switch-over design [Design Issues]

posted by Helmut Homepage – Vienna, Austria, 2007-01-31 14:49 (6266 d 22:20 ago) – Posting: # 500
Views: 8,645

Dear shabana!

❝ […] yes, the washout period will be longer than in the single dose, naturally.


Why are you applying a washout at all?
To quote myself

❝ ❝ […] in a multiple dose steady we dont need a washout phase at all; we may directly switch from one formulation to the other.

…and some guidelines:
EMEA (EU), TGA (Australia): In steady-state studies wash out of the previous treatment last dose can overlap with the build-up of the second treatment, provided the build-up period is sufficiently long (at least three times the terminal half-life).
BPFK (Malaysia): In steady-state studies washout of the last dose of the previous treatment can overlap with the build-up of the second treatment, provided the build-up period is sufficiently long (at least three (3) times the dominating half-life).
ACCSQ (ASEAN States): In steady-state studies wash out of the previous treatment last dose can overlap with the build-up of the second treatment, provided the build-up period is sufficiently long (at least three times the terminal half-life).

❝ no regulatory body recommends a washout less than at least 7-10 half-lives in steady state studies.


No one?
Specific for steady-state studies (EU, AUS, MZ, ASEAN-States; see above)

General about wash-outs:
WHO: … more than five times the terminal half-life of the API.
http://www.fda.gov/cder/guidance/5356fnl.pdf FDA: … more than 5 half lives of the moieties to be measured.
Japan: … should usually be more than 5 times the elimination half life of the parent drug or active metabolites.
CDSCO (India): … two phases of treatment separated by an adequate washout period which should ideally be equal to or more than five half life's of the moieties to be measured.

You are only right for Canada (a little bit outdated – 1996)…
HPFB:
The interval between study days should […] normally be not less than 10 times the mean terminal half-life of the drug (generally, the interval between study days should not exceed four weeks).
Steady state is usually achieved when repeated doses of a formulation are administered over a period that exceeds five disposition half-lives of the modified-release form.
… and ANVISA (Brazil):
The interval between the periods must be, at least, of seven half-lives of the drug or the metabolite elimination.

❝ the fact that the study has been coducted as a crossover, shows that there was a possibility of an effective washout period.


:confused:

❝ of course, if the drug has accumulated and not completely removed from body in the washout period, it will show up as significant pre-dose concentration in the next period,and there you are caught!!! then the second period will never be considered for PK and statistical analysis at all.


Forget about washouts in steady-state; they are just a waste of time, increasing the chance of subjects dropping out from the study (see above)!
You may google for 'switch-over' design.
:google:

It's a basic principle in linear PK (superposition principle: AUCτ=AUC) that irrespective of the level we're starting from, we always obtain the same steady-state concentrations.
[image]
To give you an example (1 compartment open, D=100, V/F=1, k01=0.6931, k10=0.06931, τ=24h).

The green line shows the saturation phase after a wash-out (or in period 1), the red line shows what we would expect in a switch-over design where test=reference (starting from a residual concentration), and the blue line shows what we would expect if the BA of the formulation administered in period 1 is 2× the formulation we administer in period 2.

Do you see any difference in steady-state levels? OK, to be precise, at 120h we get 25.966 (after washout), 25.972 (T=R), and 25.979 (P1=2×P2). :-D

❝ As to the last point re regulatory acceptance. i am sure the regulatory says "In addition to the single-dose studies described ........, a comparison should be made between .......................... at steady state." its how you interpret it. when you say "in addition to", does it mean in a separate trial, or a different phase?

❝ "musable" issues, if you ask me.;-)


Appendix 1 of EMEA's NfG leaves no space for interpretation (clearly talks about studies, not study phases).

❝ i found a recent declaration by the DKMA quite amusing. it said that "the 90% confidence interval for the ratio test versus reference should include 100% irrespective of whether acceptance limits of 80-125% or narrower are employed.". looks like someone was playing hookey with the guidelines!!!!:-D


Not quite recent;-)
… but in practice in Denmark (see also this post).
In the last two years I had to handle quite a lot of deficiency letters from other European Regulatory Agencies as well concerning the '100% not included in the CI'-issue. All of them could be resolved, and you're true, I think it's just nuts.
Actually there are only two possible reasons for such a result:P.S. Please avoid full quotes.


Edit: FDA-link corrected to latest archived copy. [Helmut]

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