cher0424
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China,
2014-12-16 02:30
(3390 d 17:53 ago)

Posting: # 14074
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 BE study inclusion & exclusion criteria [Design Issues]

Dear all:
Have a good day!
I have some queries concerning the rationale BE study inclusion & exclusion criteria.
what's the exactly impart to study when subjet abuse smoking ? and why donation of blood (one unit or 350 mL) within 90 days prior to study check-in in exclusion criteria and so on.......
I saw most of the criteria in all BE studies are nearly same.
Is it have any guideline or literature can explain them?

Many thanks advance!!!!
Helmut
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Vienna, Austria,
2014-12-16 15:53
(3390 d 04:30 ago)

@ cher0424
Posting: # 14085
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 BE study inclusion & exclusion criteria

Hi cher0424,

❝ what's the exactly impart to study when subjet abuse smoking ?


Define abuse. ;-) EMA’s 2001 GL stated “Subjects should preferably be non-smokers […]. If moderate smokers are included (less than 10 cigarettes per day) they should be identified as such and the consequences for the study results should be discussed.” The second sentence was removed in the 2010 GL.
Well, cough… An influence of the smoking-status is only expected if the drug is metabolized by CYP450 1A1. Even then: If a subject doesn’t decide to quit smoking in the washout between study periods, what’s the problem?

❝ and why donation of blood (one unit or 350 mL) within 90 days prior to study check-in in exclusion criteria


Tradition?

❝ I saw most of the criteria in all BE studies are nearly same.


Copy & paste?

❝ Is it have any guideline or literature can explain them?


Not that I recall. The rationale behind most of these criteria is to ensure that subjects are healthy indeed. It is common misconception that tightening the limits (f.i. of the BMI) might reduce the variability and therefore, increase the chances to pass BE. In a crossover-study between-subject differences are irrelevant.
Parallel designs are another cup of tea. Keeping groups as similar as possible (even by genotyping) makes sense indeed.

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Ohlbe
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France,
2014-12-16 18:29
(3390 d 01:54 ago)

@ Helmut
Posting: # 14087
Views: 12,901
 

 BE study inclusion & exclusion criteria

Dear cher0424 and Helmut,

❝ ❝ and why donation of blood (one unit or 350 mL) within 90 days prior to study check-in in exclusion criteria


❝ Tradition?


Well, not only ! The amount of blood collected during a BE trial is of the same order of magnitude as the volume taken during a blood donation. In the interest of subject safety, most CROs just replicate the usual timelines between two blood donations.

Regards
Ohlbe
cher0424
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China,
2014-12-17 03:19
(3389 d 17:04 ago)

@ Ohlbe
Posting: # 14090
Views: 12,908
 

 BE study inclusion & exclusion criteria

❝ Well, not only ! The amount of blood collected during a BE trial is of the same order of magnitude as the volume taken during a blood donation. In the interest of subject safety, most CROs just replicate the usual timelines between two blood donations.


Your explain inspire me to think just only focus on BE study and here is one exclude criteria i quote from protocol
"Positive results for drugs of abuse (benzodiazepines, cocaines, opioids, amphetamines, cannabinoids and barbiturates) in urine during the study check-in of each period."
why just include these six drugs, the thing is our drug test plate can test out tricyclic antidepressant (TCA) and Phencyclidine (PCP) also. One subject TCA show positive in the test. In this situation what should we do test again or exclude? if test again, what's the interval is proper?
Helmut
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Vienna, Austria,
2014-12-17 15:42
(3389 d 04:41 ago)

@ cher0424
Posting: # 14094
Views: 12,812
 

 Drugs of abuse

Hi cher0424,

❝ […] here is one exclude criteria i quote from protocol

"Positive results for drugs of abuse (benzodiazepines, cocaines, opioids, amphetamines, cannabinoids and barbiturates) in urine during the study check-in of each period."

❝ why just include these six drugs, the thing is our drug test plate can test out tricyclic antidepressant (TCA) and Phencyclidine (PCP) also.


TCAs might be relevant. They have long half-lives (and their metabolites even longer ones). If you think that here might be an interaction testing would make sense. PCP (“Angel Dust”) was a popular street-drug in the 1980s. No idea about the current status. Personally I never saw a positive result in the last 20 years.
Barbiturates? Yes, I know they a part of many standard tests but realistically they are history…

❝ One subject TCA show positive in the test. In this situation what should we do test again or exclude? if test again, what's the interval is proper?


If a positive result is part of the exclusion criteria – exclude the subject. Otherwise, why did you test for it and state it in the protocol? BTW, I never saw a protocol which allows retesting. Given the half-lives of TCAs likely you will get another positive result anyway.

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cher0424
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China,
2014-12-18 05:54
(3388 d 14:29 ago)

@ Helmut
Posting: # 14101
Views: 12,575
 

 Drugs of abuse

Hi Helmut

❝ ❝ One subject TCA show positive in the test. In this situation what should we do test again or exclude? if test again, what's the interval is proper?


❝ If a positive result is part of the exclusion criteria – exclude the subject. Otherwise, why did you test for it and state it in the protocol? BTW, I never saw a protocol which allows retesting. Given the half-lives of TCAs likely you will get another positive result anyway.


You mean no retesting in drug abuse or other clinic exam also? I saw hematology can be retested.
TCA isn't listed in protocol, but can be test out in our drug abuse test card. So here is a pratical operated problem. The protocol writer didn't combine the reality with protocol. So all the things just refer to the protocol, then ignore the positive result of TCA?
Helmut
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Vienna, Austria,
2014-12-18 15:02
(3388 d 05:21 ago)

@ cher0424
Posting: # 14109
Views: 12,586
 

 Stick to the protocol, but…

Hi cher0424,

❝ You mean no retesting in drug abuse or other clinic exam also?


The former. Other re-tests are common.

❝ TCA isn't listed in protocol, but can be test out in our drug abuse test card. So here is a pratical operated problem. The protocol writer didn't combine the reality with protocol. So all the things just refer to the protocol, then ignore the positive result of TCA?


Formally yes. Whether you want a volunteer on TCAs in the study is another question. Common sense: Given the side-effects of TCAs I don’t think that the subject took them for fun. I guess the pre-study exam contains a complete anamnesis (including neurologic or psychiatric illness, prior/present medication & therapy). Maybe he/she lied? Even if there are no inter­actions possible with the study’s drug, I would exclude the subject.
If the subject will jump out of the window in a suicidal episode, would the PI keep him/her in the study only because this was not foreseen as one of the exclusion criteria in the protocol?

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Helmut
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Vienna, Austria,
2014-12-17 14:33
(3389 d 05:50 ago)

@ Ohlbe
Posting: # 14091
Views: 12,770
 

 BE study inclusion & exclusion criteria

Dear Ohlbe,

❝ ❝ Tradition?


❝ Well, not only ! The amount of blood collected during a BE trial is of the same order of magnitude as the volume taken during a blood donation. In the interest of subject safety, most CROs just replicate the usual timelines between two blood donations.


Oh, you are right; THX for reminding me!

@cher0424: See also these old threads: #1297, #5244, #6180. I didn’t find a specific value in CDE’s BE-GL (2005). Is there a newer one?

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cher0424
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China,
2014-12-17 03:02
(3389 d 17:21 ago)

@ Helmut
Posting: # 14089
Views: 12,876
 

 BE study inclusion & exclusion criteria

Dear Hulmet

❝ Well, cough… An influence of the smoking-status is only expected if the drug is metabolized by CYP450 1A1. Even then: If a subject doesn’t decide to quit smoking in the washout between study periods, what’s the problem?


So you mean smoking influence to drugs actually is case by case? Well, I had no idea about subjet smoking during wash-out, coz smoking status depends on their chief complaint

❝ ❝ and why donation of blood (one unit or 350 mL) within 90 days prior to study check-in in exclusion criteria


❝ Tradition?


❝ ❝ I saw most of the criteria in all BE studies are nearly same.


❝ Copy & paste?


Maybe are, the protocol prepare in same CRO.

❝ The rationale behind most of these criteria is to ensure that subjects are healthy indeed. It is common misconception that tightening the limits (f.i. of the BMI) might reduce the variability and therefore, increase the chances to pass BE. In a crossover-study between-subject differences are irrelevant.


Speaking about BMI, if the value is 18, and some guideline said <18 is unhealthy, so 18 can be include or not?
Helmut
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Vienna, Austria,
2014-12-17 15:24
(3389 d 04:59 ago)

@ cher0424
Posting: # 14093
Views: 12,962
 

 BE study inclusion & exclusion criteria

Hi cher0424,

❝ Dear Hulmet


Helmut, if you don’t mind.

❝ ❝ […] An influence of the smoking-status is only expected if the drug is metabolized by CYP450 1A1.


❝ So you mean smoking influence to drugs actually is case by case?


Scientifically, yes. If a drug is not metabolized by an enzyme system which is induced or inhibited by other compounds (BTW, if smoking is concerned: it’s the tar, not the nicotine) – which inter­action do you expect? Smoking is not the only condition which may interact with the study’s drug. To name a few: charcoal-broiled meat (polycyclic aromatic hydrocarbons), coffee/tea/cocoa/colas (methylxanthines), grapefruit (furanocoumarins, flavonoids), oranges (hesperidin), cran­berry juice (flavonoids), vegetables of the cabbage family (vitamin K1), red pepper (capsaicinoids), herbal remedies like St John’s wort (hypericin)…
Note that regulations are not 100% scientifically driven (politely speaking). EMA don’t want smokers; only the other stuff is case-by-case:

The subjects should abstain from food and drinks, which may interact with circulatory, gastrointestinal, hepatic or renal function (e.g. alcoholic drinks or certain fruit juices such as grapefruit juice) during a suitable period before and during the study. Subjects should not take any other concomitant medication (including herbal remedies) for an appropriate interval before as well as during the study.

See also this post.

❝ ❝ If a subject doesn’t decide to quit smoking in the washout between study periods, what’s the problem?


❝ Well, I had no idea about subjet smoking during wash-out,…


I meant something else. In a crossover it is irrelevant whether a subject is a smoker or not – even if the drug is metabolized by CYP450 1A1 (interaction possible). We will see higher between-subject variability (compared to a study in nonsmokers), but the within-subject variability will not be influenced. To quit smoking between study periods is not a good idea. Returning CYP450 1A1 to levels seen in nonsmokers takes a while, but you may see differences between periods. Very bad.

❝ […] smoking status depends on their chief complaint


Don’t understand what you mean by “chief complaint”. Don’t rely on what subjects tell you. If you decide to include nonsmokers only, perform cotinine-tests in the pre-study exam as well as in hospitalization of each period. Having smokers in the study who abstain from smoking during the sampling periods is a bad idea. Withdrawal symptoms can play havoc on the circulation.

❝ ❝ The rationale behind most of these criteria is to ensure that subjects are healthy indeed. It is common misconception that tightening the limits (f.i. of the BMI) might reduce the variability and therefore, increase the chances to pass BE. In a crossover-study between-subject differences are irrelevant.


❝ Speaking about BMI, if the value is 18, and some guideline said <18 is unhealthy, so 18 can be include or not?


I think that any limit of the BMI in a crossover is nonsense.
You set the limits in the protocol. In your example a subject with a BMI of 18 is fine. BTW, according to the Chinese GL:. Weight ≥50kg and BMI in the “standard weight range” (acc. to [image]-translate). The WHO defines the normal range as 18.50–24.99 kg/m².

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Ohlbe
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France,
2014-12-17 18:35
(3389 d 01:48 ago)

@ cher0424
Posting: # 14096
Views: 12,677
 

 BE study inclusion & exclusion criteria

Dear Cher0424

❝ what's the exactly impart to study when subject abuse smoking ?


In addition to what Helmut already replied: one reason for selecting only non-or light-smokers is that they will have to abstain from smoking during the in-house period (they will not be allowed to smoke in the clinic). Heavy smokers will become nervous and difficult to manage after a few hours...

Helmut, couldn't a sudden smoking cessation also influence the gastrointestinal motility, or sumfink like this ?

Regards
Ohlbe
Helmut
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Vienna, Austria,
2014-12-17 18:48
(3389 d 01:35 ago)

@ Ohlbe
Posting: # 14097
Views: 12,751
 

 Smoking

Dear Ohlbe,

❝ Helmut, couldn't a sudden smoking cessation also influence the gastrointestinal motility, or sumfink like this ?


Absolutely (GI transit time may increase). Either include only non-smokers (confirmed by cotinine tests) or allow (moderate) smokers to smoke. :smoke:
In the latter case a dedicated area is a must (check that smokers don’t exceed the daily allowance stated in the protocol). If the clinical site doesn’t have a smoking area, include only non-smokers. Sending smokers to the street and exposing them to demanding climatic conditions (winter in Moscow or Saskatoon easily –40 ℃; summer-monsoon in India) is not an alternative.

But again: In a crossover whatever one has chosen shouldn’t matter. I would not suggest that smokers refrain from smoking during hospitalization. Their craving symptoms might even annoy other volunteers and the clinical staff.

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cher0424
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China,
2014-12-18 03:08
(3388 d 17:15 ago)

@ Helmut
Posting: # 14100
Views: 12,593
 

 Thanks for solving out

Hi Helmut and Ohlbe

Many thanks to help me solve out these questions!!!
d_labes
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Berlin, Germany,
2014-12-18 09:08
(3388 d 11:15 ago)

@ Helmut
Posting: # 14102
Views: 12,559
 

 Smoking

Dear Helmut,

❝ … I would not suggest that smokers refrain from smoking during hospitalization. Their craving symptoms might even annoy other volunteers and the clinical staff.


Here spoke a practitioner :-D :smoke:

Regards,

Detlew
Mahesh M
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India,
2014-12-18 14:50
(3388 d 05:33 ago)

@ Helmut
Posting: # 14108
Views: 12,521
 

 Smoking

Dear All,

Why only Non smokers subjects are required to conduct BE on OIPs or MDI prodcts ?

Regards
ElMaestro
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Denmark,
2014-12-18 15:10
(3388 d 05:13 ago)

@ Mahesh M
Posting: # 14110
Views: 12,352
 

 Smoking

Hi Mahesh M,

❝ Why only Non smokers subjects are required to conduct BE on OIPs or MDI prodcts ?


It is sometimes a good idea to use nonsmokers since smoking directly affects lung function and the ability to inhale and have an API absorbed through the lung mucosa.
The outcome could thus depend a lot on whether the pt. smoked "20 mins ago" or "120 mins ago", figuratively speaking. Smoking can thus play tricks with the intra-subject and between-subject variabilities regardless of whether we talk PK or PD.
Of course there might be compelling scientific arguments for including smokers somehow. If you come up with any, please tell me, I am curious and eager to learn about it.

Pass or fail!
ElMaestro
Mahesh M
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India,
2014-12-19 08:14
(3387 d 12:09 ago)

(edited by Ohlbe on 2014-12-19 09:33)
@ ElMaestro
Posting: # 14116
Views: 12,230
 

 Smoking

Hi ElMaestro,

❝ Of course there might be compelling scientific arguments for including smokers somehow. If you come up with any, please tell me, I am curious and eager to learn about it.


Please find below literature and share your thoughts on it ?

Difference in pulmonary absorption of inhaled terbutaline in healthy smokers and non-smokers
Birgitta Schmekel, Lars Borgstrom, Per Wollmer


Any references for effect of smocking on OIPs ?

Regards


Edit: standard quotes restored [Ohlbe]
ElMaestro
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Denmark,
2014-12-19 12:35
(3387 d 07:48 ago)

@ Mahesh M
Posting: # 14118
Views: 12,098
 

 Smoking

Hi Mahesh,

❝ Any references for effect of smocking on OIPs ?


Thanks.
I am sure there are references but I don't keep them in my collection; when it comes to proving BE for OIPs the available literature is very biased and I find most papers out there of limited use.
Some companies seem to have a lot of interest in making sure their products are not being copied...

My advice to you and companies developing OIPs in general: Do your own pilot trials to see what's going on. Your product with quite some likelihood does not behave like any other product described in the literature. And don't even think about IVIVCs unless you have generated a boatload of in vitro and in vivo info with your own formulation as well as the ref. formulation.

Pass or fail!
ElMaestro
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