BE-proff
●    

2016-02-18 18:56
(2960 d 17:12 ago)

Posting: # 16007
Views: 7,224
 

 Missed tablets administration in a steady state study [Study As­sess­ment]

Hi All,

Let's assume that I want to conduct steady state study with the following terms:

- Test and Reference are administered in 7 days; 8th day is a PK-session with blood sampling
- Test is to be taken twice a day
- Reference is to be taken 3 times a day
- 2 period, cross-over study

Drug accountability done by a CRA showed several missed administrations of medications.:angry:

Is it possible to assess how missed administrations influenced on concentrations and therefore on PK-parameters?:confused:
ElMaestro
★★★

Denmark,
2016-02-19 08:24
(2960 d 03:45 ago)

@ BE-proff
Posting: # 16008
Views: 6,341
 

 Missed tablets administration in a steady state study

Hi BE/proff,

❝ - Test and Reference are administered in 7 days; 8th day is a PK-session with blood sampling

❝ - Test is to be taken twice a day

❝ - Reference is to be taken 3 times a day

❝ - 2 period, cross-over study


❝ Drug accountability done by a CRA showed several missed administrations of medications.:angry:


❝ Is it possible to assess how missed administrations influenced on concentrations and therefore on PK-parameters?:confused:


Yes, most certainly this affects concentrations and affects the study outcome. How much etc. depends on a lot of ADME factors and you can probably simulate it but I guess it will be a waste of time. Assuming they ignored/forgot the study medication at random there's still hope.

It is an important lesson for you: Compliance in a trial is not necessarily good, but you can be fairly sure that even though some subjects forgot to take their medication, all of them will remember to pick up their compen$ation.
Be aware that issues with DA is an inspection trigger. I think most experienced assessors will understand that in an home setting an issue with DA is a regular compliance issues and not necessarily as serious as DA trouble with subjects housed within a CRO.

All sorts of solutions have been tried. More and better verbal and written communication. Daily email reminders. Text messages via phone or phone apps ("Dear Mr. 123, this message is sent to you from Dr. Quack. It is time for you take your medication. It will be in the dispensing bag labelled 123-06 Monday June 15, 2015" etc), but it will not necessarily get rid of the problem. Some subjects apparently don't want to be poisoned but just want to be rewarded.

Pass or fail!
ElMaestro
BE-proff
●    

2016-02-19 09:36
(2960 d 02:32 ago)

@ ElMaestro
Posting: # 16009
Views: 6,384
 

 Missed tablets administration in a steady state study

Hi ElMaestro,

It's clear that money is the strongest motivator for people but what to do if all subjects have been already dosed and sampled and accountability showed missed administrations:-)

What would you write in reports except statement of deviations?

Nobody can guarantee that a regulator will not reject your results saying they were obtained from deviated people :-|
Ohlbe
★★★

France,
2016-02-19 10:37
(2960 d 01:31 ago)

@ BE-proff
Posting: # 16010
Views: 6,314
 

 Missed tablets administration in a steady state study

Dear BE-proff,

❝ It's clear that money is the strongest motivator for people but what to do if all subjects have been already dosed and sampled and accountability showed missed administrations:-)


Is there any way you can still find out which subject missed which dose ? Or could it be just any subject, on any day ?

Regards
Ohlbe
ElMaestro
★★★

Denmark,
2016-02-19 11:37
(2960 d 00:31 ago)

@ BE-proff
Posting: # 16011
Views: 6,362
 

 Missed tablets administration in a steady state study

hi BE-proff,

❝ What would you write in reports except statement of deviations?


I actually would not do much, but just deal with it.
For out-patients or out-subjects you will always expect some degree of noncompliance.

Typically you have the little dispensing bags or something so that you can keep track of who missed which doses. You can easily -I assume?- get a list of protocol violators.

In BE the conservative population is the PP population and not the ITT population. So, depending on wording in your protocol, the primary analysis to submit is either done on the compliant subjects or on "everyone" for lack of better wording.
If noncompliance is not at random (say, hypothetically if T has more side effects than R, so subjects stop specifically taking T purposefully) then it is of course another matter but this would be only theoretical, I hope.

❝ Nobody can guarantee that a regulator will not reject your results saying they were obtained from deviated people :-|


If this discussion is about deviated people (what an absolutely wonderful term!!!) then you have certainly come to the right place. In this forum they are aplenty :-D.

I am not entirely sure the problem in your case is really, really big. It is an issue yes, but an experienced assessor should acknowledge it. Mainly I see this as potential lack of power due to exclusions. Let's hear a bit more details. This does not have to be frightening.

Pass or fail!
ElMaestro
BE-proff
●    

2016-02-19 13:18
(2959 d 22:50 ago)

@ ElMaestro
Posting: # 16012
Views: 6,280
 

 Missed tablets administration in a steady state study

Hi ElMaestro,

So, it to sum up - single missed administrations can hardly influence seriously on PK-results. Correct? ;-)
ElMaestro
★★★

Denmark,
2016-02-19 17:39
(2959 d 18:30 ago)

@ BE-proff
Posting: # 16013
Views: 6,269
 

 Missed tablets administration in a steady state study

Dear BE-proff,

❝ So, it to sum up - single missed administrations can hardly influence seriously on PK-results. Correct? ;-)


No, that is not what I meant.
Single missed administrations can badly screw up everything. But they don't necessarily do so. It all comes down to ADME properties and stochastics and everything.
Clearly missed administration have the potential to depress 'apparent' SS profiles. But in BE we are looking at GMR's; if the missed doses happened at random then even though individual profiles are screwed up badly there is still a chance that the study outcome is positive.

I think I will propose this:
Let GMR be the true ratio. Let GMR' be the observed geometric mean ratio in case of no missed doses. Let GMR'' be the observed geometric mean ratio when missed doses happen. Provided the missed doses happen at random I would think that these quantities can be expected to be the same (in spite of the fact that in case of missed doses some PK-profiles may be a lot different from what they'd look like without missed doses).

All hope is therefore not lost. I hope you see what I mean.
Желаю хорошо провести выходные.

Pass or fail!
ElMaestro
BE-proff
●    

2016-02-21 09:07
(2958 d 03:01 ago)

@ ElMaestro
Posting: # 16015
Views: 6,170
 

 Missed tablets administration in a steady state study

Hi ElMaestro,

Yes, now your point of view is clear :-)

Have a nice day! (Хорошего дня!)
Helmut
★★★
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Homepage
Vienna, Austria,
2016-02-21 16:06
(2957 d 20:03 ago)

@ BE-proff
Posting: # 16016
Views: 6,118
 

 BE with PP-population

Hi BE-proff,

the BE-assessment is always done with the PP-population. Imagine a single dose study where 2 × 50mg (Test) is compared to 1 × 100mg (Reference) and you discover that one subject managed it to spit one of the T-tablets into the toilet. Expected T/R 50%. Doesn’t make sense. Exclude the subject.
Same in steady state. If a subject didn’t take the drug(s) the T/R-ratio will be biased. The bias on the profile day will not be so dramatic as in the single dose example but it still exists. Whatever clever things you will do (e.g., PK-modeling,…) it is only exploratory. No regulator would buy that.
Subject wasn’t fully compliant ⇒ exclusion. Full stop.
However, the case is not lost. The impact of dropouts & excluded subjects on power is overrated. There are good chances that the study will still pass. Prepare for an inspection.

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BE-proff
●    

2016-02-25 08:53
(2954 d 03:16 ago)

@ Helmut
Posting: # 16026
Views: 5,866
 

 BE with PP-population

Hi Helmut,

Thanks a lot for clarification :ok:
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