PMID- 18446515
OWN - NLM
STAT- MEDLINE
DCOM- 20080922
LR  - 20211020
IS  - 1550-7416 (Electronic)
IS  - 1550-7416 (Linking)
VI  - 10
IP  - 1
DP  - 2008
TI  - Highly variable drugs: observations from bioequivalence data submitted to the FDA 
      for new generic drug applications.
PG  - 148-56
LID - 10.1208/s12248-008-9015-x [doi]
AB  - INTRODUCTION: It is widely believed that acceptable bioequivalence studies of 
      drugs with high within-subject pharmacokinetic variability must enroll higher 
      numbers of subjects than studies of drugs with lower variability. We studied the 
      scope of this issue within US generic drug regulatory submissions. MATERIALS AND 
      METHODS: We collected data from all in vivo bioequivalence studies reviewed at 
      FDA's Office of Generic Drugs (OGD) from 2003-2005. We used the ANOVA root mean 
      square error (RMSE) from bioequivalence statistical analyses to estimate 
      within-subject variability. A drug was considered highly variable if its RMSE for 
      C (max) and/or AUC was > or =0.3. To identify factors contributing to high 
      variability, we evaluated drug substance pharmacokinetic characteristics and drug 
      product dissolution performance. RESULTS AND DISCUSSION: In 2003-2005, the OGD 
      reviewed 1,010 acceptable bioequivalence studies of 180 different drugs, of which 
      31% (57/180) were highly variable. Of these highly variable drugs, 51%, 10%, and 
      39% were either consistently, borderline, or inconsistently highly variable, 
      respectively. We observed that most of the consistent and borderline highly 
      variable drugs underwent extensive first pass metabolism. Drug product 
      dissolution variability was high for about half of the inconsistently highly 
      variable drugs. We could not identify factors causing variability for the other 
      half. Studies of highly variable drugs generally used more subjects than studies 
      of lower variability drugs. CONCLUSION: About 60% of the highly variable drugs we 
      surveyed were highly variable due to drug substance pharmacokinetic 
      characteristics. For about 20% of the highly variable drugs, it appeared that 
      formulation performance contributed to the high variability.
FAU - Davit, Barbara M
AU  - Davit BM
AD  - US Food and Drug Administration, Center for Drug Evaluation and Research, Office 
      of Generic Drugs, 7520 Standish Place, Rockville, Maryland 20855, USA. 
      barbara.davit@fda.hhs.gov
FAU - Conner, Dale P
AU  - Conner DP
FAU - Fabian-Fritsch, Beth
AU  - Fabian-Fritsch B
FAU - Haidar, Sam H
AU  - Haidar SH
FAU - Jiang, Xiaojian
AU  - Jiang X
FAU - Patel, Devvrat T
AU  - Patel DT
FAU - Seo, Paul R H
AU  - Seo PR
FAU - Suh, Keri
AU  - Suh K
FAU - Thompson, Christina L
AU  - Thompson CL
FAU - Yu, Lawrence X
AU  - Yu LX
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20080305
PL  - United States
TA  - AAPS J
JT  - The AAPS journal
JID - 101223209
RN  - 0 (Drugs, Generic)
SB  - IM
MH  - Clinical Trials as Topic/methods/standards
MH  - Drug Approval/*methods
MH  - Drugs, Generic/*pharmacokinetics/*standards
MH  - Humans
MH  - Therapeutic Equivalency
MH  - United States
MH  - *United States Food and Drug Administration
PMC - PMC2751460
EDAT- 2008/05/01 09:00
MHDA- 2008/09/23 09:00
PMCR- 2009/03/05
CRDT- 2008/05/01 09:00
PHST- 2007/09/18 00:00 [received]
PHST- 2008/01/28 00:00 [accepted]
PHST- 2008/05/01 09:00 [pubmed]
PHST- 2008/09/23 09:00 [medline]
PHST- 2008/05/01 09:00 [entrez]
PHST- 2009/03/05 00:00 [pmc-release]
AID - 9015 [pii]
AID - 10.1208/s12248-008-9015-x [doi]
PST - ppublish
SO  - AAPS J. 2008;10(1):148-56. doi: 10.1208/s12248-008-9015-x. Epub 2008 Mar 5.