A new EU Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic was released on 28.04.2020. The Norwegian Medicines Agency (NoMA) has therefore updated the information below in accordance with this. The changes are a further clarification of the information provided by the NoMA. The main changes to the information are regarding monitoring of the study and the sending of study drugs to a trial participant.
Information regarding processing times for Clinical Trial and Substantial Amendment Applications
The Norwegian Medicines Agency is currently experiencing reduced staffing levels due to the measures implemented by the government as a result of the covid-19 outbreak in Norway. Therefore, longer processing times for applications will need to be expected for both Clinical Trial and Substantial Amendment Applications (please note that this is not applicable for covid-19 related applications).
Information regarding changes to Clinical Trials as a result of the covid-19 outbreak
The changes, as described below, are applicable until further notice from the Norwegian Medicines Agency.
Due to given measures implemented throughout all sectors in Norway including the Health Service, it is likely that many clinical trials will be affected and may not be able to be conducted as planned.
Firstly, NoMA would like to encourage all clinical trial investigators and their teams to take appropriate precautions regarding infection control. Secondly, we request that sponsors and their affected research units make the necessary priorities and measures as early as possible, so that the changes can be implemented in the safest possible way. NoMA would also like to encourage all clinical trial investigators and their teams to carefully consider whether it is appropriate to burden the Health Service with the commencement and implementation of new clinical trials that are not related to covid-19 during this current period of an ongoing pandemic.
NoMA defines all changes that must be made to ongoing clinical trials as a result of covid-19 readiness as safety measures. This means that safety measures can be implemented before they are sent for approval to NoMA. Further information regarding this process can be found below.
A temporary halt of the inclusion of new trial participants for ongoing studies due to the covid-19 pandemic can be implemented without sending a notification to NoMA. A temporary halt can be lifted without sending a notification to NoMA. If the sponsor decides at a later stage that the study will not be continued (premature end of trial), we request that the sponsor sends a Declaration of the End of Trial Form to NoMA.
During this current period of the pandemic, the Norwegian Medicines Agency requests that changes that are implemented due to covid-19 are implemented as a security measure. This means that the sponsor can implement the changes without notifying or sending a substantial amendment application to NoMA. However, it is important that changes are documented and communicated in writing to all the principal investigators of the study.
The Norwegian Medicines Agency assumes that Sponsors have internal procedures in place for managing the implementation of these changes and therefore wishes to have a flexible approach regarding its management, as long as they are well documented.
We consider most of the changes in this situation could either directly or indirectly affect the patients’ safety and therefore, in most cases, will mean a substantial amendment to the study. Substantial changes will need to be submitted for approval.
We also recommend both substantial and non-substantial changes due to the pandemic be included in an Appendix to the protocol. It is the sponsor’s responsibility to assess whether an amendment is to be regarded as substantial or non-substantial.
This will make it easier to follow-up and update the changes during the course of study. The appendix should be submitted as a consolidated amendment along with any other possible changes, e.g. to the protocol, EudraCT form, etc. when the pandemic situation is stable and there is a lowered probability for the need for further covid-19-related changes in the immediate future, or when the sponsor wishes to do so. A single submission by the same sponsor with the list of concerned trials and an aggregated list of changes is acceptable.
We request that all submissions relating to covid-19 are clearly marked, preferably in the subject heading of your e-mail. All covid-19 submissions will be prioritised by NoMA.
We will also try to answer all you questions sent by e-mail to klut@legemiddelverket.no. Please ensure that any questions relating to covid-19 are clearly marked covid-19 in the subject field.
Questions and Answers relating to covid-19 and Clinical Trials
What is the sponsor's responsibility in the current situation?
The covid-19 situation may present additional challenges when conducting clinical trials in accordance with the approved protocol. The sponsor will need to make a risk assessment (see ICH-GCP, section 5) for changes that are deemed as necessary. Risk assessments should focus on critical tasks and how they can best be implemented. Patient safety should be given particular importance. Risks must be continuously identified, assessed and evaluated. Risk assessments as well as any decisions made must be documented in the Trial Master File. This is also applies for any re-assessments that are conducted. The risk assessment will need to be performed before the implementation of urgent safety measures, as well as prior to sending a substantial amendment application to NoMA.
The Sponsor must ensure that close communication is maintained with the principal investigator, in order to convey the changes the sponsor wishes to implement, as well as safeguard any prospective problems that may arise at the site(s), so that they may be communicated to the sponsor.
The Norwegian Medicines Agency recognises the need for adjustments to the trial during the pandemic, and that this may lead to more protocol deviations than normal. These protocol deviations may not trigger the need for sending a substantial amendment application to NoMA. The Norwegian Medicines Agency expects the Sponsors to manage and escalate these protocol deviations in accordance with standard procedure(s).
Please note that our GCP inspectors will take the current situation into account when conducting future inspections.
Is it possible to send study drugs to a patient’s home, for ongoing clinical trials?
Yes, the Norwegian Medicines Agency (NoMA) considers the sending of study drugs to the patient’s home acceptable. Study drugs must be acquired using standard routines by the Principal Investigator or by the Study Physician who has been delegated this task. The study drugs must be delivered directly to the patient, at their place of residence. They cannot be left in the patient’s letterbox. All individual deliveries of the study drug must be documented.
In the event that study drugs are sent directly to a patient, the changes should be documented in same manner as other changes, and can be submitted as an aggregated list of changes, via a single submission to NoMA.
The direct shipping (from outside of Norway) of study drugs from the Sponsor to the patients address is not acceptable. For further information, please see guidance document “Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic (Version 3, 28/04/2020), section 9 (Changes in the distribution of the investigational medicinal products).”
Import of medicinal products for clinical studies in Norway may only be performed by a company which has the necessary authorisation. For this reason it is not possible to send study drugs from abroad directly home to the patient.
The sponsor can also investigate whether packages can be sent to a specific Pharmacy in Norway where they can undertake the task of sending the medication directly to each patient. The principal investigator/study physician at the study site will need to confirm which package the patients will receive, prior to the pharmacy sending the package. The activities associated with this task must be managed by the sponsor of the study. It should not be necessary to disclose any identifiable information about the patient as it is the pharmacy’s responsibility for the distribution of the medication.
Does the Norwegian Medicines Agency have any challenges in processing substantial amendment applications for clinical trials in the near future?
NoMA is prioritising all clinical trial and substantial amendment applications that arise as a result of the covid-19 outbreak. We request that all submissions relating to covid-19 are clearly marked, preferably in the subject heading of your e-mail. All covid-19 submissions will be prioritised by NoMA. Please note however, that NoMA is experiencing reduced staffing levels at present. Therefore, longer processing times for other types of applications will need to be expected.
What should I do with changes to ongoing clinical trials as a result of the covid-19 outbreak?
NoMA defines all changes that must be made to ongoing clinical trials as a result of covid-19 readiness as safety measures. This means that the sponsor can implement the changes without notifying or sending a substantial amendment application to NoMA. However, it is important that changes are documented and communicated in writing to all the principal investigators of the study.
The Norwegian Medicines Agency assumes that Sponsors have internal procedures in place for managing the implementation of these changes, and therefore wishes to have a flexible approach regarding its management, as long as they are well documented.
We consider most of the changes in this situation could either directly or indirectly affect the patients’ safety and therefore, in most cases, will mean a substantial amendment to the study. Substantial changes will need to be submitted for approval.
We also recommend both substantial and non-substantial changes due to the pandemic be included in an Appendix to the protocol. It is the sponsor’s responsibility to assess whether an amendment is to be regarded as substantial or non-substantial.
This will make it easier to follow-up and update the changes during the course of study. The appendix should be submitted as a consolidated amendment along with any other possible changes, e.g. to the protocol, EudraCT form, etc. when the pandemic situation is stable and there is a lowered probability for the need for further covid-19-related changes in the immediate future, or when the sponsor wishes to do so. A single submission by the same sponsor with the list of concerned trials and an aggregated list of changes is acceptable.
Is it possible to invite clinical trial participants to attend their appointments at different site? Can another physician/investigator examine the participant for study-related examinations or tests?
NoMA considers this to be necessary change for ongoing clinical trials, given the current measures implemented by the government.
If the changes relating to site or personnel are considered acceptable by all parties involved i.e. the principal investigator, the clinical trial team as well as the patient/participant, then it is acceptable to do so.
All extraordinary appointments must be documented at the original site and the temporary site, as well as in the patient’s records etc. An agreement must be made regarding how the transfer of study data will be communicated between the two (or more) sites.
Any significant medical decisions made during the appointment must be communicated immediately to the principal investigator at the site to which the patient belongs.
For further information, please see information regarding the submission of substantial amendments for clinical trials.
Can we implement the use of telemedicine for ongoing clinical trials during this period?
NoMA considers this to be necessary change for ongoing clinical trials, given the current measures implemented by the government.
The sponsor must decide whether this will be medically justifiable with regard to further treatment of the patients.
For further information, please see answer regarding clinical trial participants attending other sites, as well as our answer regarding the submission of substantial amendments for clinical trials.
Can remote/electronic information or forms for recruitment, patient information or patient consent be used during this period?
Changes in procedures regarding the use of remote/electronic information or forms for recruitment, patient information, or patient consent will need to be reviewed by an Ethics Committee.
We recommend that you get in touch with the Ethics Committee for Medical and Health Research (REK) in your region for further advice regarding the application process.
Is it possible to change the method for study-specific examinations during this period? Can a study nurse, for example, carry out examinations at the patient's home, or by other methods without physically visiting the patient?
NoMA considers this to be necessary change for ongoing clinical trials, given the current measures implemented by the government
The sponsor will need to decide whether this will be medically justifiable with regard to further treatment of the patients. Personnel carrying out study-related tasks must be trained in the examinations being carried out. This training must be documented. Changes to the procedures must also be documented.
For further information, please see our answer regarding clinical trial participants invited to attend a different site/attended by another investigator for study-related tests or examinations.
How will the changes affect the monitoring of studies?
It is the Sponsor’s responsibility for keeping track of the study. When the study sites are not able to receive monitoring visits, this overview must be maintained by other measures.
It is the Sponsor’s responsibility to conduct a risk assessment. A part of this risk assessment is a risk-based approach to monitoring. For example, to focus on specific study sites, specific data points or on certain processes/routines that are critical to ensuring the rights and safety of patients and the quality of the study.
It is also considered possible to increase frequency of centralised monitoring as this is based on data in electronic Case Report Forms. For further information, please see ICH-GCP 5.18.3 Extent and Nature of Monitoring (including the addendum). The main focus should be on what is crucial for patient safety and the data, for example the endpoints of the study. Plans for monitoring must be updated in accordance with what has been determined and will need to be detailed enough for the monitor to be able understand what they need to do and report, in order for the sponsor to be able to keep track of the study. The date(s) of change(s) to any procedures (this includes at a later stage the stop-date for these special measures) must be included in the plans.
Study monitors should have regular contact with each of the sites, for example by telephone, in order to keep track of their status, the number of patients still participating in the study (including the number of interruptions, number completed, etc.), problems with patient visits related to covid-19 infection (patients, staff, access to hospital etc.), any new SAEs and whether they are reported as expected, any issues identified during the centralised monitoring by the sponsor, study drug shipments (IMP and any non-IMP - not study drug), as well as any other relevant issues for the study, should also be kept track of.
Remote Source Data Verification (Remote SDV) is normally not recommended by NoMA. Exceptions may be made for studies with the indication for the prevention or treatment of Covid-19 infection, and for studies that are in the final phase of data cleaning before closing the database in regards to serious or life-threatening conditions where alternative treatment is not available.
As mentioned in the European guidelines, a review of medical records via video is based on the assumption that copies will not be sent to the monitor and that no recording of the videoconference will be made. The guidelines also state that the monitor must conduct the videoconference in a room where other people cannot see or hear the details of the review and discussion. Furthermore, any electronic links to scheduled videoconferences must be arranged using secure methods, and only to be sent those who will actually be participating in the conference call.
If Remote SDV is considered, as described above, the principal investigator, together with those responsible at the institution and the Data Protection Official/Officer (Personvernombud) must assess whether the source verification and processing of data is in accordance with The Personal Data Act (personopplysningsloven). It is assumed that the institution responsible for the study has detailed written procedures for safeguarding all matters related to access to electronic patient records for person(s) who not involved in the treatment of the patient.
The assessment must be documented in sufficient detail so that it is clear what is considered acceptable. Assessments must be filed in the Investigator Site File for the study, and made available upon inspection.
A follow-up will need to be planned and ready for implementation when the situation has normalised. This may involve increased on-site monitoring for a given period afterwards.
Does NoMA have any plans to fast track the review process for clinical trial applications with covid-19 indication and are considered to be of relevant interest in Norway?
Yes, fast track processing times will be applicable for all clinical trial applications where the indication of the study is covid-19 prevention or treatment. Expected processing time for applications is 3 working days from a receiving a valid application. Clinical trial applications for more complex studies may extend current processing times, and therefore should be expected.
Are they any covid-19 studies that are currently underway and can be recommended by the NoMA?
Yes, there are currently 2 protocols that the EUs Scientific Committee CHMP recommends:
- WHO Solidarity
- INSERM DisCoVeRy (no studies currently in Norway)
Please contact the Norwegian Medicines Agency klut@legemiddelverket.no for further information regarding the protocols.
