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Back to the forum  Query: 2017-07-26 10:30 CEST (UTC+2h)
 
Helmut
Hero
Homepage
Vienna, Austria,
2017-04-03 16:55

Posting: # 17218
Views: 1,023
 

 Regulations ≠ Science [Regulatives / Guidelines]

Dear all,

I stumbled across this old post. History (about exclusion of low profiles of gastric-resistant formulations):
  1. Q&A-document Rev. 12 (25 June 2015); removed in Rev. 13.
    • […] concentration profiles (either non-existing or extremely delayed) can be obtained. […] only under the conditions that sampling times are designed to identify very delayed absorption and that the incidence of this outlier behaviour is observed with a comparable frequency in both, test and reference products, these incomplete profiles can be excluded from statistical analysis provided that it has been considered in the study protocol.
  2. MR-GL, Draft (21 February 2013)
    • Gastric emptying of single unit dosage forms that do not disintegrate in the stomach (e.g. enteric coated tablets) may be prolonged and highly erratic. The consequences of this effect on the enteric coating of delayed release formulations are largely unpredictable. If the active substance release occurs prior to stomach emptying degradation of the active substance can result and non-existing concentration profiles can be obtained. If the incidence of this outlier behaviour is observed with a comparable frequency in both, test and reference product, data of a period with non-existing profile can be excluded from statistical analysis provided that it has been pre-specified in the study protocol.
  3. MR-GL, Final (20 November 2014)
    • Gastric emptying of modified release dosage forms that do not disintegrate in the stomach (e.g. enteric coated tablets) may be prolonged and highly erratic. The consequences of this effect on the enteric coating of delayed release formulations are largely unpredictable and can result in non-existing or aberrant concentration profiles. If the incidence of this outlier behaviour is observed with a comparable frequency (e.g. the number of cases is not numerically higher in the test product) in both, test and reference product, data of a period with non-existing or aberrant profile can be excluded from statistical analysis provided that it has been pre-specified in the study protocol.
At the meeting in Bonn (June 2013; between #2 and #3) I presented the example in the post linked above, which the PKWP did not like at all. Am I guilty for the red text? I don’t believe that the comments on the draft will ever be published (though promised “within the next week” on 30 April 2015…).

Try this one (64 subjects, 5% outliers after R and exactly one more after T):

n        <- 64        # sample size
pct      <- 5         # percent of outliers of R
alpha    <- 0.05      # significance level
alt      <- "greater" # any of: "greater", "two.sided", "less"
##############################################################
R        <- as.integer(n*pct/100)
T        <- R + 1     # exactly one more
TR       <- T/R       # ratio of T/R
Ha       <- alt
comp     <- "than 1"
outliers <- matrix(c(T, n-T, R, n-R), nrow=2,
                   dimnames=list(Guess=c("Test", "Reference"),
                                 Truth=c("Test", "Reference")))
FT       <- fisher.test(outliers, alternative=alt, conf.level=1-alpha)
txt      <- ";\nalternative hypothesis: true odds ratio is"
txt      <- paste(txt, Ha, comp)
if (alt == "greater") {
  test <- "\np (T > R)"
  conf <- sprintf("(%s %.5g%% %s %.5g)", "lower", 100*(1-alpha), "CI:",
                                         FT$conf.int[1])
}
if (alt == "two.sided") {
  test <- "\np (T = R)"
  Ha   <- "not equal"
  comp <- "equal to 1"
  CI   <- c(FT$conf.int[1], FT$conf.int[2])
  conf <- sprintf("(%g%% %s %.5g, %.5g)", 100*(1-alpha), "CI:",
                                          FT$conf.int[1], FT$conf.int[2])
}
if (alt == "less") {
  test="\np (T < R)"
  conf <- sprintf("(%s %g%% %s %.5g)", "upper", 100*(1-alpha), "CI:",
                                       FT$conf.int[2])
}
txt      <- paste(txt, "\nOdds ratio   :", sprintf("%.5g", FT$estimate), conf)
sig      <- "significantly different"
if (FT$p.value >= alpha) sig <- paste("not", sig)
cat(sprintf("%s %i %s %s %i (%.2f%%), %s %i (%.2f%%)%s%.4f",
            "\nSample size  :", n,
            "\nOutliers     :",
            "T =", T, 100*T/n,
            "R =", R, 100*R/n,
            "\nOutlier-ratio: ", TR),
    sprintf("%s%s%s%s%s %.4g (%s)%s",
            "\n", FT$method, txt, test, "    :",
            FT$p.value, sig, "\n\n"))

# Sample size  : 64
# Outliers     : T = 4 (6.25%), R = 3 (4.69%)
# Outlier-ratio: 1.3333
# Fisher's Exact Test for Count Data;
# alternative hypothesis: true odds ratio is greater than 1
# Odds ratio   : 1.3523 (lower 95% CI: 0.28317)
# p (T > R)    : 0.5 (not significantly different)


Splendid. A p-value of 0.5. Try to increase the sample size and/or lower the percentage of outliers. I love n <- 120 and pct <- 0.2. Zero outliers after R and one after T in a study with 120 subjects. Is this pure chance? Guess. Are we allowed to exclude the single outlier? According to the EMA’s eternal wisdom: No.
Before the final MR-GL I would have thought that „comparable frequency” calls for a two-sided test.

# Sample size  : 64
# Outliers     : T = 4 (6.25%), R = 3 (4.69%)
# Outlier-ratio: 1.3333
# Fisher's Exact Test for Count Data;
# alternative hypothesis: true odds ratio is not equal equal to 1
# Odds ratio   : 1.3523 (95% CI: 0.2187, 9.623)
# p (T = R)    : 1 (not significantly different)

Oh no!

I can’t follow the argument that the reference has a documented efficacy/safety record whereas the test has not. Essentially T and R should be dealt with equally. The BE-GL:

The data from all treated subjects should be treated equally.

The FDA states somewhere nicely (can’t find it – changed the structure of the website again) that bioequivalence is bijective, i.e., the test of T vs. R gives exactly the same result as the test of R vs. T. If we follow the EMA’s logic above, this is no more the case.

OK, we lost our virginity already to reference-scaling. Only if CVwT = CVwR we would arrive at the same conclusion. I know, I know, the reference is safe and efficacious, :blahblah:. But does that represent reality? Sometimes a patient starts with a generic (prescribed by a general practitioner) and when hospitalized is switched to the originator. Common practice. What if CVwR > CVwT?

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
nobody
Senior

2017-04-03 17:38

@ Helmut
Posting: # 17219
Views: 899
 

 Regulations ≠ Science

» Sometimes a patient starts with a generic (prescribed by a general practitioner) and when hospitalized is switched to the originator. Common practice.

Really? Which hospital, country?

This rule (don't care too much for a total loser in the REF group) was invented to make life easier to generics (don't f*ck up your BE-study because REF had a kind of hick-up). Would not use this against authorities. MY opinion... ;-)

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2017-04-03 17:55

@ nobody
Posting: # 17220
Views: 895
 

 Regulations ≠ Science

Hi nobody,

» » Sometimes a patient starts with a generic (prescribed by a general practitioner) and when hospitalized is switched to the originator. Common practice.
»
» Really? Which hospital, country?

Yes. Regularly in Austrian university hospitals. Maybe ’cause these super-bright professors (aka „key opinion leaders”) are invited to “conferences” in Monte-Carlo or the Bahamas? Or do originators give more huge discounts than the Generikahütten? Quite often I find out that physicians only know the brand-name (and not the drug). The equation is diclofenac = Voltaren.

» This rule (don't care too much for a total loser in the REF group) was invented to make life easier to generics (don't f*ck up your BE-study because REF had a kind of hick-up). Would not use this against authorities. MY opinion... ;-)

Well, I don’t like the double (moral?) standards behind.
  All animals are equal,
but some animals are more equal than others.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
nobody
Senior

2017-04-03 18:15

@ Helmut
Posting: # 17221
Views: 892
 

 Regulations ≠ Science

» Well, I don’t like the double (moral?) standards behind.
»   All animals are equal,
» but some animals are more equal than others.

I think I have a track record of seeing lousy standards/moral, but in this case: Problem -> Solution. Life is to short to start searching for problems ;-)

btw I know countries (formerly known as so-called "first world") where you are nowadays supposed to bring in your chronic medication for a stay for (elective) treatment. Hint: BE is NOT the reason... :-D

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2017-04-03 18:28

@ nobody
Posting: # 17222
Views: 885
 

 Regulations ≠ Science

Hi nobody,

» btw I know countries (formerly known as so-called "first world") where you are nowadays supposed to bring in your chronic medication for a stay for (elective) treatment. Hint: BE is NOT the reason... :-D

Great. This will safe the economy. IIRC, one of the “aides” of the guy with the great haircut said in an interview that in the future it will be sufficient for the FDA to get evidence that new drugs are safe. Proof of efficacy will no more be required since the “free market” will kick the bad drugs out anyway. Amazing. Renaissance of sham surgery, Doktor Mayer’s Muschel­mehl, and a boost for homeopathy? :crying:

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
nobody
Senior

2017-04-03 18:50

@ Helmut
Posting: # 17223
Views: 884
 

 Regulations ≠ Science

...what gives me green dots in the face is the mayor scientific f*ckup called "real-life data" wrt drug approval. Really lousy suff! But EMA and FDA are under way...

The "safety-only" guy (friend to orange little-handed guy) didn't make it to head FDA, but I guess the fun-part as a staffer at the FDA will be very limited the next years. And will be nice to where the EMA turns to (maybe Hungary? Poland? Slovakia?)

‘May he live in interesting times.’
(nobody knows where it comes from)

Kindest regards, nobody
ElMaestro
Hero

Denmark,
2017-04-03 20:05

@ nobody
Posting: # 17224
Views: 888
 

 Regulations ≠ Science

Can someone please sum up with max four sentences what this thread is about? :confused:

Many thanks :pirate:

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
nobody
Senior

2017-04-04 10:33

@ ElMaestro
Posting: # 17225
Views: 808
 

 Regulations ≠ Science

Helmut thinks Guideline is unscientific. Nobody thinks Guideline is pragmatic (as Guidelines are always politics, never science). The rest is this and that.

My opinion: There is no such thing as science in pharma (any longer? ever been?). We do drug development and want marketing authorization. Sometimes we use scientific methods to achieve our goals. Sometimes it's just voodooo (worked in the past... :-D ).

Kindest regards, nobody
DavidManteigas
Regular

Portugal,
2017-04-04 12:04

@ nobody
Posting: # 17226
Views: 790
 

 Regulations ≠ Science

@nobody

You would be surprised if you attended a primary care consultation in Portugal :-D

In my experience, physicians only know one thing about pharmacokinetics: the medicine half-life. Now, imagine when we start to talk about bioequivalence, AUC and stuff like that. They simply don't have the necessary knowledge to understand the concept of bioequivalence. The common wisdow (should be read "Medical Information Delegate" or more recently "Medical Science Liasion") is that generics are a lot different from innovators (there is always one history of some old lady who switched from innovator to generic and the generic was not as effective as the innovator). What happens frequently is that the patients asks for generics regardless of the opinion of the physician.

In my opinion, after looking at so many concentration data from bioequivalence studies and the huge inter-subject variability associated, I don't believe that using a generic or innovator makes any difference in the therapeutic effect when compared with the diet or other extrinsic factors. The API is the same and in the same amount (with some variation, of course) so I can't understand what is the mistrust the medical community have with the generics other than information manipulation from industry.
nobody
Senior

2017-04-04 13:20

@ DavidManteigas
Posting: # 17227
Views: 784
 

 Regulations ≠ Science

@David

Is that an invitation? ;-)

Medicine (physician...) is not Pharmaceutics. End of story. When we go into clinical settings, everything changes. And that physicians don't know much about pharmaceutics/drugs is common knowledge all around the world.

What makes the difference between generics and innovators (at least in the past) is the manufacture of the API, as innovators typically know the synthesis, know impurities and can check for. API from somewhere bought at cheapest price possible is basically trash later turned to "medicine".

My opinion. Quality of APIs might also have changed in the last 10-15 years. McKinsey and the other thugs are nowadays everywhere...

Kindest regards, nobody
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