Cec75
☆    

Argentina,
2019-11-15 15:39

Posting: # 20807
Views: 1,188
 

 Impact of Parenteral hydration in a BE study [Study As­sess­ment]

Hello everybody!

It´s my first post in this forum although I frequently read yours when I have any BA/BE doubt, but this time I didn´t find similar posts.
Sorry for my English, I´ll do my best to express myself and my question clearly.

I´m monitoring a bioequivalence study in a CRO with which we have never worked before.
It´s a two‐period cross‐over study, in healthy subjects, in fasted conditions.

While verifying the source documents of period 1 (at this time the wash out period is running), I noticed that the investigation site was administering parenteral hydration to the subjects since the first sample (pre-dose) was collected and during about the next 12 hours. The administered volumes were different between subjects and went from 1000 to 2500 ml. In addition, the volunteers were able to drink water since 2 hrs after drug administration.

This procedure wasn’t established in the study protocol. So we asked the principal investigator (PI) about that practice, their reasons and possible impact on study (since we send him the question by email I don´t have any answer yet).

I´m concerned about this situation. I have doubts about the potential impact on the results of the study but I don´t have the tools to “scientifically” support “my doubts”….

Thinking in next period of the study, the PI and his team have at least to repeat exactly the same (volume, times, etc) parenteral hydration than in first period, to not increase intra subject variability?

Do you thing administering parenteral hydration is a good practice in a BE study? Could the results of PK parameters been affected? what about de BE conclusions?

I would really appreciate your opinions or similar experiences if you have!

Thank you very much in advance….

Regards!!


Edit: Category changed; see also this post #1[Helmut]
Helmut
★★★
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Vienna, Austria,
2019-11-15 16:48

@ Cec75
Posting: # 20808
Views: 699
 

 Violation of GCP‽

Hi Cec75,

» While verifying the source documents of period 1 (at this time the wash out period is running), I noticed that the investigation site was administering parenteral hydration to the subjects since the first sample (pre-dose) was collected and during about the next 12 hours. The administered volumes were different between subjects and went from 1000 to 2500 ml.

[image]IMHO, that’s bizarre. Never heard of anything like this before. Even for a potent diuretic, water ad libitum is sufficient to keep volunteers hydrated.

» This procedure wasn’t established in the study protocol.

That’s a major protocol violation for at least two reasons:
  1. Should have been stated in the informed consent and assessed for the potential risk by the IEC.
    If I sign the ICF telling me that a certain number of blood samples will be drawn, I don’t want additionally a flask attached to me for twelve hours. :thumb down:
    BTW, were meals served to the bed? Urine bottles provided?
  2. Might change the volume of distribution and hence, the concentrations (more further down).

» So we asked the principal investigator (PI) about that practice, their reasons and possible impact on study (since we send him the question by email I don´t have any answer yet).

Great.

» I´m concerned about this situation.

You should.

» I have doubts about the potential impact on the results of the study but I don´t have the tools to “scientifically” support “my doubts”….
»
» Thinking in next period of the study, the PI and his team have at least to repeat exactly the same (volume, times, etc) parenteral hydration than in first period, to not increase intra subject variability?

#1 above is a clear violation of GCP. On the other hand, if #2 hits (unknown…) you want to keep conditions of the second period like in the first, which violates GCP again. Extremely nasty situation.

» Do you thing administering parenteral hydration is a good practice in a BE study?

No. BE is a surrogate of therapeutic equivalence (that’s the most important assumption). Studies are performed in healthy subjects instead of patients to reduce variability. It is accepted practice to reduce variability further (in-, exclusion criteria, standardized meals, limited physical activity, etc.). But: Are patients receiving this drug routinely on parenteral hydration? Even if the answer is yes, why was the procedure not stated in the protocol?

» Could the results of PK parameters been affected?

Maybe, maybe not. As I wrote above in #2 the volume of distribution might be affected. Once homeostasis sets in (i.e., the [image] renin–angiotensin system is activated) increased renal excretion will counteract that. If the drug is mainly excreted via the kidneys, clearance increases (half life decreases) and you will see lower concentrations than usual.

» what about de BE conclusions?

If you continue like in the first period, likely results are fine. However, the violation of GCP is a serious issue. Think about setting the study on hold, update the ICF, get a new IEC vote (hopefully positive), and proceed. I can image that regulators are not happy with this study – regardless its outcome.

Maybe better: Stop the study. Your legal department should check the contract with the CRO. I have seen CROs repeating studies at their own cost in much less problematic cases.

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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ElMaestro
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Belgium?,
2019-11-15 20:51

@ Cec75
Posting: # 20810
Views: 673
 

 Impact of Parenteral hydration in a BE study

Hi,

thanks for telling this story.
I would consider it a potentially serious issue. Did the PI or delegates note anything about protocol deviations or AEs necessitating parenteral fluids?
If no, then I'd say here a big issue (big as in major or critical).
I would collect immediately (copies of):
1. The delegation logs
2. Source docs for AEs and PDs, and any forms documenting the administration of the fluids and the reason for doing so.
3. CRFs
And I would note down for posterity in writing, if written docs (in the form of PDs or AEs) do not exist just in case you worry about post-hoc back-dating of documentation.

I am not so worried about the BE proof itself, but about the ethics, just like Hötzi points out. The sponsor is in a serious regulatory/ethical and possible legal limbo if a subject has, say, a case of fever and septicemia after the parenteral administration (this will likely end up as a discussion where the trial insurer and the doctor's / clinic's insurer are pointing at each other, and the subjects will accordingly suffer).

I could be wrong, but...
Best regards,
ElMaestro
Cec75
☆    

Argentina,
2019-11-19 15:03

@ ElMaestro
Posting: # 20829
Views: 610
 

 Impact of Parenteral hydration in a BE study

Hi Helmut and ElMaestro,

Thanks a lot for your answers and your comments.

I totally agreed with all you said about protocol deviation and the ethics concern. Rights, safety and well-being of the study subjects is all that matters and all that we must worry about.

Just for you to know, finally we contacted the PI. His explanation for using parenteral hydration was related to the sample collection. Specifically, to keep the permeability of the intravenous route. That it was a normal procedure for them and it´s described in the site´s sops. I have never heard or read something like this! 1000 – 2500 ml of solution for that! ........

Best regards,

CEC75
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