheless remains the same as set out in the Healthcare Act for patient information sheets and informed consent forms.
As patient security is top priority, the on-site monitoring of clinical trials are advised to be reduced and the sponsor should implement appropriate alternative methods. When choosing alternative monitoring methods it is important to consider that such methods do not place a disproportionate burden on the study site and staff, and at the same time, data security considerations receive due attention. For example, remote and central monitoring through an EDC system may be an appropriate alternative (although its scope is limited), while sharing of patient data and remote access of the sponsor’s representative to the electronic database of healthcare institutions is not acceptable.
It is emphasised that the sponsor and the study site must continue respecting the provisions of GDPR and Hungarian laws in relation to the transfer and sharing of health data in the context of monitoring (or otherwise). The study site may only share pseudonymised or anonymised health data with the sponsor or other stakeholders and, in case of the former, only the study site may be authorised to reverse the pseudonymisation.
After the normalisation of the present situation proper follow-up is to be carried out regarding the transitional monitoring measures. For example, increased or more frequent on-site monitoring in order to identify and address the possible negative effects of the transitional measures.
In case of COVID-19 related trials
The NIPN does not provide specific rules for monitoring COVID-19 clinical trials, however the NIPN states that applicable European guidelines should also be duly observed. This includes the guidelines recently adopted by the European Data Protection Board on the processing of health data for research purposes in the context of the COVID-19 outbreak, that address legal questions concerning international data transfers.
Home delivery of investigational medicinal products (IMPs)
In case of clinical trials where the patient self-administers the medication at home, the home delivery of IMPs is possible. The principal investigator is responsible for the home delivery. The person who performs the home delivery must know the relevant rules for handling such IMP, and if there are any special storage conditions, they must be documented at all times. It is useful to note that it is not necessary to inform the NIPN on the special conditions/changes.
The NIPN does not accept direct IMP delivery from the sponsor to the patient’s home as sensitive health data may be revealed.
In summary, the NIPN shows reasonable flexibility concerning the adjustments of clinical trials to the current situation and highlights that patient safety is top priority. If risk assessment proves necessary, deviations from the protocol may be executed and the NIPN confirms that it will follow a fair approach when reviewing such deviations.
Regulatory and data protection requirements should be respected when obtaining informed consents or carrying out monitoring of the study, but there is leeway for appropriate alternative methods. The NIPN allows for certain opportunities to use telecommunication devices, e-mail, phone for informing and obtaining consent from patients, in particular for COVID-19 related trials. Monitoring of clinical trials may be carried out via remote and central EDC systems.
The regulatory landscape is changing rapidly, especially concerning clinical trials related to the fight against COVID-19. New guidelines are published daily on the European and national level. Therefore, it is important for sponsors to remain up-to-date with the latest developments.