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11/4/2003:
The FDAMarch 2003 guidance for BA/BE studiesrecommends that study
population should be representative of population that will take the
drug. Recommends that sponsor "attempt to include similar proportions
of males and females in the study [section III A. 5 Study Population)."
I would like to put a question to the group relating to performing a
bioequivalence study using subjects of mixed gender. As stated above
FDA recommends using both male and female subjects be used for the
crossover bioequivalence study. Some Europeancolleagues of mine have
expressed stronglythe point of view that using subjects of mixed
gendershould be avoided if possible. They feel that as a basic
scientific principle introducing another variable (gender)into the
bioequivalence study makes the design more complex and would prefer
that the same gender be used.
I invite comments on this topic as to whether there are situations
where it is more difficult to achieve bioequivalence using a mixed
gender population compared with a single gender population,or does the
balancedcrossover Latin Square design dictate that no more risk to
achieving bioequivalence is incurredwhen different genders are
included in the study.
Arethere scientific and statistical differing points of view on this
issue?
Angus McLean Ph.D.
BioPharm Global Inc.
8125 Langport Terrace,
Suite 100
Gaithersburg,
MD 20877
301-869-1009
301-869-5737
BioPharm Global Inc.
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In my experience - this is not an issue. Random variability between
subjects is far greater than any differences that may be explained by
gender.
Furthermore, with BE, the analysis is paired, making this even less
relevant in estimation of BE.
Noel Cranswick
Noel E Cranswick
Director, Clinical Pharmacology, Royal Children's Hospital
Director, APPRU, Royal Children's Hospital
Associate Professor, University of Melbourne
5th Floor, Main Building
Royal Children's Hospital,
Parkville
Victoria 3052
Australia
Phone: 61-3-9345 6987
Fax: 61-3-9345 5093
Web:www.appru.com
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Dear Dr. McLean,
As an outsider in the field of regulatory affairs, I would make the
following comments:
> The FDA March 2003 guidance for BA/BE studies recommends that study
> population should be representative of population that will take the
> drug. Recommends that sponsor "attempt to include similar proportions
> of males and females in the study [section III A. 5 Study Population)."
In my view this makes sense. We test a drug to be reasonably sure that
it
can be given safely and effectively in patients.
> Some European colleagues of mine have
> expressed strongly the point of view that using subjects of mixed
> gender should be avoided if possible. They feel that as a basic
> scientific principle introducing another variable (gender) into the
> bioequivalence study makes the design more complex and would prefer
> that the same gender be used.
IMHO, this does not make sense. Excluding females implies,
scientifically
speaking, that we cannot draw any conclusion for female subjects.
Therefore
excluding females from a BA/BE study (and almost any human study with
drugs)
is a methodological flaw.
The argument of the scientific principle to avoid variables as much as
possible is correct for scientific studies, but not for BA/BE studies
intended to demonstrate bioequivalence of different products. In my
view the
main argument of this 'scientific principle' is that this allows to
reduce
the sample size of a study by reducing the variability and reducing the
influence of confounders. This is fine for demonstrating a 'proof of
concept', but not for a test to demonstrate that a product is safe and
effective. For the latter we need a representative sample from the
population.
The argument of Noel Cranswick that gender difference are usually minor
compared to intersubject variability is fair, but not really convincing.
Indeed it is reasonable to assume that bioequivalence demonstrated in
man
will be true also in women, but this is not more than reasonable. Is
that
enough for demonstrating BA/BE? I don't think so.
Please note that the argument of a paired analysis is not correct in my
opinion. Gender differences in disposition are not relevant; in BA./BE
studies the topic is the rate and extent of bioavailability, and these
parameters are not paired.
Best regards,
Hans
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.at.farm.rug.nl
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Dear readers
With context to bioequivalence study, we are following either height -
weight chart or BMI as one of the inclusion criteria. My question is,
if we are including one or two subjects not falling in height-weight
chart or BMI, is it going to afftect final outcome of Bioequivalence
study? In short, how can you corelate that deviation with final outcome
of study?
Thanks
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Dear Angus,
For what it's worth I agree with Noel Cranswick that the individual
variation within genders is far greater that the variation between
them, so
it is not logical to separate the genders in BE studies even if you are
not
using the normal crossover design.
I find it saddening that the rigid GCP approach like the one you
describe so
often ignores the science and insists on unnecessary conditions which
make
our research less and less relevant to real life. Our latest example is
a
client who is insisting we use only one brand of bacon and egg sandwich
for
breakfasts...no other sandwich will do! So we won't be recruiting
vegetarians, or observant jews and moslems...
On the other hand I do agree with some of the more recent restrictions.
For
example like most units we make all volunteers sit up in bed for 2 hours
after an oral dose because ia uniform posture removes significant
variance
in the Pk profiles, but the results certainly don't mirror real life.
Like
you I'm interested in a professional forum like ours pooling our
experience
to agree what should and should not be adopted as "best practice".
Andrew Sutton
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The following message was posted to: PharmPK
Dear Dr McLean,
Your question has stimulated some very interesting comments. If I could
add
my 10 cents' worth as well:
Keeping in mind that the primary variable being invetsigated in a
bioequivalence study is the effect of a generic formulation on the rate
and
extent of absorption of the active ingredient, gender would certainly
add an
extra variable to the study (albeit in most cases of negligible
consequence). If gender does indeed affect the absorption of an active
ingredient, including disproportionate numbers of males and females in a
study may lead to the incorrect conclusion that the generic formulation
is
not bioequivalent to the innovator/comparator. There are two approaches
to
control for this potential source of variation, either to include
subjects
of only one gender in the study or to include similar proportions of
both
genders. Either approach seems acceptable. Perhaps the FDA chose the
latter
to increase the likelihood that any potentially gender-specific adverse
effects of the generic formulation are picked up during the
bioequivalence
study?
Ronette Gehring, BVSc MMedVet (Pharm)
Center for Chemical Toxicology Research and Pharmacokinetics
College of Veterinary Medicine
North Carolina State University
Raleigh
NC 27606
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Dear,
The prefered design for bioequivalence trials is randomized cross-over.
Therefore, each subject is its own control (paired observations: Cmax
and AUC of each occasion will be compaired pairwise).
Inter-occasion variability only counts. Inter-subject variability is
not important in this design (however, it is important for parallel
design, but this not often used).
In order to minimize the number of subjects in your trial (or increase
the power with a fixed number of subjects) you should minimize the
inter-occasion variability as much as possible (e.g. standardized
procedures, or sitting for 2 hours in bed...).
Including a representative population is increasing the inter-subject
variability. This should not matter, UNLESS the inter-occasion
variability is different for different subpopulations. Personally, I do
not think that inter-occasion variability would differ significantly
between males and females, so the request is academic to me.
Best regards,
Kees
Kees Bol, PhD
Director Clinical Pharmacokinetics
Kinesis Holding
Lage Mosten 29
4822 NK Breda
The Netherlands
tel: +31 (0) 76 54 80 621
gsm: +31 (0) 65 31 26 153
fax: +31 (0) 76 54 21 777
kees.bol.at.kinesis-pharma.com
www.kinesis-pharma.com
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Dear Angus
There are several nontechnical aspects of including female subjects in
BE trials especially in country like India
1. Because of social bearings and family practices it would be
difficult to convince a female volunteer to stay over in CPU proir to
study or if required for more number of nights.
2. Privacy of volunteers in a mixed population.
3. the risk for CRO if any untoward incidence happens like teasing
within the volunteers
4.It will be necessary to do a pregnancy test and may be repeat it
within 15 days to be sure that the female volunteer is nonpregnant.
Unmarried female subjects would not like this intrusion for various
socio-cultural reasons.
5. It will be mandatory to ask some questions like this
are you likely to be pregnant till next X weeks? You ask these
questions to unmarried females .....
6. In general female volunteers tend to have lower Hb values especially
in country like India.
7. In addition as pointed by you including female volunteer adds
additional variable.
With regards
Dr.Prashant
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Dear All:
The purpose of generic or OTC formulations is to make sure that the
drug is
available to general public from an alternative source other than the
innovator. In this case the generic company is expected to follow the
identical label claim and package inert (wording may be different in
very
few cases where specifically asked by the regulatory bodies).
The intent of including the female subjects is included with a good
intention to consider representative general public. Guidance encourages
inclusion of both gender so that we deliberately won't exclude female
subjects for anticipated PK differences due to metabolism. In the
generic
drug candidates the confidence intervals are so accommodative if you
power
your study well you shouldn't have any problem in meeting confidence
intervals, if someone still have problem guidance provides alternative
ways
to deal with the situation.
If a company is trying to introduce generic product that is known to
target
a particular gender you can always write a protocol justifying your
exclusion (you don't conduct contraceptive studies in male population
and
pediatrics, LOL)
Other issues like privacy, social stigma etc. are very much streamlined
in a
professional CROs and there are regulatory guidelines on how to deal
with
those issues.
Prasad Tata
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Having preached the following let me add little humor: in one of the
many
short courses I have taken one Professor from university of Arizona
stressing the importance of diversity in clinical trials stated the
following
Who lives in China? Chinese
Who lives in India? Indians
Who lives in Germany? Germans
Who lives in Nigeria? Nigerians
But who lives in America?.... Not Americans but folks from every
ethinicity
that is why clinical trials conducted here is US and trans-national
basis
are very important
Any credit goes to the humor part and blame goes to Prasad.
Prasad Tata
St. Louis, MO 63134
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Dear Prasad
I am commenting on specific bioequivalence for generic marketing. Here
we are checking effect of formulation and not effect of gender.
Scientifically it makes sense to include or change only one variable at
at time.
with best regards
Dr.Prashant
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Dear all,
I am somewhat confused by the discussion on inclusion/exclusion of
female subjects in a BE study. Several people have argued that
including females will add to the variability of the observed drug
concentrations. To my understanding, BE studies take place at a time
when extensive information on the fate of the drug is already
available. Thus, if there is any gender differences in the
pharmacokinetic profile of a compound, it is most probably already
known. If we know that a compound does not exhibit any gender-different
PK, I don't see any reasons for not including both male and female
subjects in a BE study. If our new formulation turns out to show an
effect of gender, while such an effect has not been observed using the
original formulation, then I guess we just have to do a better job (or
be happy that we have a gender-specific formulation!) . If the compound
is indeed known to have gender-specific PK, we should then definitely
include both genders in our study to show that the same phenomenon is
observed in our formulation as well.
The statistical testing of the BE assumes similar extend of variability
in the original and test formulation. This is further facilitated by
the fact that each subject acts as its own control. If inclusion of
gender introduces increased variability to the setting, it should
affect both the original and test formulation. Anything else would mean
non-BE formulations.
Anyway I look at it, it seems to be a good idea to include both male
and female subjects in BE studies.
Toufigh Gordi
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Colleagues:
Dr Prashant wrote:
> I am commenting on specific bioequivalence for generic marketing. Here
> we are checking effect of formulation and not effect of gender.
> Scientifically it makes sense to include or change only one variable
at
> at time.
> with best regards
> Dr.Prashant
.... but I would argue the exact opposite. Gender is not known to be a
significant variable so scientifically speaking it should not be
included. Perhaps we should ask the forum if anyone knows of
anyformulationwith different BA in the two genders? Why choose gender
when you might choose a host of other possible variables that are less
well documented ? We agree thatknownfactors should be controlled such
as food intake, diet and posture but they have been well documented so
it is “scientific” to adopt them.
Whilst we are on the subject of gender I would go so far as to say that
before the menopause the menstrual cycle could possibly affect the
outcome in some individuals. Therefore it would be scientific to
include fertile women at the same time in their cycle for all doses in
a crossover design. In fact I think that is what should be done for the
few products to be prescribed specifically for fertile women
Andrew Sutton,
Guildford Clinical Pharmacology.
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Andrew Sutton wrote:
> Perhaps we should ask the forum if anyone knows of any formulation
> with different BA in the two genders?
>
No (from a personal database of about 250 BE studies in both genders).
Regards
Helmut
--
Helmut Schütz Biokinet GmbH / Dept Biostatistics
Neubaugasse 36/11 Nattergasse 4
A-1070 Vienna/Austria A-1170 Vienna/Austria
tel/fax +43 1 9713935 tel +43 1 4856969 62
no cell phone ;-) fax +43 1 4856969 90
http://www.goldmark.org/netrants/no-word/attach.html
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Several (from a personal database of about 300 BE studies in both
genders).
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Gilberto,
> Several (from a personal database of about 300 BE studies in both
> genders).
Can you be more specific? With a database of 300 BE studies you do
indeed have a formidable body of information. I, and perhaps the group
too, would be very interested in learning:
1) How many times BE was different in females.?
2) Were there any circumstances/covariates where the difference was
more common (e.g. drug characteristics, formulation
characteristics...)?
Interestingly, Helmut Schütz, responded earlier to the group and from
a database of 250 was not aware of any formulations that showed BE
differences based on sex.
Regards
Steve Duffull
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Dear all
I have been reading the recent discussion being held on the inclusion
of female vol. in BA/BE study, I fully agree with Toufigh that it is
always better to includer at least some females in the study.
Regards
Tausif Ahmed
Ph.D. Scholar
Dept. of Pharmaceutical Medicine
Ranbaxy CPU, Hamdard Universiy,
New Delhi, India
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