krish85
☆    

India,
2022-11-14 05:06
(25 d 19:36 ago)

Posting: # 23363
Views: 581
 

 Frequent Queries from FDA: Gender Imbalance [Regulatives / Guidelines]

Hi All,

Now a days, CROs are recieving frequent queries from FDA (after publishing guidance Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA Aug 2021) like as below.


"We acknowledged that you used both male and female subjects in your fasting bioequivalence (BE) study #XXXXXX. However, it was noted that the percentage of male and female are not similar as 82% and 18%, respectively. Per the labeling of reference product, the proposed product is intended for use in both sexes. Therefore, similar proportions of males and females are recommended to be included in the study. Please provide scientific justification to support that the BE results from unbalanced male vs females subjects in the above BE study can be extrapolated to the entire population and that the unbalance male and female subjects in study population will not affect the BE conclusion."


In one of the webinar hosted by FDA where speaker said that FDA is aware that these are crossover studies and overall it may not have significant impact but FDA still wants similar proportions of males and females.


If PK of a drug in male and female are similar then a scientific justification can be drafted.

But how can CRO respond to the query where CRO has not included similar proportion of male and female (obivious reason is unavailability of female volunteers) and PK in male and female are different.


Please feel free to share your experience if anyone has recieved similary queries and what justification was provided.
dshah
★★  

India/United Kingdom,
2022-11-14 17:01
(25 d 07:40 ago)

@ krish85
Posting: # 23364
Views: 485
 

 Frequent Queries from FDA: Gender Imbalance

Dear krish85!

The query is not new!

❝ Now a days, CROs are receiving frequent queries from FDA (after publishing guidance Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA Aug 2021) like as below.


The recruitment is voluntary and many a times recruitment of female subjects are challenging. In the protocol- generally it is not written that how much percentage of male/female will be dosed. As the number of subjects are sufficient to have appropriate power, the clinical phase can be initiated. I believe unless it is not mentioned in protocol that you are going to dose 50:50 ratio, you are complying. If any sponsor wants this, they shall mention in protocol.

On the other front, CRO do not have to have their own data for justification. The SBOA's data or EMA's scientific justification data or even research article can be provided for support purpose mentioning no gender effect on PK is observed.

Regards,
Divyen Shah
ElMaestro
★★★

Denmark,
2022-11-14 22:46
(25 d 01:56 ago)

@ krish85
Posting: # 23365
Views: 467
 

 Frequent Queries from FDA: Gender Imbalance

Hi Krish85,

❝ In one of the webinar hosted by FDA where speaker said that FDA is aware that these are crossover studies and overall it may not have significant impact but FDA still wants similar proportions of males and females.


That is correct. New winds are blowing.

❝ If PK of a drug in male and female are similar then a scientific justification can be drafted.


Technically, this is not about PK being similar or dissimilar among the genders. It is about the ratio of AUC or Cmax being similar or dissimilar and that is a completely different ballgame.

The originator industry has tried for years to convince FDA that a conclusion of BE changes depending on the population (patients vs healthy volunteers, Caucasians vs Indians, smokers vs nonsmokers, females vs males etc). yet it was never clearly shown that this might be the case. And that's why it has so far always been appropriate to test medicines in one population and extrapolate to others. Meaning if BE is shown in healthy adult nonsmoking Indians then it is credible that the product is also BE in female argentinians who own a rusty bicycle. And so on.

Yet, in spite of the above, FDA have begun asking for or expecting approximate gender balance, like you noticed. You can plan for it in the future. CROs in India and Jordan -where populations tended to be exclusively male in the the past- are really going full throttle in that direction.

❝ But how can CRO respond to the query where CRO has not included similar proportion of male and female (obivious reason is unavailability of female volunteers) and PK in male and female are different.


Depending on your specific situation you may find inspiration in Deniz ôzdin's recent publication. Other than that state the argument above and hope for the best. Or make a promise to redo your study in a more balanced population - I am sure FDA would appreciate it.:-)

Pass or fail!
ElMaestro
jag009
★★★

NJ,
2022-11-22 08:02
(17 d 16:39 ago)

@ krish85
Posting: # 23373
Views: 284
 

 Frequent Queries from FDA: Gender Imbalance

Hi,

❝ Please feel free to share your experience if anyone has recieved similary queries and what justification was provided.


I am sorry but whenever I run a BE study I always ask for 60/40 split. I might allow 70/30 split depending on the sample size. If the site cannot accommodate my request then I will go somewhere else. So far I haven't received any queries from FDA.

J
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