PharmPK Discussion - 505b(2) application

• On 2 May 2011 at 17:48:13, David Wells (dwells.-a-.eagleus.com) sent the message
  

  
  When submitting a 505b(2) application where the only clinical data would  come from a bioequivalence study compared to the RLD, can I assume that  the typical 80-125% limits apply in all but very unusual cases?  Has  anyone heard of them being reduced to 90-112%?
  
  

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• On 3 May 2011 at 13:12:48, Fabrice Nollevaux (fabrice.nollevaux.aaa.arlenda.com) sent the message
  

  
  The following message was posted to: PharmPK
  
  Dear David,
  
  BE acceptance limits narrower than the usual 80-125% are sometimes  required
  for drugs with a narrow therapeutic index (aka narrow therapeutic range,  or
  critical dose drugs).
  
  To my knowledge, the 90-112% limits are only mentioned in the Canadian  HPFB
  Guidance for Industry "Bioequivalence Requirements: Critical Dose  Drugs":
   http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/prodpharma/applic-demande/g uide-ld/bio/critical_dose_critique-eng.pdf
  I am not sure where these limits are coming from, since the acceptance  of a
  10% difference should result in the multiplicative scale to  90.00-111.11%
  (e.g. as mentioned by EMA:
   http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/ 2010/01/WC500070039.pdf
  ), so should be best rounded to 90-111% to remain on
  the conservative side.
  
  For an US submission, the FDA guidance
   (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio n/Guidances/ucm070124.pdf
  ) states:
  "Unless otherwise indicated by a specific guidance, this guidance  recommends
  that the traditional BE limit of 80 to 125 percent for non-narrow
  therapeutic range drugs remain unchanged for the bioavailability  measures
  (AUC and Cmax) of narrow therapeutic range drugs." It is then up to you to check whether there is any specific BE  requirement
  for your product.
  
  All the best,
  Fabrice
  
  Fabrice Nollevaux,
  Pharmacometrician
  Arlenda SA
  www.arlenda.com
  
  

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• On 4 May 2011 at 16:00:58, "DR.GUNA SAKARAN" (drgunasakaran.-at-.gmail.com) sent the message
  

  
  Dear Sir,
  
  The 90 percent confidence interval of the relative mean AUC of the test  to reference formulation will be reduced to 90.0 to 112.0 percent for  Critical Drugs as per Canadian Guidelines.
  
  "Critical dose drugs" are defined as those drugs where comparatively  small differences in dose or concentration lead to dose-and  concentration-dependent, serious therapeutic failures and/or serious  adverse drug reactions which may be persistent, irreversible, slowly  reversible, or life threatening, which could result in inpatient  hospitalization or prolongation of existing hospitalization, persistent  or significant disability or incapacity, or death. Adverse reactions  that require significant medical intervention to prevent one of these  outcomes are also considered to be serious.
  
  The 90 percent confidence interval of the relative mean measured Cmax of  the test to reference formulation should be between 80.0 and 125.0  percent.
  
  These requirements are to be met in both the fasted and fed states.
  
  Reference: Comparative Bioavailability Standards: Formulations used for  Systemic Effects, Health Canada
  
  Regards,
  Dr.S.Gunasakaran, MD
  
  

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• On 5 May 2011 at 14:52:17, Helmut Schuetz (helmut.schuetz.at.bebac.at) sent the message
  

  
  The following message was posted to: PharmPK
  
  Dear Fabrice!
  
  PharmPK wrote:
  > To my knowledge, the 90-112% limits are only mentioned in the Canadian
  > HPFB Guidance for Industry "Bioequivalence Requirements: Critical Dose
  > Drugs"
  >
  
  Correct.
  
  > I am not sure where these limits are coming from, since the acceptance
  > of a 10% difference should result in the multiplicative scale to
  > 90.00-111.11%
  >
  
  Also correct.
  I asked Eric Ormsby at the BioInternational 2008 about this discrepancy
  and he answered that HPFB is aware about it, but requires 90-112% "for
  simplicity".
  
  > [...], so should be best rounded to 90-111% to remain on
  > the conservative side.
  >
  
  Well, 1.11 # 1/0.9 ;-)
  EMA wants the 90% CI (rounded to two decimal figures) to be within
  90.00-111.11%.
  
  All the best,
  Helmut
  
  -
  Ing. Helmut SchAtz
  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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Copyright 1995-2011 David W. A. Bourne (david@boomer.org)