Regulatory Open Forum

This message was posted by a user wishing to remain anonymous

Dear Colleagues:

In a clinical study with a study drug (unapproved for any indication) combined with an approved drug (in this case either ipilimumab or pembrolizumab), is it necessary to provide the investigators and the IRB with the Investigator Brochure for the ipilimumab and pembrolizumab when those 2 approved drugs are not approved for the indication being studied?  Is it enough that the prescribing information is available?  Of course the IB is being provided to investigators and the IRB for the brand new study drug unapproved for any indication, but my understanding is that an IB must be provided and in the TMFs for any study drug in a clinical trial if that study drug is approved for other indications and not the indication being treated in the clinical trial.  However, I have been told by a source that the prescribing information for the ipilimumab and pembrolizumab, which is publicly available, is enough.  

I appreciate your time and expertise!

Ms. Anonymous

Hello Ms. Anonymous,

I recently went through a similar process. IB is for the investigational product (IP) and is frequently updated (at least annually) since the safety/tolerability data for the IP is limited. For marketed products (approved for any indication), there is enough evidence demonstrating the clinical safety of the drug and the PI contains the most up to date information about the drug. So, even if you are studying an approved drug for an unapproved indication in combination with your company drug, you need not provide the approved drugs IB. Only the PI for the marketed drug (Pembrolizumab) is suffice. 


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Saurabh Kothari MSRA, MSBE, RPh, CCRP, RAC
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Original Message:
Sent: 18-Nov-2018 08:46
From: Anonymous Member
Subject: Investigator Brochure Question

This message was posted by a user wishing to remain anonymous

Dear Colleagues:

In a clinical study with a study drug (unapproved for any indication) combined with an approved drug (in this case either ipilimumab or pembrolizumab), is it necessary to provide the investigators and the IRB with the Investigator Brochure for the ipilimumab and pembrolizumab when those 2 approved drugs are not approved for the indication being studied?  Is it enough that the prescribing information is available?  Of course the IB is being provided to investigators and the IRB for the brand new study drug unapproved for any indication, but my understanding is that an IB must be provided and in the TMFs for any study drug in a clinical trial if that study drug is approved for other indications and not the indication being treated in the clinical trial.  However, I have been told by a source that the prescribing information for the ipilimumab and pembrolizumab, which is publicly available, is enough.

I appreciate your time and expertise!

Ms. Anonymous

Agree 100% with your assessment i.e. approved label/PI for approved drugs are sufficient. However, your IB for the drug which is being studied/investigated along with approved drugs should contain information/data on any preclinical/clinical (published/unpublished or provide references) that you or anyone performed in support of this new IND combination study. If you need further clarification contact me directly.

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GRSAOnline
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Original Message:
Sent: 18-Nov-2018 08:46
From: Anonymous Member
Subject: Investigator Brochure Question

This message was posted by a user wishing to remain anonymous

Dear Colleagues:

In a clinical study with a study drug (unapproved for any indication) combined with an approved drug (in this case either ipilimumab or pembrolizumab), is it necessary to provide the investigators and the IRB with the Investigator Brochure for the ipilimumab and pembrolizumab when those 2 approved drugs are not approved for the indication being studied?  Is it enough that the prescribing information is available?  Of course the IB is being provided to investigators and the IRB for the brand new study drug unapproved for any indication, but my understanding is that an IB must be provided and in the TMFs for any study drug in a clinical trial if that study drug is approved for other indications and not the indication being treated in the clinical trial.  However, I have been told by a source that the prescribing information for the ipilimumab and pembrolizumab, which is publicly available, is enough.

I appreciate your time and expertise!

Ms. Anonymous

​I agree with the second respondent.  It is assumed that the study in the USA and being conducted under a FDA IND.  The  PI for the commercially available drug relates to the approved uses for that drug and not for any unapproved uses or combinations with other unapproved drugs.  Therefore the IRB and the Clinical Investigators need to receive additional information on the safety of the combination, intended doses, strengths etc.  The IB should contain such information.  The only time that the PI for a commercially available drug should be used rather than the IB is when the commercially available drug is used as a comparator and when used the under the conditions, indications, doses etc. covered with the approved labeling for that drug.

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Michael Trapani
Senior Consultant
Monroe Township NJ
United States
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Original Message:
Sent: 19-Nov-2018 10:29
From: Narayan Rao
Subject: Investigator Brochure Question

Agree 100% with your assessment i.e. approved label/PI for approved drugs are sufficient. However, your IB for the drug which is being studied/investigated along with approved drugs should contain information/data on any preclinical/clinical (published/unpublished or provide references) that you or anyone performed in support of this new IND combination study. If you need further clarification contact me directly.

------------------------------
GRSAOnline

Original Message:
Sent: 18-Nov-2018 08:46
From: Anonymous Member
Subject: Investigator Brochure Question

This message was posted by a user wishing to remain anonymous

Dear Colleagues:

In a clinical study with a study drug (unapproved for any indication) combined with an approved drug (in this case either ipilimumab or pembrolizumab), is it necessary to provide the investigators and the IRB with the Investigator Brochure for the ipilimumab and pembrolizumab when those 2 approved drugs are not approved for the indication being studied?  Is it enough that the prescribing information is available?  Of course the IB is being provided to investigators and the IRB for the brand new study drug unapproved for any indication, but my understanding is that an IB must be provided and in the TMFs for any study drug in a clinical trial if that study drug is approved for other indications and not the indication being treated in the clinical trial.  However, I have been told by a source that the prescribing information for the ipilimumab and pembrolizumab, which is publicly available, is enough.

I appreciate your time and expertise!

Ms. Anonymous

Just to tag on to what Michael has mentioned here, I would also state that any IRB that is truly reviewing the study in question would (and should) ask for any additional information on the combination of the products involved as well as any data that might be readily available to a sponsor of the intended study with respect to risks of using even approved drugs for unapproved uses.  As a member of an IRB in a prior life, that was something that our team would regularly require or would require an absolute statement that the product combination or that the currently approved drugs had never been studied for this indication.  It is also likely that your IRB will want something specific about that in the patient materials, informed consent, disclosure statements from clinical staff, etc. in order to ensure that the participants have full information before agreeing to enroll in or continue with your planned clinical trial.

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Victor Mencarelli
Director Regulatory Affairs
United States
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Original Message:
Sent: 20-Nov-2018 08:58
From: Michael Trapani
Subject: Investigator Brochure Question

​I agree with the second respondent.  It is assumed that the study in the USA and being conducted under a FDA IND.  The  PI for the commercially available drug relates to the approved uses for that drug and not for any unapproved uses or combinations with other unapproved drugs.  Therefore the IRB and the Clinical Investigators need to receive additional information on the safety of the combination, intended doses, strengths etc.  The IB should contain such information.  The only time that the PI for a commercially available drug should be used rather than the IB is when the commercially available drug is used as a comparator and when used the under the conditions, indications, doses etc. covered with the approved labeling for that drug.

------------------------------
Michael Trapani
Senior Consultant
Monroe Township NJ
United States

Original Message:
Sent: 19-Nov-2018 10:29
From: Narayan Rao
Subject: Investigator Brochure Question

Agree 100% with your assessment i.e. approved label/PI for approved drugs are sufficient. However, your IB for the drug which is being studied/investigated along with approved drugs should contain information/data on any preclinical/clinical (published/unpublished or provide references) that you or anyone performed in support of this new IND combination study. If you need further clarification contact me directly.

------------------------------
GRSAOnline

Original Message:
Sent: 18-Nov-2018 08:46
From: Anonymous Member
Subject: Investigator Brochure Question

This message was posted by a user wishing to remain anonymous

Dear Colleagues:

In a clinical study with a study drug (unapproved for any indication) combined with an approved drug (in this case either ipilimumab or pembrolizumab), is it necessary to provide the investigators and the IRB with the Investigator Brochure for the ipilimumab and pembrolizumab when those 2 approved drugs are not approved for the indication being studied?  Is it enough that the prescribing information is available?  Of course the IB is being provided to investigators and the IRB for the brand new study drug unapproved for any indication, but my understanding is that an IB must be provided and in the TMFs for any study drug in a clinical trial if that study drug is approved for other indications and not the indication being treated in the clinical trial.  However, I have been told by a source that the prescribing information for the ipilimumab and pembrolizumab, which is publicly available, is enough.

I appreciate your time and expertise!

Ms. Anonymous

I respectfully disagree with the advice to include information on the investigational use of comparators in the IB unless it impacts on the safety of the investigational product that is the subject of the IB. Remember that the IB is information for the investigator about the investigational product and not the specific study being conducted. That IB has to be relevant to other studies of the product as well. If there is information related to the safety of the comparators that is not covered by the labeling for those products, that information should be provided in the protocol.  If the use of the comparator in the study significantly changes the risk profile for the product, doesn't that make it an investigational product on its own?

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Glen Park
Jersey City NJ
United States
------------------------------

Original Message:
Sent: 18-Nov-2018 08:46
From: Anonymous Member
Subject: Investigator Brochure Question

This message was posted by a user wishing to remain anonymous

Dear Colleagues:

In a clinical study with a study drug (unapproved for any indication) combined with an approved drug (in this case either ipilimumab or pembrolizumab), is it necessary to provide the investigators and the IRB with the Investigator Brochure for the ipilimumab and pembrolizumab when those 2 approved drugs are not approved for the indication being studied?  Is it enough that the prescribing information is available?  Of course the IB is being provided to investigators and the IRB for the brand new study drug unapproved for any indication, but my understanding is that an IB must be provided and in the TMFs for any study drug in a clinical trial if that study drug is approved for other indications and not the indication being treated in the clinical trial.  However, I have been told by a source that the prescribing information for the ipilimumab and pembrolizumab, which is publicly available, is enough.

I appreciate your time and expertise!

Ms. Anonymous

This message was posted by a user wishing to remain anonymous

I agree with the person above. If the safety profile of the concomitant (combination) drug differs so greatly from its indicated use in the study, then it becomes an investigational medicinal product itself. I have had differing EU health authorities classify the concomitant drug as non-IMP and as IMP in the same study, so it was a non-IMP in one country and an IMP in another.
Original Message:
Sent: 21-Nov-2018 09:12
From: Glen Park
Subject: Investigator Brochure Question

I respectfully disagree with the advice to include information on the investigational use of comparators in the IB unless it impacts on the safety of the investigational product that is the subject of the IB. Remember that the IB is information for the investigator about the investigational product and not the specific study being conducted. That IB has to be relevant to other studies of the product as well. If there is information related to the safety of the comparators that is not covered by the labeling for those products, that information should be provided in the protocol.  If the use of the comparator in the study significantly changes the risk profile for the product, doesn't that make it an investigational product on its own?

------------------------------
Glen Park
Jersey City NJ
United States

Original Message:
Sent: 18-Nov-2018 08:46
From: Anonymous Member
Subject: Investigator Brochure Question

This message was posted by a user wishing to remain anonymous

Dear Colleagues:

In a clinical study with a study drug (unapproved for any indication) combined with an approved drug (in this case either ipilimumab or pembrolizumab), is it necessary to provide the investigators and the IRB with the Investigator Brochure for the ipilimumab and pembrolizumab when those 2 approved drugs are not approved for the indication being studied?  Is it enough that the prescribing information is available?  Of course the IB is being provided to investigators and the IRB for the brand new study drug unapproved for any indication, but my understanding is that an IB must be provided and in the TMFs for any study drug in a clinical trial if that study drug is approved for other indications and not the indication being treated in the clinical trial.  However, I have been told by a source that the prescribing information for the ipilimumab and pembrolizumab, which is publicly available, is enough.

I appreciate your time and expertise!

Ms. Anonymous