Regulatory Open Forum

Hi all-

I have a question pertaining to comparator arm [investigator's choice chemotherapy] in clinical trial safety reporting. As they are marketed drugs, with approved labels and particular events provided as part of the label [expected/serious, etc] this is the static reference point.

It was my understanding that while all AEs would be collected on the investigational drug and comparator arms in a trial, focusing on a subset of AEs delineated as "of interest" by the sponsor [not the sponsor of the marketed drug] characterized based on the safety signals from their drug isn't allowed? The guidance is a bit tricky to interpret. I am building out a CO and all the narratives. This will be both a US and EMA filing as well. 

Thoughts/opinions and direction to proper guidance appreciated.

All best,

Colleen

Hello Colleen,

I agree that the June 2021 Draft Guidance for Sponsor on reporting of AEs is difficult to interpret (see footnote 12 on page 8). My interpretation has always been that for an open label trial AEs do not need to be collected for an active comparator, and there is no obligation on the part of the sponsor to report serious events if they are not the NDA/BLA holder. However, I believe that there is an ethical obligation on the part of the sponsor to notify NDA/BLA holders of serious, unexpected, adverse reactions to their marketed product as would be expected for any health care provider.  

Hi all-

I have a question pertaining to comparator arm [investigator's choice chemotherapy] in clinical trial safety reporting. As they are marketed drugs, with approved labels and particular events provided as part of the label [expected/serious, etc] this is the static reference point.

It was my understanding that while all AEs would be collected on the investigational drug and comparator arms in a trial, focusing on a subset of AEs delineated as "of interest" by the sponsor [not the sponsor of the marketed drug] characterized based on the safety signals from their drug isn't allowed? The guidance is a bit tricky to interpret. I am building out a CO and all the narratives. This will be both a US and EMA filing as well. 

Thoughts/opinions and direction to proper guidance appreciated.

All best,

Colleen

Hi Glen,

Thank you for providing confirmation that the guidance is a bit tricky. The issue I am having is that this was a blinded trial, the IC chemo[s] data is being scrutinized for AEs that are particular to the investigational drug. None of the events they have identified in their SAP are part of the IC Chemo labels. Further, the mechanism of action is extremely different between the investigational drug and IC chemo, so I am not sure what they expect to draw from this analysis. My concern is the sponsor wants these specific events in the IC chemo arm to be part of the narratives, with unblinded Investigator causality;  also these narratives will be part of both an FDA and EMA filing. I think they might be tripping themselves up--regulatory-wise? Any thoughts on this?

Hello Colleen,

I agree that the June 2021 Draft Guidance for Sponsor on reporting of AEs is difficult to interpret (see footnote 12 on page 8). My interpretation has always been that for an open label trial AEs do not need to be collected for an active comparator, and there is no obligation on the part of the sponsor to report serious events if they are not the NDA/BLA holder. However, I believe that there is an ethical obligation on the part of the sponsor to notify NDA/BLA holders of serious, unexpected, adverse reactions to their marketed product as would be expected for any health care provider.  

Hi all-

I have a question pertaining to comparator arm [investigator's choice chemotherapy] in clinical trial safety reporting. As they are marketed drugs, with approved labels and particular events provided as part of the label [expected/serious, etc] this is the static reference point.

It was my understanding that while all AEs would be collected on the investigational drug and comparator arms in a trial, focusing on a subset of AEs delineated as "of interest" by the sponsor [not the sponsor of the marketed drug] characterized based on the safety signals from their drug isn't allowed? The guidance is a bit tricky to interpret. I am building out a CO and all the narratives. This will be both a US and EMA filing as well. 

Thoughts/opinions and direction to proper guidance appreciated.

All best,

Colleen

Hello Colleen,

I can tell you from the UK perspective and I think this is applicable for the EU countries too. 

You need to collect AEs and SAEs related to the comparator (the chemo in your case). The idea of these blinded trials where you have standard of care chemo + study drug is also to evaluate the safety of the drug given in combination with chemo. It's not only how the drug works but you want to see if the combination increases the toxicity. 

In terms of reporting you need to report to the authorities all SAEs which are classified as product related. You have to submit to the authorities unblinded safety information so you need to have someone in drug safety who is unblinded.

Have a great week,

Olga

Hi Glen,

Thank you for providing confirmation that the guidance is a bit tricky. The issue I am having is that this was a blinded trial, the IC chemo[s] data is being scrutinized for AEs that are particular to the investigational drug. None of the events they have identified in their SAP are part of the IC Chemo labels. Further, the mechanism of action is extremely different between the investigational drug and IC chemo, so I am not sure what they expect to draw from this analysis. My concern is the sponsor wants these specific events in the IC chemo arm to be part of the narratives, with unblinded Investigator causality;  also these narratives will be part of both an FDA and EMA filing. I think they might be tripping themselves up--regulatory-wise? Any thoughts on this?

Hello Colleen,

I agree that the June 2021 Draft Guidance for Sponsor on reporting of AEs is difficult to interpret (see footnote 12 on page 8). My interpretation has always been that for an open label trial AEs do not need to be collected for an active comparator, and there is no obligation on the part of the sponsor to report serious events if they are not the NDA/BLA holder. However, I believe that there is an ethical obligation on the part of the sponsor to notify NDA/BLA holders of serious, unexpected, adverse reactions to their marketed product as would be expected for any health care provider.  

Hi all-

I have a question pertaining to comparator arm [investigator's choice chemotherapy] in clinical trial safety reporting. As they are marketed drugs, with approved labels and particular events provided as part of the label [expected/serious, etc] this is the static reference point.

It was my understanding that while all AEs would be collected on the investigational drug and comparator arms in a trial, focusing on a subset of AEs delineated as "of interest" by the sponsor [not the sponsor of the marketed drug] characterized based on the safety signals from their drug isn't allowed? The guidance is a bit tricky to interpret. I am building out a CO and all the narratives. This will be both a US and EMA filing as well. 

Thoughts/opinions and direction to proper guidance appreciated.

All best,

Colleen

Hi Glen,

Thank you for providing confirmation that the guidance is a bit tricky. The issue I am having is that this was a blinded trial, the IC chemo[s] data is being scrutinized for AEs that are particular to the investigational drug. None of the events they have identified in their SAP are part of the IC Chemo labels. Further, the mechanism of action is extremely different between the investigational drug and IC chemo, so I am not sure what they expect to draw from this analysis. My concern is the sponsor wants these specific events in the IC chemo arm to be part of the narratives, with unblinded Investigator causality;  also these narratives will be part of both an FDA and EMA filing. I think they might be tripping themselves up--regulatory-wise? Any thoughts on this?

Hello Colleen,

I agree that the June 2021 Draft Guidance for Sponsor on reporting of AEs is difficult to interpret (see footnote 12 on page 8). My interpretation has always been that for an open label trial AEs do not need to be collected for an active comparator, and there is no obligation on the part of the sponsor to report serious events if they are not the NDA/BLA holder. However, I believe that there is an ethical obligation on the part of the sponsor to notify NDA/BLA holders of serious, unexpected, adverse reactions to their marketed product as would be expected for any health care provider.  

Hi all-

I have a question pertaining to comparator arm [investigator's choice chemotherapy] in clinical trial safety reporting. As they are marketed drugs, with approved labels and particular events provided as part of the label [expected/serious, etc] this is the static reference point.

It was my understanding that while all AEs would be collected on the investigational drug and comparator arms in a trial, focusing on a subset of AEs delineated as "of interest" by the sponsor [not the sponsor of the marketed drug] characterized based on the safety signals from their drug isn't allowed? The guidance is a bit tricky to interpret. I am building out a CO and all the narratives. This will be both a US and EMA filing as well. 

Thoughts/opinions and direction to proper guidance appreciated.

All best,

Colleen