Regulatory Open Forum

Hi,

I work in a large pharma company and I'm helping set up an internal SOP for requests for FDA Form 1572 waivers if an investigator at a non-U.S. clinical trial site refuses to sign the form (based on the 2021 guidance/Q&A on this topic). Some good questions have come up as I discuss this guidance with other functional lines. I'm afraid I don't know the answer to these since my knowledge is limited to that of the guidance documents, and I'm not sure how other regulatory colleagues are addressing these. I welcome any insights/thoughts you have about this process!  

1) Has FDA shared in any forum when the guidance is expected to be final, and what are the consequences of noncompliance?
2) Do we know of any examples of consequences of non-compliance?
3) Are other Sponsors requesting retrospective waiver requests, or is the industry focusing on prospective site initiations?
4) Does anyone have experience submitting this information for proposed, rather than selected, sites?

I really appreciate any thoughts on this, as I figure I'm not the only one trying to figure out the most straightforward and fastest way to be compliant while also not slowing down clinical studies.  

 Hello 

1. I would not be concerned about the finality of the guidance, you cannot be non-compliant with a non-binding guidance (i.e., a guidance that does not have the force of law). In fact, you are asking FDA to agree to a non-compliant action when you request a waiver of an IND requirement (per 21 CFR 312.10), specifically of the requirement of 21 CFR 312. 23(a)(6)(b) to obtain a signed 1572 and to submit the investigator information that is on that form.
   
   By requesting a waiver, you are acknowledging that you will not be compliant with this requirement, but you are explaining why you cannot comply and making the case that this non-compliance will not impact FDA's review or the quality of the study, in that you have an alternative way to meet the spirit (but not the letter) of the law.  In this case, this would be by showing how you will ensure that investigators will comply with GCP and local requirements, so that the validity and veracity of the data from these sites can be assured and that FDA can rely on data from these sites when they review your NDA.
    
2. Without a waiver for this planned non-compliance, I think that FDA could technically put the study (or potentially the entire IND) on clinical hold and/or terminate the IND on the grounds that, by not submitting the required investigator information for their evaluation AND not obtaining a waiver from the requirement, you have not provided FDA with sufficient information required under 312.23 for them to assess the risks to subjects since they have to concur that investigators are qualified - § 312.42(b)(iv) and § 312.44(b)(ii).  However, this would require FDA to determine this during the study.  I am not sure how easily that would be discovered, perhaps if you submitted an investigator to the IND with only a CV and no 1572?
   
   If non-waived non-compliance is not discovered until later, it is possible that FDA would not consider the data from the sites in your NDA. You could attempt to make your case that the data can be relied upon, but the bar would likely be higher and questions about your overall study conduct more significant than if you had obtained the waiver.
       
3. I am not sure what you mean by retrospective requests. Are these sites that you previously advised FDA would be non-IND sites (and that you had a plan for how you would analyze data from these sites in context of the full protocol)?  And now you want to convert these to IND sites and need the 1572 waiver to do so? I am not sure - you may have to check with FDA unless others know the answer.  Part of the waiver request requires that you indicate that the site has not yet enrolled any patients. 
4. I think that the sites need to be identified to make a waiver request. I am not sure how FDA could be expected to grant a waiver for a site if they are not given definitive information on that site.
   
   

While my experience with obtaining 1572 waivers is limited, FDA has promptly granted waivers in response to requests that include the rationale and supporting documentation outlined in the guidance, in some cases a matter of days.  You may want to batch as many sites that have the same rationale as possible (for example, for a country where investigators cannot sign the 1572) to minimize the number of submissions.  Also note that the waiver is for the site rather than the investigator.  This means that you do not need to request another waiver if the investigator changes.

Sorry that this is lengthy, but I hope that it is helpful even though I do not have all the answers.  As you say, many of us are working to find the best way to implement these waiver requests.  

Hi,

I work in a large pharma company and I'm helping set up an internal SOP for requests for FDA Form 1572 waivers if an investigator at a non-U.S. clinical trial site refuses to sign the form (based on the 2021 guidance/Q&A on this topic). Some good questions have come up as I discuss this guidance with other functional lines. I'm afraid I don't know the answer to these since my knowledge is limited to that of the guidance documents, and I'm not sure how other regulatory colleagues are addressing these. I welcome any insights/thoughts you have about this process!  

1) Has FDA shared in any forum when the guidance is expected to be final, and what are the consequences of noncompliance?
2) Do we know of any examples of consequences of non-compliance?
3) Are other Sponsors requesting retrospective waiver requests, or is the industry focusing on prospective site initiations?
4) Does anyone have experience submitting this information for proposed, rather than selected, sites?

I really appreciate any thoughts on this, as I figure I'm not the only one trying to figure out the most straightforward and fastest way to be compliant while also not slowing down clinical studies.