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Hello everyone
thanks for given the answer for the first question i have asked.
I have some doubts in my mind ie
for Bioequivalence studies,
1. have to choose 12, 24,96 healthy volunteers. This selection is on
what basis.i think it depend upon the regulatory (like indian, others
and FDA). How this number is decided. any reason.
2. How to decide the blood withdrawl interval> If i am correct 11-13
times we can withdraw the blood from the volunteers. is it possible
to take more number or what.
3. if cmax attains between 0.5 to 2.5 hrs, then how to decide the
time interval for the blood withdrawl.
thank you
devisha
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Dear Devisha,
Making an attempt to answering you questions #02 the blood sample
time points are decided considering the value of Tmax and T1/2 of
the drug under investigation. Usually, to adequately characterize the
absorption profile of the drug, atleast five points are taken around
the Tmax (i.e. two points before and two points after the Tmax).
Whenever Cmax is given in the range, you can take average and then
proceed.
Depending upon the half life of the drug, you can decide the sample
time points. during the elimination of the drug. (i.e. adequate time
points to characterize the elimination profile.) It is advisable to
take sample till five half lives.
Considering both above fact, one should decide the number of sample
points in the Bio study. One should also bear the total blood loss in
the entire trial. (Large blood loss in the short period is not
recommended however vice versa can be true). Replying to the total
number of sample that can be withdrawn will surely depend on the
volume of each sample. High sensitive bioanalytical method (lower
Limit of quantification) will afford to work with small sample volume.
For further detail, please refer following USFDA guideline.
http://www.fda.gov/cder/guidance/_Toc32045835
I guess, it will help.
Regards,
Rakesh Dadhania
Junior Scientist, Clinical Development,
Discovery Research, Dr. Reddy's Laboratories Limited,
Bollaram Road, Miyapur, Hyderabad.
Andra Pradesh, India.
Phone No-040 23045439 Ext No 144
Fax No-040 23042973
Email: rakeshd.aaa.drreddys.com
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hi krish,
the n-size is calculated on the intrasubject variability, either from
published literature or from pilot study. guidelines from regulatory
authorities tells what the minimum number of subjects for BE study
should be.
FDA guidelines for BA/BE study recommend 16-18 samples. if your study
demands more blood samples you should have justification for it and
see to it that the total volume doesnot exceed 250-300ml.
u should have 3-4 time points in the absorption phase.
plz refer US FDA guideline for BA/BE study
DCGI's guidelines (DRAFT GUIDELINES FOR BIOAVAILABILITY /
BIOEQUIVALENCE STUDIES ON CONVENTIONAL AND EXTENDED RELEASE DOSAGE
FORMS )
Cordially,
Dr. Renu Jain
Research Associate
Clinical Research & Regulatory Affairs
Torrent Research Centre
Phone: 079 - 2396 9100 Ext.: 608
cell: 98256 33607
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The following message was posted to: PharmPK
Dear Devisha
1. Choosing the no. of volunteers is based on the %CV
(intrasubject variability) of the drug for a given
power of the study (which should be 80%). The table
which describes the required no. of volunteers for
different %CVs is very well provided in regulatory
guidance of MCC (South Africa) and other literature
sources. Moreover, the regulatory agencies also have
specifications for minimum no. of subjects in which
the study has to be carried out(which differs for each
regulatory).
2. To have a good PK profile 15-18 samples in a period
will be a good choice. Your time points should be good
enough to capture the Tmax, Kel and AUC as accurate as
you could. There is no specific restriction on the no.
of samples you collect in a period until your time
points are meaningful and it does not exceed the
acceptable limit of blood loss.
3. The time interval to capture depends on the drug
half-life. Imagine, if the drug has an half-life of 2
to 4 hours, then you can very well have 15 to 20
minutes interval up to 3 hrs (if Tmax is 0.5 to 2.5
hrs)and should reduce the interval if half life is
less. I would suggest that, you should go according to
the data obtained from earlier studies (if any) in the
same race or country.
Regards
v.rajesh
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Dr. Renu
As per USFDA, a blood loss upto 450 ml is acceptable.
While a person donates blood, the usual volume
collected is 350 ml (1 unit) and is considered
medically safe to collect upto 550 ml in healthy
males. Considering the above facts, I feel that it is
not mandatory to restrict the blood loss to 300 ml.
V.Rajesh
Research Associate
Ranbaxy
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v. rajesh,
i do agree with you about the medical safety of blood donation upto
450-500ml but by and large for BE studies 18 samples of 5-7ml for 2
periods would not exceed blood vol beyond 300ml and if the study
demands more blood volume, one can always reasonably justify that.
renu
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Dear all,
We would like to know whether an active drug metabolite should be
monitored
in bioequivalence studies.
We are particular interested in a process of registration of generic
drugs,
and we are wondering the following:
1. Since the BE studies are conducted in order to approve the
equivalence of
the rate and the extent of drug absorption from two formulations,
monitoring
of an active metabolite seems to be unnecessary (as the metabolite
disposition is not affected by drug absorption, except for prodrugs).
2. However, as bioequivalence studies are conducted to confirm the
therapeutic equivalence of two drug products, is it correct to state
that
two drug products are therapeutically equivalent based only on the
parent
drug monitoring?
Can you suggest any guidance?
Regards,
Anita Rakic and Ivan Kovacec
Medicines and Medical Devices Agency of Serbia
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You can refer to FDA Guidance which gives a clear indication when the
metabolite estimation is to be done.
http://www.fda.gov/cder/guidance/4964dft.htm#P401_45865
For BE studies, measurement of only the parent drug released from the
dosage form, rather than the metabolite, is generally recommended. The
rationale for this recommendation is that the concentration-time
profile of the parent drug is more sensitive to changes in formulation
performance than a metabolite, which is more reflective of metabolite
formation, distribution, and elimination. The following are exceptions
to this general approach.
* Measurement of a metabolite may be preferred when parent drug levels
are too low to allow reliable analytical measurement in blood, plasma,
or serum for an adequate length of time. The metabolite data obtained
from these studies should be subject to a confidence interval approach
for BE demonstration. If there is a clinical concern related to
efficacy or safety for the parent drug, sponsors and/or applicants
should contact the appropriate review division to determine whether the
parent drug should be measured and analyzed statistically.
* A metabolite may be formed as a result of gut wall or other
presystemic metabolism. If the metabolite contributes meaningfully to
safety and/or efficacy, the metabolite and the parent drug should be
measured. When the relative activity of the metabolite is low and does
not contribute meaningfully to safety and/or efficacy, it does not need
to be measured. The parent drug measured in these BE studies should be
analyzed using a confidence interval approach. The metabolite data can
be used to provide supportive evidence of comparable therapeutic
outcome.
I hope this will help you.
With Best Regards
Dr. Shahid Karim
Lecturer,
Department of Pharmacy Practice,
First floor, Majeedia Hospital
Jamia hamdard,
New Delhi-62
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Dear sirs,
Plese give me answer of following question?
(1) What is 90% confindent interval?. How it is decided that Cmax
and AUC is determined at 90% confindential interval and why not at
95% or at 100%.
(2) Please give me limit for Cmax, Tmax and AUC for highly variable
drug, SR product , delayed release product and IR product.
(3)How can we say that our product is bioequivalence to reference
product?
Thanks
Best regards
kishor kapadia
Zydus cadila
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(1) What is 90% confindent interval?. How it is decided that Cmax
and AUC is determined at 90% confindential interval and why not at
95% or at 100%.
Response: A confidence limit is a method of quantifying the
uncertainty of an estimated value in a statistic (e.g. mean). The
width of the confidence interval gives us some idea about how
uncertain we are about the statistic (precision). For a 90% CI, it is
the range of values within which we can be 90% sure that the true
value for the whole population lies. So really we are saying that 90
out of 100 times in repeated experiments the estimated value would
lie within the range defined by the 90% CI.
Remember that the ratio is still vary important for this evaluation,
since the closer to 1 that the ratio lies, the easier it is pass a
bioequivalence study. An increased sample size can shrink the CI.
90% is not always used, but it is the regulation for 'simple' drugs.
In Canada, the guidances sometimes call for the 95% CI (e.g. highly
toxic drugs, drugs with NTR). The 90% CI is based on a two-sided
hypothesis test with an alpha value of 0.05. I suggest that you read
the introduction in "Design and Analysis of BA and BE Studies" by
Chow and Liu.
(2) Please give me limit for Cmax, Tmax and AUC for highly variable
drug, SR product , delayed release product and IR product.
Response: Please explain what you are asking for exactly. Each
regulatory authority has 'limits'/regulations required to prove BE
for each of these products. Note: generally there is no difference
in the regulations to prove BE between IR, SR or delayed release
products. There are no 'limits' on the Tmax parameter. I suggest
that you read the guidance published by the FDA, TPD or EMEA.
Robert Lepage, M.Sc. CCRP
Associate Pharmacokineticist & Assistant Study Director
Pharma Medica Research Inc.
E-Mail: rlepage.at.pharmamedica.com
Phone: (905) 624-9115 x3300
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Hi Kishor, is your BE study for academia or a drug submission?
To answer your last question, "How can we say that our product is
bioequivalence to reference product?", it really depends, and the
criteria
are evolving.
The following is a brief (and certainly not exhaustive) summary of BE
requirements for single-dose studies to give you an idea of what is
involved. I make no guarantees about the accuracy of this information.
Regulations (particularly draft guidances) like to change, so you
have to
keep on top of them to make sure you are submitting the correct
information
and applying the right criteria. If anyone finds something blaringly
wrong
here, please let me know.
Standards for Bioequivalence for Single Dose Studies (in a nutshell)
FDA
Standards for BE:
-90%CI of point estimates for Cmax, AUCt, AUCinf within
80.00-125.00%, met
on ln-transformed data
-measure and pass on both parent and metabolite if metabolite
significantly
contributes to efficacy
-for long half-life drugs (t1/2>12hrs), use AUC72 instead of AUCt and
AUCinf
Other PK Parameters to Estimate:
-untransformed AUCt, AUCinf, Cmax, tmax, t1/2, lambda
-for fast onset drugs or safety issues, use partial AUC as early
exposure
measure
Other Details:
-For immediate release, if vomiting occurs at or before 2 times median
tmax, exclude subject. For modified release, if vomiting occurs at any
time, remove subject.
-FDA allows for a re-dosing mini-study for an outlier who fails the
study.
TPD
Standards for BE:
-Point estimate for Cmax within 80-125%
-90% CI of point estimate for AUCt within 80-125%
-Met on potency un-corrected and corrected ln-transformed data
-for long half-life drugs (t1/2>24 hrs), use AUC72 instead of AUCt and
AUCinf
-don't measure metabolite unless prodrug where parent is not detected
-where early onset time or rapid absorption rate is important (e.g.
sumatriptan, ibuprofen), 90%CI of point estimate for Cmax and AUCt
within
80-125%, and the point estimate for AUCrefTmax within 80-125%.
-For critical dose drugs (formerly Report C, e.g. phenytoin,
cyclosporin),
the 90% CI of the point estimate for AUCt within 90-112% and the 90%
CI of
the point estimate for Cmax within 80-125% in both fasted and fed
states on
both potency un-corrected and corrected data (draft guidance).
Other PK Parameters to Estimate:
-untransformed AUCt, AUCinf, Cmax, tmax, t1/2, lambda
-for a modified release drug, evaluate AUCx and AUCx/AUCi (x=dosing
interval). If AUCx/AUCi < 0.8, accumulation is important and a steady-
state
study is required.
Other Details:
-TPD allows for add-on studies (>=12 subjects) if a study fails. This
should be mentioned in the protocol prospectively.
EMEA
Standards for BE:
-90%CI of point estimate for Cmax, AUCt, AUCinf within 0.80-1.25, met on
ln-transformed data
-In some cases, a wider CI may be used (0.75-1.33) if the drug is
variable
-pass on Tmax if rapid release is claimed or rate of absorption
related to
adverse events (I have yet to see this invoked).
-for long half-life drugs (t1/2>12hrs), use AUC72 instead of AUCt and
AUCinf
-measure and pass on both parent and metabolite if metabolite
significantly
contributes to efficacy
Other PK Parameters to Estimate:
-untransformed AUCt, AUCinf, Cmax, tmax, t1/2, lambda
-calculate 90% CI of point estimate for tmax using a non-parametric
method
(e.g. bootstrapping)
If you meet the appropriate criteria and conduct your BE trial in
accordance with the appropriate guidances, then you can say that
bioequivalence was demonstrated between your test drug and the reference
product.
Hope this helps,
David Dubins, B.A.Sc., Ph.D.
PK Scientist
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Hey Dave,
That was very thourough...nice done. I have only one argument.
You state that for the FDA, "-measure and pass on both parent and
metabolite if metabolite significantly contributes to efficacy"
The FDA guidance for BE states, "For BE studies, measurement of only
the parent drug released from the dosage form,
rather than the metabolite, is generally recommended."
Sponsors generally want the metabolite data as it makes the study
stronger for submission and who knows what the regulatory authorities
will ask for after submission. Regardless, the guidance is JUST A
GUIDE and not law. Generally, the metabolite data should pass BE if
the parent passes.
Have a great Holiday Season.
Robert Lepage, M.Sc. CCRP
Associate Pharmacokineticist & Assistant Study Director
Pharma Medica Research Inc.
E-Mail: rlepage.-a-.pharmamedica.com
Phone: (905) 624-9115 x3300
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Hi Rob,
It's funny, but the FDA doesn't spell out exactly if/how they want the
metabolite to pass (what parameters?) or even if the study would fail if
the parent passes and the metabolite doesn't. It is left frustratingly
ambiguous. So, when there is a borderline case, I ask the FDA.They
reply,
on average, 3-6 months later. I have various correspondence letters with
the FDA and they have quite often asked for metabolites (even recently),
when the metabolite contributes significantly to the efficacy of the
drug.
The FDA guidance for BE states:
"The moieties to be measured in biological fluids collected in BA and BE
studies are either the active drug ingredient or its active moiety in
the
administered dosage form (parent drug) and, when appropriate, its active
metabolites (21 CFR 320.24(b)(1)(i)). This guidance recommends the
following approaches for BA and BE studies. For BA studies (see section
II.B), we recommend that determination of moieties to be measured in
biological fluids take into account both concentration and activity.
Concentration refers to the relative quantity of the parent drug or
one or
more metabolites in a given volume of an accessible biological fluid
such
as blood or plasma. Activity refers to the relative contribution of the
parent drug and its metabolite(s) in the biological fluids to the
clinical
safety and/or efficacy of the drug. For BA studies, we also recommend
that
both the parent drug and its major active metabolites be measured, if
analytically feasible."
I have seen both sides of the coin, when sponsors wish to measure a
metabolite that doesn't appear to be important, and when sponsors
wish not
to measure what is clearly an active principal metabolite circulating in
significant quantities. It seems to me that a recent trend is only to
look
at the point estimates for the metabolite and not compare their
confidence
intervals.
I liked your answers to the first and second questions on confidence
intervals, very clear and well put. Have a great holiday!
-Dave
David Dubins, B.A.Sc., Ph.D.
PK Scientist
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