Nowadays the FDA is focused on ensuring the highest level of protection against the infectious Coronavirus Disease 2019 (COVID-19) caused by the virus “SARS-CoV-2” or the “novel coronavirus”. The guidance describes the way the pandemic could impact the clinical trials of medical products and provides all parties involved with the particular recommendations regarding the ways such impact could be reduced to the lowest extent possible.
It is also important to mention that due to the state of National Emergency announced in the US earlier on March 13, 2020, the provisions of the guidance should be implemented immediately without any prior consultations. At the same time, the Agency confirms that it still would receive and process feedback from the stakeholders while such a procedure is necessary to accelerate the implementation of the new guidance.
According to the guidance, the difficulties related to the COVID-19 could arise from:
- Quarantines and additional restrictive measures,
- Closure of sites and facilities,
- Travel restrictions and limitations,
- Additional risks related to the infecting personnel or trial subjects.
Under certain circumstances, it could be necessary to deviate from the requirements related to the clinical trial protocols since some of these requirements could be impossible to meet due to the reasonable difficulties. To assist in maintaining compliance with the general principles, the FDA describes the way such necessary modifications could be made to find the balance between maintaining compliance with good clinical practice (GCP) and ensuring the safety of patients.
Key Aspects of Clinical Trials
The document highlights the most important aspects it is necessary to take into consideration, applicable to both already ongoing clinical trials and ones that are currently on the design step.
In particular, the FDA recommends the following:
- First of all, it is necessary to focus on the safety of patients participating in trials. All elements of the clinical trials should be assessed from a safety standpoint. It is required to assess current circumstances and evaluate all existing risk factors to make decisions regarding the possibility to continue the recruitment of the new participants, to continue using the investigational product for participants already involved, and also regarding any changes to the monitoring methods that could be reasonably necessary. At the same time, the sponsors organizing the trials should duly inform the participants about any changes to the plans or procedures taken.
- Depending on the results of risk assessment related to the ongoing situation, the decision taken could be either to continue the clinical trials in accordance with existing protocols and pre-defined plans or to suspend further investigation process to mitigate risk the participants could be exposed to. The appropriate decision should be made case-by-case depending on the nature of the product, the possibility to ensure safety. The decision should be also based on the potential impact and consequences of such suspension.
- Under certain circumstances, the participants of clinical trials could be unable to attend the facilities as prescribed by the study protocols. To address these issues, it is important to establish the alternative methods of communication (e.g. contact via the phone or virtual visits). The decision regarding the alternative options should be based on the nature of the investigation. The necessity of in-person visits should be also taken into consideration when making a decision regarding the continuation of the trials or their suspension. Sometimes the participant would require additional monitoring after the suspension of access to the investigational product.
- Any decision made regarding the deviation from the protocols should be based on the rigorous assessment of existing conditions and risks associated thereto.
- Additional screening and monitoring procedures related to the COVID-19, that could be implemented in the process of clinical trials due to the requirements set forth by healthcare facilities should not be deemed as significant changes to study design and thus do not create the obligations on reporting, except the cases when they are implemented as the additional objectives of the study.
- According to the general rule, any significant changes to the study protocols should be reviewed and approved in advance, so it is required to start communications regarding the pending changes at the earliest possible steps. At the same time, under certain conditions, changes related to the COVID-19 could be implemented without prior notice while it is still required to report on these changes afterward.
- It is necessary to perform all procedures as close to initial protocols, as possible, and all additional measures should be properly documented. In particular, it is required to document the impact of COVID-19 on the trial process, including the indication of the actual impact on the patients participating in clinical trials.
- Since some of the changes to the procedures of trials, such as delayed or canceled visits could lead to situations when the trial data would be partially missed, it is necessary to document all such cases indicating the scope of the information being missed to be assessed during further evaluation of clinical trials protocols.
- Depending on the nature of investigational products, they could be allowed for self-administration or should be administered only by healthcare professionals. In case if normal administering of investigational products requires visiting healthcare institutions, it would be necessary to agree with the FDA on the alternative approach to be used. In any case, the sponsors and clinical investigators should establish proper accountability of investigational products being administered and duly document all procedures.
- The Agency also emphasizes on the necessity of evaluating all changes to the clinical trial protocols from the efficacy assessment standpoint – the changes implemented due to the current situation should not impact the accuracy and reliability of the efficacy assessment since some of the changes could lead to the situation when certain types of assessment would be unavailable.
Notwithstanding whether the particular trials has been already commenced or are still in the process of design and development, it is required to add a separate section to the study report or a separate document containing the following information:
- Additional measures implemented to reduce the risks associated with the COVID-19, and also to mitigate the impact of restrictive measures associated thereto.
- A list of all patients, participating in clinical trials, the changes would impact on.
- Rigorous analysis of the potential impact the proposed and implemented changes would have on the accuracy and reliability of the safety and performance results of the clinical trials.
The Agency requires sponsors, clinical investigators and other parties involved to document properly all measures taken, and all modifications to study protocols while maintaining the amended protocols as close to initial ones, as it would be reasonably possible.
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