Background and Introduction:
This document provides guidance on the conduct of Phase III clinical trial on specific issues, which may arise because of the COVID-19 pandemic and subsequent actions to be considered for the smooth conduct of the trial. The Pandemic may lead to difficulties to maintain complete adherence to the approved protocol, regulatory provisions/procedures, and applicable guidelines in respect of various activities involved in the conduct of clinical trials including recruitment of trial subjects, laboratory testing, diagnosis, administration of the investigational medicinal product, reporting of SAEs, scheduled visits, assessment of safety & efficacy parameters, etc. Coming up with a pragmatic solution to deal with the clinical trial activities and meet regulatory requirements could be a challenge due to the rapidly changing pandemic environment, evolving COVID-19 management protocols, inadequate resources and several logistics concerns due to COVID – 19 outbreaks. Keeping this as a rationale the current guidance is prepared. It should be noted that the measures proposed in this document will only last during the current pandemic, revocation of this guidance can be done when the COVID -19 outbreak in India has resolved.
1. Ensuring Subject safety:
Irrespective of any disruptions, the priority should be the safety of trial participants and this should be the primary focus while conducting the trial. This guidance shall be updated as per new regulations stipulated by the state, central governments, any other related regulatory requirements and evidence-based scientific knowledge/information that is available in the public domain Pragmatic actions may be required to deal with the challenges of conducting research, and in ensuring the rights, safety and wellbeing of subjects. In addition, subjects involved in the clinical trials should be properly educated on covid preventive measures, before and during the conduct of a trial.
Precautionary Measure:
Explanation Regarding COVID-19 (Superficial disease knowledge)
a) Preventive Measures explanation - Social distancing, use of mask, frequent hand washing and avoiding gathering, no touching to nose, eyes, face
b) Educate the subjects regarding signs and symptoms
c) Use a medical facility if any related symptoms develop
2. Developing a plan to ensure GCP:
Compliance with GCP provides assurance that the rights, safety and well-being of trial subjects are protected and that the results of the clinical trials are accurate and credible. Understanding the current pressure on the medical profession due to the pandemic, the pertinence of enrolling new trial participants in the current trial will be assessed carefully so that GCP compliance is ensured throughout the trial.
3. Ethics Committee (EC) Guidance:
· In the present pandemic situation Ethics Committee may allow the online submission of the EC dossier and there are chances that even the approval might be online, the members review the documents remotely and then possibility that through webinar or skype call the meeting might be conducted and approval may be given. a of the Meeting will be documented, and approval will be issued.
· EC guidance pertaining to the current pandemic situation will be verified and ensured that it is in place at the time of study initiation. It is ensured that EC guidance is followed during the entire study period, in accordance with the local regulatory authority (CDSCO).
· It is also ensured that all the site-related activities like site monitoring, Data monitoring, are in accordance with the site-specific SOP and EC should be notified for any other study-specific amendments.
· With respect to efficacy assessments, if there are immediate patient safety hazards then EC should be notified regarding protocol modifications for the collection of efficacy endpoints, such as the use of virtual assessments, delays in assessments, and alternative collection of research-specific specimens, if feasible. If there are no safety hazards, then the usual pathway for protocol amendment should be instituted.
· In case of suspension of ongoing recruitment of the trial or temporary, halt of the ongoing trial Investigator may decide to discontinue the recruitment and treatment of patients completely in order to avoid unnecessary risks and need to be communicated with a rationale to the Ethics Committee, Sponsor and the Regulatory Authority.
4. Subject selection:
· The ability to confirm eligibility, and to conduct key safety assessments and study evaluations, is of particular importance.
· Where required, recruitment should be temporarily halted or suspended and subjects can be discontinued based on PI discretion. Such decisions should be proportionate and based on benefit-risk considerations and the impact on the health and safety of the subject.
· For the utmost safety and well-being of the subject – in-person visits should be suspended because high risk of contamination with COVID-19 in high-risk zones.
· During the pandemic period to ensure no patient is entered into the clinical trial with Covid symptoms a verbal health care questionnaire is prepared and based on the PI's discretion the subject selection is done.
5. Obtaining Informed consent from the patients:
1) An unsigned consent form is provided to the patient by a healthcare worker who has entered the isolation room
2) If direct communication with the patient in isolation is not feasible or safe, the investigator (or their designee) obtains the patient’s phone number and arranges a three-way call or video conference with the patient, an impartial witness and, if desired and feasible, allow additional participants requested by the patient.
3) To ensure that patients are approached consistently, a standard process should be used that will accomplish the following:
a. Identification of who is on the call
b. Review of the informed consent with the patient by the investigator (or their designee) and response to any questions the patient may have
c. Confirmation by the witness that the patient’s questions have been answered
d. Confirmation by the investigator that the patient is willing to participate in the trial and sign the informed consent document while the witness is listening on the phone
e. Verbal confirmation by the patient that they would like to participate in the trial and that they have signed and dated the informed consent document that is in their possession
f. Documentation of the entire process
6. Subject Visit to the sites:
Since trial participants may not be able to come to the investigational site for protocol-specified visits for clinical assessments, evaluation of laboratory parameters, and safety assessments alternative methods could be implemented when necessary and feasible and would be sufficient to assure the safety of trial participants. They are:
· Phone contact
· Virtual visit
· Alternative locations for clinical assessment can be implemented through satellite labs and the evaluation of laboratory parameters can be done.
· It is necessary to address if any in-patient visits are required and assure the safety of the trial participants based on PI discretion e.g: In making decisions to continue the use or administration of the Investigational medicinal products, Changes in study visit schedules, missed visits, or patient discontinuations: It may lead to missing information (e.g., for protocol-specified procedures). It will be important to capture specific information in the case report form that explains the basis of the missing data, including the relationship to COVID-19, for missing protocol-specified information (e.g., from missed study visits or study discontinuations due to COVID-19). This information, summarized in the clinical study report, will be helpful to the sponsor and regulatory authority.
7. Investigator and site staff considerations
When there is a difficult for principal investigators to maintain their medical oversight over the trial subject, and affect the completion of study assessments, completion of study visits, and the provision of IMP to the trial subjects, the Recruitment should be temporarily halted or suspended and equally qualified & experienced medical person nearer to the subject’s house would be delegated by the investigator to ensure the safety & wellbeing of the trial subjects.
Based on benefit-risk ratio considerations if needed subjects can be discontinued from the trial upon discussion and confirmation from the sponsor. However, the safety follow-up of the subject will be done.
· The Investigator and site staff may consider the Covid checklist questionnaire every 2-3 months for assessment of any Covid-related symptoms. The Clinical research coordinator takes responsibility for the assessment of the questionnaire.
8. Remote SIVs & remote monitoring (Including Data monitoring, Source Data Verification):
Remote SIVs:
As per the standard practice, all the required/delegated team members shall be available for the training at SIV but in this situation, we should allow the team members to attend the training from home/site.
Delegated CRA can take the responsibility of conducting remote SIV through teleconference and necessary aspects like protocol training, e- CRF, lab investigations can be discussed with the site personnel
Remote Monitoring:
The guidance for conducting clinical trials during COVID-19 restrictions supports remote monitoring for oversight of clinical sites. A risk-based decision should be made on what data are critical to monitor while ensuring subject safety, data quality, and data integrity.
Remote monitoring methods to be followed during the study are as mentioned below:
· Periodic remote monitoring can be done to supplement the frequency of visits if necessary.
· Teleconferencing or videoconferencing with the trial staff can be implemented.
· Centralized monitoring and centralized review of data: Centralised monitoring of data acquired by electronic data capture systems (e.g. eCRFs, central laboratory or ECG / imaging data, etc.) that are in place or could be put in place provides additional monitoring capabilities that can supplement and temporarily replace on-site monitoring through a remote evaluation of ongoing and/or cumulative data collected from trial sites, in a timely manner.
· The remote monitoring visits sessions (videos) will be recorded and archived for any future inspection by the regulatory.
Remote Source Data Verification:
Remote source data verification can be implemented unless it does not cause an additional burden on the trial staff or in specific for data that may possess acceptable risks to the safety or the reliability/ integrity of the trial results.
· It must be ensured that critical parameters like the primary endpoint, which includes ACR Response rates, DAS 28 Score, HAQ assessments, are properly documented.
· Exceptional methods (e.g., teleconferencing or videoconferencing with trial staff) can be implemented for data source verification and regulated by the sponsor or CRO and evaluated.
9. Capturing of protocol deviations:
The COVID-19 situation is likely to introduce more protocol deviations than normal. The PDs occurred specifically due to Covid-19 situations, will be handled based on the criticality on case to case basis:
1) May need to modify protocol specified procedure
2) Document the specific protocol deviation by using the standard or alternative processes for example in person visit to the site for monitoring and a virtual visit (via phone or video calls).
3) Wide change in protocol conduct and amendments, which are necessary to prevent harm to subject – implement immediately with subsequent submission and formal approval by sponsor, EC and local regulatory authority.
4) Certain amendments that are required for the safety risks can be implemented after approval
5) Several modifications to the protocol can be captured in a single amendment
6) PI can document protocol deviations in any modification that occur prior to submission /approval
7) In case of protocol amendment/deviation/modification, the Sponsor will assess the impact and take appropriate decision, wherever necessary, in consultation with the investigator and the ethics committee to ensure the rights, safety, well-being of trial subjects, as well as integrity of the clinical data and maintain complete records of the same including the reasons for such amendments/deviations etc.
10. Communication:
In view of the present situation, the communications between sponsor, investigator and EC required for the implementation of protocol amendments/deviations/modifications can be made through email or any other electronic mode. Submission/reporting of such activities to the CDSCO may also be made through mail at dci@nic.in with a copy to the concerned division of CDSCO (HQ).
11. Concomitant medication usage at home? How to validate?
Any changes in the concomitant medication have to be done by the Principal Investigator, if necessary through the video consultation and the same need to be written on the doctor's notes and the scan copy of the doctor’s notes has to be shared with the subject to the personal email.
12. How to Document?
The date and time of the real-time video interaction, the location of the trial subject, and the location of the investigator or personnel conducting the remote visit should be documented in the case report form, similar to how it would be done for face-to-face interactions.
13. Clinical Trial Supplies & Biological Sample Management:
· Adequate clinical trial supplies can be provided to the subjects to minimize the interim site visits.
· If in case the subject cannot undertake IMP/Non-IMP, care given can pick up the IMP/Non-IMP from the pharmacy of the site
·Participants must consent verbally (and this should be documented in their source notes) for providing contact details for shipping purposes.
· If the participant does not want to sign for the delivery due to self-isolation, then a follow-up phone call could be used to confirm they have received the package.
· The sponsor may also consider if any training is required for the administration and storage of the IMP. Adequate provisions should be made to assure the integrity of the product during transit.
14. COVID-19 Clinical Guidance for Adult Patients with Rheumatic Diseases
Guidance for the management of Rheumatoid arthritis patients in Phase III Clinical trial during COVID-19 is explained in the covid management plan following the guidance of the American College of Rheumatology (ACR).
15. References
01. CDSCO Notice – Conduct of Clinical trial in the present situation due to outbreak of COVID-19 – Reg, 30 March 2020
02. National Guidelines for Ethics Committees reviewing biomedical & health research during COVID-19 Pandemic, Indian Council of Medical Research, April 2020
Further reading
01. Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency- Guidance for Industry, Investigators, and Institutional Review Boards, USFDA, Updated on Dec 4 2020.
02. Guidance on the management of Clinical trials during the COVID-19 Pandemic, EMA, 28 April 2020
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