Back to the Top
The following message was posted to: PharmPK
Dear David Dubins:
Please, could you say me where I could find more details about this
exclude criteria (vomiting occurs)?
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.
Many thanks
Mari Carmen Llopis Garcia
Pharmacokinetic and Metabolism Service
Clinical PK Unit
Ipsen Pharma, S.A.
Ctra. Laurea Miro, 395
08980 Sant Feliu de Llobregat
Barcelona (Spain)
Tf.: +34 93 685 81 00 (Ext. 347)
Fax +34 93 685 1053
em.at.il: mari-carmen.llopis.-a-.ipsen.com
Back to the Top
Dear Mari Carmen Llopis Garcia,
1. "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"
You may refer to http://www.fda.gov/cder/guidance/5356fnl.pdf for
"Data deletion due to vomiting" (page 25).
FDA recommends that "data from subjects who experience emesis during
the course of a BE study for immediate-release products be deleted
from statistical analysis if vomiting occurs at or before 2 times
median Tmax. In the case of modified-release products, the data from
subjects who experience emesis any time during the labeled dosing
interval can be deleted"
2. FDA allows for a re-dosing mini-study for an outlier who fails the
study.
As per my understanding, FDA does not recommend for a redosing of an
outlier in a ministudy. If you look at the guidelines on statistical
approaches to establishing bioequivalence http://www.fda.gov/cder/
guidance/3616fnl.pdf, FDA discourages deletion of outlier data in non
replicated studies.One has to consult with the appropriate review
staff for further action.
Redosing has been discussed in Canadian regulatory agency...You may
find the discussion at
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/sci-com/bio/
sacbb_rop_ccsbb_crd_2004-06-03_e.html
Hope this helps.
Regards
Ganesh
Back to the Top
The following message was posted to: PharmPK
Dear Group
This is further to discussion on data deletion due to vomiting. FDA
guideline does not specify rationale for data deletion specifically with
respect to Modified Drug. It says that data should be deleted from PK
and stat analysis if subject has vomited during dosing interval. It is
understandable that if subject vomits around median Tmax time period, or
arround two times of median Tmax, he / she should be dropped. But,
there is no point in dropping subject, if he has vomited at 23 hr post
dose and Tmax is 6 hr.
Group can bring more clarity on this issue.
Thanks in advance and one can always correct me.
Regards
Mitesh Gandhi
Back to the Top
The following message was posted to: PharmPK
Hi Ganesh, the error was mine. You are correct in citing the guidance,
vomiting should occur at any time during the dosing interval rather than
any time during the study for subject exclusion. It would depend on the
dosing interval when the cutoff would be.
Regarding the FDA mini-studies, they are indeed possible with an FDA
submission. I am at a loss for the electronic version of this file, but
Barbara Davit (Deputy Director, Division of BE/OGD) delivered a
presentation entitled "Outliers and Inadequate Profiles in
Bioequivalence
Studies: U.S.-FDA Perspective" (Scientific Advisory Committee for
Bioavailability and Bioequivalence, June 3, 2004). In this presentation,
she outlined the FDA's position on mini-studies. She does indicate "FDA
discourages deletion of outlier subjects." However she highlights the
FDA's
position on Subjects with Anomalous Responses:
-An anomalous response may be due to an unexpected event, such as a
technical flaw
-FDA believes applicants should have [a] chance to demonstrate that
response was truly aberrant
-Applicants can conduct a re-dosing study
-Re-dosing study must include suspect subject and, as controls, several
subjects from pivotal BE study
-If suspect subject shows normal response in re-dosing study,
confirms that
response was truly aberrant in pivotal BE study
-***If subject is confirmed to be truly aberrant in this manner, can
drop
from pivotal BE study***
She then provided an example where a 23-subject BE study of an
anti-inflammatory prodrug failed on the 90%CI's, and Subject 10 had
unusually low T/R values. The applicant conducted a re-dosing study, and
based on the results the FDA allowed the applicant to drop Subject 10.
There were no set "criteria", only that Subject 10 responded "normally"
when re-dosed, and so the FDA concluded that it was acceptable to drop
Subject 10 from the main study. There was a large difference in T/R
ratio
for this subject (Cmax and AUCT ratios were 0.28 and 0.25 in the main
study, then 0.98 and 0.94 for the redosing mini-study). Two other
subjects
were added in for controls. It turned out that excluding Subject 10 from
the analysis passed the BE study.
On a subsequent slide entitled "FDA-Recommended Solutions for Erratic PK
Profiles", she states: "If suspect subject had anomalous data, conduct
re-dosing study."
And finally, in a slide entitled "Summary: Outlier Issues" she states:
-FDA discourages dropping outliers from BE analysis
-Applicants should not drop from BE analysis subjects at extremes of the
study population
-FDA encourages applicants to confirm that an extreme response is an
anomaly by conducting a re-dosing study
Hope this helps,
-Dave
David Dubins, B.A.Sc., Ph.D.
Pharmacokinetic Scientist
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)