yatish gosai
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India,
2019-05-22 07:49

Posting: # 20289
Views: 732
 

 Impartial Witness in BABE study [GxP / QC / QA]

Can Husband act as an Impartial witness for Screening and Enrollment of his wife in BABE study?

Yatish Gosai
QA Professional


Edit: Category changed; see also this post #1[Helmut]
Ohlbe
★★★

France,
2019-05-22 10:48

@ yatish gosai
Posting: # 20290
Views: 650
 

 Impartial Witness in BABE study

Dear Yatish Gosai,

» Can Husband act as an Impartial witness for Screening and Enrolment of his wife in BABE study?

I could not find a definition of an "impartial witness" in the New Drugs and Clinical Trials Rules, 2019. ICH GCP § 1.26 defines the impartial witness as
A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.

In a Phase 3 trial I would say yes as there is no financial benefit. In a BA/BE trial, one may object that the husband has a direct interest in having his wife participate (he will benefit from the money). The husband is not impartial as he may be influenced by the financial incentive... The wife's consent may not be freely given (particularly in the case of illiterate subjects, which is the situation where you would need an impartial witness, where wifes are used to obeying their husband).

Regards
Ohlbe
yatish gosai
☆    

India,
2019-05-22 11:04

@ Ohlbe
Posting: # 20292
Views: 642
 

 Impartial Witness in BABE study

Thanks for valuable opinion
Yatish Gosai


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5[Helmut]
Helmut
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Vienna, Austria,
2019-05-24 12:20

@ Ohlbe
Posting: # 20300
Views: 531
 

 New Drugs and Clinical Trials Rules: Wrong definition of BE

Dear Ohlbe and all,

» I could not find a definition of an "impartial witness" in the New Drugs and Clinical Trials Rules, 2019.

Thank you for pointing me to this reference! Unfortunately BE is wrongly defined (Chapter I, 2. Definitions (f), page 148):

“bioequivalence study” means a study to establish the absence of a statistically significant difference in the rate and extent of absorption of an active ingredient from a pharmaceutical formulation in comparison to the reference formulation having the same active ingredient when administered in the same molar dose under similar conditions;

(my emphases)

One error and a doubtful term:
  1. Statistically significant? No way. Maybe the CDSCO’s gurus had a look at the FDA’s definition given in the CFR21 I D §320.23 (b)(1):
    • Two drug products will be considered bioequivalent drug products if they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the active moiety under similar experimental conditions, either single dose or multiple dose.
    Note the absence of ‘statistically’. In the FDA’s definition ‘significant’ is used in its common meaning (1 or 2a). If BE would require “absence of a statistically significant difference”, [image] should consider a union with [image].*
  2. Similar conditions? Nope. They should be the same (food, beverages, time of administration, physical activity, :blahblah:). Though similar is also stated in the FDA’s definition, it is not mentioned in the EMA’s BE-GL (common sense!)…
This reminds me on a story Salomon Stavchansky once told me. He wrote more or less single-handed ANVISA’s first guidances, only to discover that a wrong definition of bioavailability was not only stated in the guidance (Resolução) but also in the law (Legislação). Whilst the former could have been corrected rather quickly, it took Brazil two years to change the latter.


  • Example for a drug with low variability. Minimum sample size (in India only if justified 12), 14 subjects dosed, no dropouts; consequently extremely high power:
    library(PowerTOST)
    CV  <- 0.1
    n   <- 14
    pe  <- seq(0.84, 1, length.out=100)
    pe  <- sort(unique(c(pe, 1/pe)))
    res <- data.frame(pe=100*pe, lower=NA, upper=NA, BE=FALSE, PE=FALSE, p=NA)
    for (j in seq_along(pe)) {
      res[j, 2:3] <- round(100*CI.BE(pe=pe[j], CV=CV, n=n), 2)
      if (res$lower[j] >= 80 & res$upper[j] <= 125) res$BE[j] <- TRUE
      if (res$lower[j] < 100 & res$upper[j] >  100) res$PE[j] <- TRUE
      res$p[j] <- pvalue.TOST(pe=pe[j], CV=CV, n=n)
    }
    op  <- par(no.readonly=TRUE)
    par(pty="s")
    plot(pe, res$p, type="n", log="x", xlab="point estimate", ylab="p", las=1)
    grid(); abline(h=0.05)
    box()
    lines(pe, res$p, lwd=3, col="red")
    lines(res$pe[res$BE == TRUE]/100, res$p[res$BE == TRUE], lwd=3, col="magenta")
    lines(res$pe[res$PE == TRUE]/100, res$p[res$PE == TRUE], lwd=3, col="blue")
    legend("top", inset=0.02, box.lty=0, bg="white", lwd=3,
           col=c("red", "magenta", "blue"),
           legend=c("fails BE", "passes BE", "n.s. (CI includes 1)"))
    par(op)


    [image]

    Studies with point estimates of 85.6–116.8% pass everywhere except in [image][image], where the PE has to lie within 93.5–106.9%. Bizarre.

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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Helmut
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Vienna, Austria,
2019-05-22 10:52

@ yatish gosai
Posting: # 20291
Views: 652
 

 Husband ≠ impartial

Hi Yatish,

» Can Husband act as an Impartial witness for Screening and Enrollment of his wife in BABE study?

Look up impartial in a dictionary. A married couple is a paradigm of not being impartial. 
See the definition of impartial witness in the ‘Ethical Guidelines for Biomedical Research on Human Subjects’ of the Indian Council of Medical Research:

A literate person, who is independent of the research and would not be unfairly influenced by people involved with the study, who attends the informed consent process if the participant […] cannot read, and understand the informed consent form and any other written information supplied to the participant.


Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
yatish gosai
☆    

India,
2019-05-22 11:04

@ Helmut
Posting: # 20293
Views: 647
 

 Husband ≠ impartial

Thanks for valuable opinion
Yatish Gosai


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5[Helmut]
nobody
nothing

2019-05-22 15:56

@ yatish gosai
Posting: # 20294
Views: 615
 

 Husband ≠ impartial

These are no "opinions" (i.e. subjected to matters of taste or which can be discussed), these are facts. And it's amazing (to say the least) that such a question arises in the first place in a forum for BA/BE experts...

Kindest regards, nobody
ElMaestro
★★★

Denmark,
2019-05-22 16:11

@ yatish gosai
Posting: # 20295
Views: 610
 

 Impartial Witness in BABE study

Hi yatish gosai
and all posters on this thread,

to be honest I think this is a great, great question and it is one that made me think very hard for a prolonged moment.

The mere fact that such a question is asked should give rise to a lot of reflection on the part of regulators. What is obvious to a regulator or someone from one geographical region is obviously not obvious to others. At the end of the day guidelines are not intended solely for regulators but for all involved parties.

So here's something to work with.

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