Regulatory Open Forum

For our global clinical trial for a drug, we are experiencing push back from EU investigators with signing the 1572 since the 1572 referencing compliance to 21 CFR in several places. We have created a 1572-like form which essentially just removes any references to 21 CFR and asking PI's to sign this form in place of a 1572. So we are collecting the same information and commitments from the PI's. We are planning to submit a general correspondence along with this alternate form to FDA to request agreement that submitting this form is acceptable. I'm curious if anyone is having similar issues and if so how are you handling?

Thank you.

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Tom
Senior Director, Regulatory Affairs CMC
Chicago
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This message was posted by a user wishing to remain anonymous

I don't believe you can do an IND study without a 1572. One mechanism we have used is amending the CTA (clinical trial agreement) with the European institution in question (to which the PI belongs) to provide that to the extent FDA requirements are not as strict as local (country X) requirements, Country X requirements would apply. Also it would be good to have a comparison of which US vs EU/Country X regulations governing clinical trials differ and in what way.

The general principles for doing clinical trials are essentially identical, so its reasonable to do the comparison, and to outline in which specific cases which country's laws will apply. And if you comply with the stricter of the two, then you will be complying with the other anyways. We had this occur in the middle of our studies, filed under INDs, where the PIs wanted to withdraw the 1572 (hence amended CTA).

Another option is to do the studies as non-IND studies. Data can always be submitted to the IND later as long as its done under GCP.
Original Message:
Sent: 27-Feb-2020 12:42
From: Tom Stothoff
Subject: Ex-US Investigators refusal to sign 1572

For our global clinical trial for a drug, we are experiencing push back from EU investigators with signing the 1572 since the 1572 referencing compliance to 21 CFR in several places. We have created a 1572-like form which essentially just removes any references to 21 CFR and asking PI's to sign this form in place of a 1572. So we are collecting the same information and commitments from the PI's. We are planning to submit a general correspondence along with this alternate form to FDA to request agreement that submitting this form is acceptable. I'm curious if anyone is having similar issues and if so how are you handling?

Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

This message was posted by a user wishing to remain anonymous

RAPS had a great article on this topic just two months ago:
https://www.raps.org/news-and-articles/news-articles/2019/11/form-fda-1572-challenges-and-opportunities?feed=Regulatory-Focus
Original Message:
Sent: 27-Feb-2020 17:00
From: Anonymous Member
Subject: Ex-US Investigators refusal to sign 1572

This message was posted by a user wishing to remain anonymous

I don't believe you can do an IND study without a 1572. One mechanism we have used is amending the CTA (clinical trial agreement) with the European institution in question (to which the PI belongs) to provide that to the extent FDA requirements are not as strict as local (country X) requirements, Country X requirements would apply. Also it would be good to have a comparison of which US vs EU/Country X regulations governing clinical trials differ and in what way.

The general principles for doing clinical trials are essentially identical, so its reasonable to do the comparison, and to outline in which specific cases which country's laws will apply. And if you comply with the stricter of the two, then you will be complying with the other anyways. We had this occur in the middle of our studies, filed under INDs, where the PIs wanted to withdraw the 1572 (hence amended CTA).

Another option is to do the studies as non-IND studies. Data can always be submitted to the IND later as long as its done under GCP.
Original Message:
Sent: 27-Feb-2020 12:42
From: Tom Stothoff
Subject: Ex-US Investigators refusal to sign 1572

For our global clinical trial for a drug, we are experiencing push back from EU investigators with signing the 1572 since the 1572 referencing compliance to 21 CFR in several places. We have created a 1572-like form which essentially just removes any references to 21 CFR and asking PI's to sign this form in place of a 1572. So we are collecting the same information and commitments from the PI's. We are planning to submit a general correspondence along with this alternate form to FDA to request agreement that submitting this form is acceptable. I'm curious if anyone is having similar issues and if so how are you handling?

Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

There was a very interesting session on the last Convergence conference just on that topic.

The consensus was that FDA would allow using alternative forms to the 1572 as long as long as you ask for a waiver and include description of equivalent standards and explanation on how those will be followed - but even that does not grantee the FDA will grant it. (see 21CFR312.120(c)(1)).

It is quite a problem as some countries in Europe actually made it "illegal" to make the commitments that appears on the 1572, and if found on an audit will make it a serious finding. 

You can always conduct the study not under IND in Europe and discuss with FDA how to combine the data together. 

If you have access to the slides set from the last RAPS conference I suggest you look over that session.


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Shy Shorer MD, MBA, EJD
Director, Office of Sponsor and Regulatory Oversight
Center for Cancer Research
National Cancer Institute
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Original Message:
Sent: 27-Feb-2020 12:42
From: Tom Stothoff
Subject: Ex-US Investigators refusal to sign 1572

For our global clinical trial for a drug, we are experiencing push back from EU investigators with signing the 1572 since the 1572 referencing compliance to 21 CFR in several places. We have created a 1572-like form which essentially just removes any references to 21 CFR and asking PI's to sign this form in place of a 1572. So we are collecting the same information and commitments from the PI's. We are planning to submit a general correspondence along with this alternate form to FDA to request agreement that submitting this form is acceptable. I'm curious if anyone is having similar issues and if so how are you handling?

Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

I first suggest that you take a look at the May 2010 FDA guidance Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs. However, it really does not go very far in answering all of the questions one might have about how to handle the issue. It may be easier now than in the past to get FDA to approve a waiver, but I tried it a number of years ago and their response was so burdensome that we chose to drop the request. We included the non-1572 investigators and an explanation on how we assured GCP compliance in Appendix 16.1.4 of the CSRs and got no pushback from the Agency. I have also done that subsequently. One of the ways we have documented the process is to use a "1572-like" form for the investigators to sign, as suggested by other respondents here. It is my thinking that FDA will refuse to accept data from ex-US sites only in cases where they are not provided evidence that GCP was followed as strictly as done in the US.

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Glen Park PharmD
Executive Director, Regulatory Affairs and Quality Assurance
Jersey City NJ
United States
------------------------------

Original Message:
Sent: 27-Feb-2020 12:42
From: Tom Stothoff
Subject: Ex-US Investigators refusal to sign 1572

For our global clinical trial for a drug, we are experiencing push back from EU investigators with signing the 1572 since the 1572 referencing compliance to 21 CFR in several places. We have created a 1572-like form which essentially just removes any references to 21 CFR and asking PI's to sign this form in place of a 1572. So we are collecting the same information and commitments from the PI's. We are planning to submit a general correspondence along with this alternate form to FDA to request agreement that submitting this form is acceptable. I'm curious if anyone is having similar issues and if so how are you handling?

Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

There is a very good position paper from the EFPIA from January 2020 on the use of Form 1572 outside the US and the exact problem you face.  Just search on EFPIA and 1572 form and you should find it.  I have also attached it for reference.  This pretty much mimics what FDA has said at meetings, etc.

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Michael Hamrell, Ph.D., RAC, FRAPS
Huntington Beach CA
United States
------------------------------

Original Message:
Sent: 27-Feb-2020 12:42
From: Tom Stothoff
Subject: Ex-US Investigators refusal to sign 1572

For our global clinical trial for a drug, we are experiencing push back from EU investigators with signing the 1572 since the 1572 referencing compliance to 21 CFR in several places. We have created a 1572-like form which essentially just removes any references to 21 CFR and asking PI's to sign this form in place of a 1572. So we are collecting the same information and commitments from the PI's. We are planning to submit a general correspondence along with this alternate form to FDA to request agreement that submitting this form is acceptable. I'm curious if anyone is having similar issues and if so how are you handling?

Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

Thank you everyone for the feedback, suggestions and references to guidelines and papers. Very much appreciated and I'm grateful that so many people took the time to share their thoughts and experiences.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

Original Message:
Sent: 28-Feb-2020 16:55
From: Michael Hamrell
Subject: Ex-US Investigators refusal to sign 1572

There is a very good position paper from the EFPIA from January 2020 on the use of Form 1572 outside the US and the exact problem you face.  Just search on EFPIA and 1572 form and you should find it.  I have also attached it for reference.  This pretty much mimics what FDA has said at meetings, etc.

------------------------------
Michael Hamrell, Ph.D., RAC, FRAPS
Huntington Beach CA
United States

Original Message:
Sent: 27-Feb-2020 12:42
From: Tom Stothoff
Subject: Ex-US Investigators refusal to sign 1572

For our global clinical trial for a drug, we are experiencing push back from EU investigators with signing the 1572 since the 1572 referencing compliance to 21 CFR in several places. We have created a 1572-like form which essentially just removes any references to 21 CFR and asking PI's to sign this form in place of a 1572. So we are collecting the same information and commitments from the PI's. We are planning to submit a general correspondence along with this alternate form to FDA to request agreement that submitting this form is acceptable. I'm curious if anyone is having similar issues and if so how are you handling?

Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

Thank you everyone for the feedback, suggestions and references to guidelines and papers. Very much appreciated and I'm grateful that so many people took the time to share their thoughts and experiences.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

Original Message:
Sent: 28-Feb-2020 16:55
From: Michael Hamrell
Subject: Ex-US Investigators refusal to sign 1572

There is a very good position paper from the EFPIA from January 2020 on the use of Form 1572 outside the US and the exact problem you face.  Just search on EFPIA and 1572 form and you should find it.  I have also attached it for reference.  This pretty much mimics what FDA has said at meetings, etc.

------------------------------
Michael Hamrell, Ph.D., RAC, FRAPS
Huntington Beach CA
United States

Original Message:
Sent: 27-Feb-2020 12:42
From: Tom Stothoff
Subject: Ex-US Investigators refusal to sign 1572

For our global clinical trial for a drug, we are experiencing push back from EU investigators with signing the 1572 since the 1572 referencing compliance to 21 CFR in several places. We have created a 1572-like form which essentially just removes any references to 21 CFR and asking PI's to sign this form in place of a 1572. So we are collecting the same information and commitments from the PI's. We are planning to submit a general correspondence along with this alternate form to FDA to request agreement that submitting this form is acceptable. I'm curious if anyone is having similar issues and if so how are you handling?

Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------