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Back to the forum  Query: 2017-11-22 10:25 CET (UTC+1h)
 
ElMaestro
Hero

Denmark,
2017-10-13 20:29

Posting: # 17895
Views: 623
 

 Enrollment when exclusion criteria are met [GxP / QC / QA]

Hi all,

I have a question about a recent warning letter posted here.

Long story short: a subject had a long QTc interval which should imply exclusion and the investigator included the subject anyway.
Then FDA write: "(...) you should have received permission from the sponsor before enrolling the subject."

Can someone explain this principle in slow motion to me?

I am not aware ever of exclusion criteria being dismissable by Sponsor's decree. I am not aware of anyone other than the PI or her/his delegated colleagues who can take decisions about enrolling or not in cases of doubt about fitness for the trial so I would be surprised if the protocol makes provisions for such a thing.
Please educate me here. Do you think FDA meant the investigator should have conferred with the PI (and not the sponsor) or what on Earth am I overlooking?

Many thanks for educating me.:ok:

I could be wrong, but…


Best regards,
ElMaestro

No, I still don't believe much in the usefulness of IVIVCs for OIPs when it comes to picking candidate formulations for the next trial. This is not the same as saying I don't believe in IVIVCs.
Ohlbe
Hero

France,
2017-10-13 22:21

@ ElMaestro
Posting: # 17896
Views: 538
 

 Enrollment when exclusion criteria are not met

Dear ElMaestro,

» Then FDA write: "(...) you should have received permission from the sponsor before enrolling the subject."
»
» Can someone explain this principle in slow motion to me?
»
» I am not aware ever of exclusion criteria being dismissable by Sponsor's decree.

21CFR312.53 states that
Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following: [...]
(vi) A commitment by the investigator that he or she:
(a) Will conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, the rights, or welfare of subjects


Strangely, this has been interpreted by a number of US sponsors (and apparently accepted by the FDA) as meaning that investigators could deviate from the protocol with the agreement of the sponsor, without any submission of any kind of amendment to the Ethics Committee and competent authorities. This is often labelled by sponsors as a "protocol waiver".

This is not quite in agreement with section 4.5.1 of ICH GCP, and they seem to have only read the first part of the sentence:
The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)).

In Europe, the GCP Inspectors Working Group has published a crystal clear opinion on this topic in their Q&A.

Regards
Ohlbe
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