Published EMA : Posted 08 October 2020 | By
The European Medicines Agency (EMA) on Thursday released a new guideline offering nine questions and answers on issues related to the role of data monitoring committees (DMCs) in the conduct and management of clinical trials.
EMA explains that the recommendations of DMCs are not binding for trial sponsors, but that sponsors should justify and document and instances where such recommendations are not followed.
“The ultimate responsibility for a clinical trial rests with the study sponsor, and thus the sponsor must conclude whether or not to follow DMC recommendations,” EMA writes.
However, EMA says that in cases where a DMC recommends stopping or substantially modifying a trial, the sponsor should notify the ethics committee and regulatory authorities if they are not planning to follow the recommendations. EMA notes that DMCs do not have the ability to stop a trial on their own.
EMA points out that changes in study design should, “as far as possible, be pre-planned and should also be clearly described and justified in the study protocol to ensure credibility of study outcome and trial integrity,” and that pre-planned design changes should be described in the DMC charter.
Sponsors are advised not to try to glean information about results from ongoing trials by asking questions of the DMC and are encouraged to seek advice from outside experts if questions can be answered without knowledge of the trial results.
Any unplanned changes to a trial must be made via protocol amendments. EMA says it considers changes that would affect the confirmatory nature of a study to be substantial, requiring approval of the competent authority and ethics committee. EMA recommends that urgent safety measures be implemented immediately, then followed up by a substantial protocol amendment.
EMA explains that communication about data monitoring will typically be conducted between the competent regulatory authority and the trial sponsor. But, “In exceptional circumstances related to a public health concern based on trial data or information from other sources than the trial at hand, competent regulatory authorities may consider it necessary to obtain more detailed information from the DMC before making decisions about further conduct of the trial at hand or other trials.” In such situations, EMA says that sponsors should still be involved, “to ensure that its respective roles and responsibilities are not undermined.” EMA says that these principles also apply to communication between ethics committees and DMCs.
When it comes to communication with investigators, EMA explains that the goal of communicating DMC recommendations, “Is to preserve the trial’s integrity as much as possible.” Therefore, EMA says it does not object to notifying investigators when the DMC has met and recommends continuing the trial as planned or when the DMC makes recommendations to improve data quality. EMA adds that important DMC recommendations related to safety or negative benefit-risk should be communicated immediately and that investigators should be notified promptly if the sponsor adopts a DMC recommendation to stop a trial.
EMA says that competent authorities should be notified of DMC meeting outcomes in the case of unexpected safety findings as soon as possible, and that other meeting outcomes should be included in other required or planned reporting activities.
Additionally, EMA lays out recommendations for how DMCs should proceed when contemplating stopping a trial. “The guiding principle in this situation is to minimize the impact on trial integrity should the trial subsequently continue,” EMA writes, adding that DMCs should first get the advice of outside experts in closed meetings to resolve any issues it lacks the expertise to address.
If a DMC does recommend stopping a trial and the sponsor’s representative disagrees, EMA says that, “Every effort should be made by both sides to reconcile their opposing views.” If those views cannot be resolved, EMA says the next step would be to convene a closed session with the DMC, external experts and senior sponsor staff to attempt to reach a common decision.
“This is important, as providing two opposing views on proceeding the trial to the investigators will leave them in an impossible situation and will introduce operational bias,” EMA says, noting that without reconciliation the DMC may be forced to involve the ethics committee or regulators to stop the trial.
The agency also explains when a DMC may be needed in early phases of development, while acknowledging that in-depth knowledge of a product might be necessary and that, “For early phase trials, such information might mostly be available within the sponsor’s institution.”
EMA
EMA explains that the recommendations of DMCs are not binding for trial sponsors, but that sponsors should justify and document and instances where such recommendations are not followed.
“The ultimate responsibility for a clinical trial rests with the study sponsor, and thus the sponsor must conclude whether or not to follow DMC recommendations,” EMA writes.
However, EMA says that in cases where a DMC recommends stopping or substantially modifying a trial, the sponsor should notify the ethics committee and regulatory authorities if they are not planning to follow the recommendations. EMA notes that DMCs do not have the ability to stop a trial on their own.
EMA points out that changes in study design should, “as far as possible, be pre-planned and should also be clearly described and justified in the study protocol to ensure credibility of study outcome and trial integrity,” and that pre-planned design changes should be described in the DMC charter.
Sponsors are advised not to try to glean information about results from ongoing trials by asking questions of the DMC and are encouraged to seek advice from outside experts if questions can be answered without knowledge of the trial results.
Any unplanned changes to a trial must be made via protocol amendments. EMA says it considers changes that would affect the confirmatory nature of a study to be substantial, requiring approval of the competent authority and ethics committee. EMA recommends that urgent safety measures be implemented immediately, then followed up by a substantial protocol amendment.
EMA explains that communication about data monitoring will typically be conducted between the competent regulatory authority and the trial sponsor. But, “In exceptional circumstances related to a public health concern based on trial data or information from other sources than the trial at hand, competent regulatory authorities may consider it necessary to obtain more detailed information from the DMC before making decisions about further conduct of the trial at hand or other trials.” In such situations, EMA says that sponsors should still be involved, “to ensure that its respective roles and responsibilities are not undermined.” EMA says that these principles also apply to communication between ethics committees and DMCs.
When it comes to communication with investigators, EMA explains that the goal of communicating DMC recommendations, “Is to preserve the trial’s integrity as much as possible.” Therefore, EMA says it does not object to notifying investigators when the DMC has met and recommends continuing the trial as planned or when the DMC makes recommendations to improve data quality. EMA adds that important DMC recommendations related to safety or negative benefit-risk should be communicated immediately and that investigators should be notified promptly if the sponsor adopts a DMC recommendation to stop a trial.
EMA says that competent authorities should be notified of DMC meeting outcomes in the case of unexpected safety findings as soon as possible, and that other meeting outcomes should be included in other required or planned reporting activities.
Additionally, EMA lays out recommendations for how DMCs should proceed when contemplating stopping a trial. “The guiding principle in this situation is to minimize the impact on trial integrity should the trial subsequently continue,” EMA writes, adding that DMCs should first get the advice of outside experts in closed meetings to resolve any issues it lacks the expertise to address.
If a DMC does recommend stopping a trial and the sponsor’s representative disagrees, EMA says that, “Every effort should be made by both sides to reconcile their opposing views.” If those views cannot be resolved, EMA says the next step would be to convene a closed session with the DMC, external experts and senior sponsor staff to attempt to reach a common decision.
“This is important, as providing two opposing views on proceeding the trial to the investigators will leave them in an impossible situation and will introduce operational bias,” EMA says, noting that without reconciliation the DMC may be forced to involve the ethics committee or regulators to stop the trial.
The agency also explains when a DMC may be needed in early phases of development, while acknowledging that in-depth knowledge of a product might be necessary and that, “For early phase trials, such information might mostly be available within the sponsor’s institution.”
EMA