PharmPK Discussion - Significant period effect

• On 28 Apr 2012 at 11:03:09, shikha rawat (shikha06rawat.-a-.gmail.com) sent the message
  

  
  dear all,
  
  greetings!
  
  In BA/BE studies has any one of you come across a study in which there was a
  significant period effect (particularly for two way crossover)? As per my
  knowledge period effect is orthogonal to treatment effect i.e., the true
  treatment effect is not affected if a statistically significant period effect is
  encountered. But i am not able to find what is the regulatory take on this &
  What could be the possible reasons for this effect.?
  
  thanks
  shikha
  

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• On 30 Apr 2012 at 01:36:07, Helmut Schuetz (helmut.schuetz.-a-.bebac.at) sent the message
  

  
  The following message was posted to: PharmPK
  
  Dear Shikha!
  
  > In BA/BE studies has any one of you come across a study in which there was a
  significant period effect (particularly for two way crossover)?
  
  Yes - but only rarely.
  
  > As per my knowledge period effect is orthogonal to treatment effect i.e., the
  true treatment effect is not affected if a statistically significant period
  effect is encountered.
  
  Correct. Take any of your 2x2 studies and calculate the ANOVA and PE/CI
  of the treatment effect. Now multiply all values of the second period by
  1000 and run the analysis again. The PE and CI of the treatment effect
  will be exactly the same as before though you will observe a highly
  significant period effect.
  
  > But i am not able to find what is the regulatory take on this
  
  EMA's draft BE guideline from 2008
  (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/
  09/WC500003011.pdf)
  contained following statement:
  [...] tests for difference and the respective confidence intervals for
  the treatment effect, *the period effect*, and the sequence effect
  should be reported for descriptive assessment. A test for carry-over
  should not be performed and no decisions regarding the analysis (e.g.
  analysis of the first period, only) should be made on the basis of such
  a test. The potential for carry-over can be directly addressed by
  examination of the pre-treatment plasma concentrations in period 2 (and
  beyond if applicable).
  Based on stakeholder's comments
  (http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/02/WC500073572.
  pdf)
  pp.141-143 the suggested tests for period and sequence/unequal
  carry-over was removed. See the current guideline
  (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/
  01/WC500070039.pdf).
  
  > &  What could be the possible reasons for this effect.?
  
  Almost everything (wheater, lunar phases...). More serious: Especially
  'novice' volunteers may show consistently different concentrations in
  the second period because they adapt to the unfamiliar clinical setting.
  However, since due to randomization both test and reference are affected
  the treatment effect is not influenced.
  
  Helmut
  
  -
  
  Ing. Helmut Schuetz
  BEBAC - Consultancy Services for
  Bioequivalence and Bioavailability Studies
  Neubaugasse 36/11
  1070 Vienna, Austria
  e-mail  helmut.schuetz.at.bebac.at
  web     http://bebac.at/
  forum   http://forum.bebac.at/
  
  

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• On 1 May 2012 at 11:13:47, shikha rawat (shikha06rawat.-at-.gmail.com) sent the message
  

  
  dear Helmut ,
  
  thanks a lot  for your reply..
  
  "Take any of your 2x2 studies and calculate the ANOVA and PE/CI
  of the treatment effect. Now multiply all values of the second period by
  1000 and run the analysis again. The PE and CI of the treatment effect
  will be exactly the same as before though you will observe a highly
  significant period effect."
  
  this is great way to prove that a period effect does'nt affect the treatment
  effects significantly and also does'nt alter the CI's.
  
  "Almost everything (wheater, lunar phases...). More serious: Especially
  'novice' volunteers may show consistently different concentrations in
  the second period because they adapt to the unfamiliar clinical setting.
  However, since due to randomization both test and reference are affected
  the treatment effect is not influenced."
  
  can we say that if we increase the washout period the period effect will surely
  be detected as insignificant? if the AUC's are higher in the 2nd period ,it
  gives me a feeling that the drug was not metabolised completely... i am not sure
  .. don't have core knowledge about ADME ... but just statistics
  
  thanks.....
  shikha rawat
  

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