ping4santosh
★

India,
2020-03-11 14:35
(197 d 00:16 ago)

Posting: # 21247
Views: 5,554

## Underrepresentation of female subjects in BE study to register Generic [Regulatives / Guidelines]

Dear All,

I request your help to arrive at a decision on male to female ratio in a BE trial. We have done a pilot study with 12 subjects (8 male and 4 female) and the results didn't meet the bioequivalence criteria. However, when we exclude the female data it marginally meets the bioequivalency crtieria of 80%-125%.

Can we conduct the pivotal study only in Males? Can we extrapolate the conclusions obtained in males to females. What would be the regulatory challenges and please prove some references that can guide me on this.

Thanks a lot for your support.
Best wishes,
SKM
Ohlbe
★★★

France,
2020-03-11 15:07
(196 d 23:44 ago)

@ ping4santosh
Posting: # 21251
Views: 3,334

## Underrepresentation of female subjects in BE study to register Generic

Dear SKM,

» We have done a pilot study with 12 subjects (8 male and 4 female) and the results didn't meet the bioequivalence criteria.

So what ? It is a pilot. Was it powered to demonstrate BE ?

» However, when we exclude the female data it marginally meets the bioequivalency criteria of 80%-125%.

Did you pre-plan this male-only analysis in your protocol or statistical analysis plan ?

» Can we conduct the pivotal study only in Males?

Where do you intend to submit your data ? USA: the FDA wants males and females. Europe: EMA accepts studies in males only, but "we fear that we may fail if we include females" will not be an acceptable rationale.

Regards
Ohlbe
ping4santosh
★

India,
2020-03-11 15:37
(196 d 23:14 ago)

@ Ohlbe
Posting: # 21253
Views: 3,331

## Underrepresentation of female subjects in BE study to register Generic

» Where do you intend to submit your data ? USA: the FDA wants males and females. Europe: EMA accepts studies in males only, but "we fear that we may fail if we include females" will not be an acceptable rationale.

Dear Ohlbe,

Thanks you your response. The pilot was not powered. Pivotal is powered given the high ISCV. We didn't pre-plan it in the pilot. We took M:Fe in the ratio of 2:1 and this is a post hoc analysis. We saw high ISCV and lower Cmax in Females as compared to Males. We intend to submit the data in EU but I won't be surprised if the management decides to submit that data in FDA at a later date.

Should you suggest me to go ahead with same M:Fe::2:1 ratio for a powered pivotal?

Cheers, SKM
Helmut
★★★

Vienna, Austria,
2020-03-11 16:31
(196 d 22:20 ago)

@ ping4santosh
Posting: # 21255
Views: 3,325

## Study planning 101

Hi SKM,

» Pivotal is powered given the high ISCV.

May I ask how? Say the CV was 25% in the pilot study, it might be as well higher in the pivotal. Its upper CL is 32% (n=12, M+F) and 35% (n=8, M). If you follow the ‘carved in stone’ approach, you shoot yourself in the foot (see there).

» We took M:Fe in the ratio of 2:1 and this is a post hoc analysis.

So far, so good. That’s one of the purposes of a pilot. Learn sumfink. Any exploratory analysis is fine.

» We saw high ISCV and lower Cmax in Females as compared to Males.

Saw! Given the small sample size I have strong doubts that these differences are (statistically) significant. As ElMaestro wrote, subgroup analyses have been tried a lot. Didn’t work because studies were not sufficiently powered. See also this post and the reference within.

» We intend to submit the data in EU but I won't be surprised if the management decides to submit that data in FDA at a later date.

The management will be surprised when the study is rejected by the FDA’s OGD right away because not the RLD was used in the study. If you want to submit to both agencies, you need a 6×3 Willi­ams’ design with both a European reference and the RLD (see there).

» Should you suggest me to go ahead with same M:Fe::2:1 ratio for a powered pivotal?

Given the notorious high dropout-rate of female subjects in India I would (for the EMA) perform a 2×2×2 in males only. The FDA requires subjects to be ‘representative of the general population’. When I was in the US last December I didn’t get the impression that it is even close to 2:1. Lots of women around…

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
ElMaestro
★★★

Belgium?,
2020-03-11 15:24
(196 d 23:27 ago)

@ ping4santosh
Posting: # 21252
Views: 3,345

## Underrepresentation of female subjects in BE study to register Generic

Hi SKM,

it sounds like random flutter or a gender x treatment interaction? It could also be that the females increase variance, and this, I think, may be somewhat more likely.
Please show the data. Can you send us the STDM and ADAM datasets?

» Can we conduct the pivotal study only in Males? Can we extrapolate the conclusions obtained in males to females. What would be the regulatory challenges and please prove some references that can guide me on this.

There are no directly relevant references. Generally speaking the innovator industry has been exploring lots and lots of opportunity for claiming population x treatment interactions, but it has so far been without much evidence.
Yes, you can likely conduct the study in males. But why would you if you think the conclusion in males can be extrapolated.

I could be wrong, but...

Best regards,
ElMaestro

R's base package has 274 reserved words and operators, along with 1761 functions. I can use 18 of them (about 14 of them properly). I believe this makes me the Donald Trump of programming.
ping4santosh
★

India,
2020-03-11 16:15
(196 d 22:37 ago)

@ ElMaestro
Posting: # 21254
Views: 3,304

## Underrepresentation of female subjects in BE study to register Generic

Hi ElMaestro,

It's not a random flutter. Females actually fall back on bioequivalncy. Cmax at 75% and range was lower too. Pioneer product behaved similar way. So it's not random. You are right. The females also has higher variance.

I didn't understand your last statement. Can you kindly clarify?

» Yes, you can likely conduct the study in males. But why would you if you think the conclusion in males can be extrapolated

Cheers,

SKM
ElMaestro
★★★

Belgium?,
2020-03-15 09:27
(193 d 05:24 ago)

@ ping4santosh
Posting: # 21273
Views: 3,049

## Underrepresentation of female subjects in BE study to register Generic

Hi ping,

» It's not a random flutter. Females actually fall back on bioequivalncy. Cmax at 75% and range was lower too. Pioneer product behaved similar way. So it's not random. You are right. The females also has higher variance.

(...)

» I didn't understand your last statement. Can you kindly clarify?

This could be a case of BE being present in males and not in females. Would you really want to put such a product on the market, if you think the conclusion from males can be extrapolated in such a way that regulators grant approval??
However, those companies that did try to investigate if BE applies in one population but not in another all failed - there are occasional rumours out there but the proof is generally rather absent. I.e. if a product is BE in one gender and not in another, or if a product is BE in a European population but not in an African population etc. Innovators have spent a lot of  on investigating it, and no solid proof was delivered so far.
I am thus a little doubtful as to whether you are really having a product with a true gender difference in terms of the BE conclusion.

"More data is needed."

I could be wrong, but...

Best regards,
ElMaestro

R's base package has 274 reserved words and operators, along with 1761 functions. I can use 18 of them (about 14 of them properly). I believe this makes me the Donald Trump of programming.
ping4santosh
★

India,
2020-03-15 09:41
(193 d 05:10 ago)

@ ElMaestro
Posting: # 21274
Views: 3,047

## Underrepresentation of female subjects in BE study to register Generic

Hi ElMaestro,

Thanks ElMaestro,

» This could be a case of BE being present in males and not in females....

In fact that's the case in the pilot. Please let me know what specific data you need?

Cheers,
SKM

ElMaestro
★★★

Belgium?,
2020-03-15 10:23
(193 d 04:28 ago)

(edited by ElMaestro on 2020-03-15 10:37)
@ ping4santosh
Posting: # 21277
Views: 3,046

## Underrepresentation of female subjects in BE study to register Generic

Dear ping,

» This could be a case of BE being present in males and not in females....
»
» In fact that's the case in the pilot. Please let me know what specific data you need?

I think I may -again- have formulated myself sub-optimally and for this I apologise.
I can't imagine that you have solid data to document that the conclusion changes between genders, but please prove me wrong.
Note that BE studies have three outcomes: BE, BE not shown (inconclusive), and bioinequivalent. I would be very astonished if you have data to show bioequivalence in one gender and bioinequivalence in the other. More likely -this is speculation on my part- you have an overlap with the acceptance range in which case you are inconclusive for that interval or population.

BE not shown in females while BE shown in males is in itself not necessarily a proof that the conclusion changes between genders.

Can you show intervals, and sample sizes?

I could be wrong, but...

Best regards,
ElMaestro

R's base package has 274 reserved words and operators, along with 1761 functions. I can use 18 of them (about 14 of them properly). I believe this makes me the Donald Trump of programming.
ping4santosh
★

India,
2020-03-16 09:13
(192 d 05:38 ago)

@ ElMaestro
Posting: # 21280
Views: 2,876

## Underrepresentation of female subjects in BE study to register Generic

Thanks ElMaestro for helping me out!

Cheers,
SKM
Ohlbe
★★★

France,
2020-03-15 19:28
(192 d 19:23 ago)

@ ping4santosh
Posting: # 21278
Views: 2,975

## Not enough subjects to say

Dear SKM,

» » This could be a case of BE being present in males and not in females....
»
» In fact that's the case in the pilot.

With only 4 females in your study you don't have enough statistical power to make such a conclusion. You may have a signal, but I would find it difficult to go any further based on the data you have at hand currently.

Regards
Ohlbe
ping4santosh
★

India,
2020-03-16 09:03
(192 d 05:48 ago)

@ Ohlbe
Posting: # 21279
Views: 2,891

## Not enough subjects to say

Thanks Ohlbe!
jag009
★★★

NJ,
2020-03-15 07:30
(193 d 07:21 ago)

@ ping4santosh
Posting: # 21272
Views: 3,056

## Underrepresentation of female subjects in BE study to register Generic

Hi,

» Can we conduct the pivotal study only in Males? Can we extrapolate the conclusions obtained in males to females. What would be the regulatory challenges and please prove some references that can guide me on this.

FDA? Even if not FDA I don't think your justification will work. You are trying not to use female subjects because they caused your study to fail. That alone is not a good justification.

J
ping4santosh
★

India,
2020-03-15 09:43
(193 d 05:08 ago)

@ jag009
Posting: # 21275
Views: 3,040

## Underrepresentation of female subjects in BE study to register Generic

» You are trying not to use female subjects because they caused your study to fail. That alone is not a good justification.

Hi Jag,

Thanks for your suggestion. What do you think should be the ratio of M:Fe, wherein you know that more female you take, the more closer you get to bioinequivalency. Whats your take?

Cheers,
SKM