Fairouz Makhlouf

Publications (3)14.26 Total impact

• Article: Evaluation of a scaling approach for the bioequivalence of highly variable drugs.

  Sam H Haidar, Fairouz Makhlouf, Donald J Schuirmann, Terry Hyslop, Barbara Davit, Dale Conner, Lawrence X Yu
  The AAPS Journal 10/2008; 10(3):480. · 5.09 Impact Factor
• Article: Evaluation of a scaling approach for the bioequivalence of highly variable drugs.

  Sam H Haidar, Fairouz Makhlouf, Donald J Schuirmann, Terry Hyslop, Barbara Davit, Dale Conner, Lawrence X Yu
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  ABSTRACT: Various approaches for evaluating the bioequivalence (BE) of highly variable drugs (CV > or = 30%) have been debated for many years. More recently, the FDA conducted research to evaluate one such approach: scaled average BE. A main objective of this study was to determine the impact of scaled average BE on study power, and compare it to the method commonly applied currently (average BE). Three-sequence, three period, two treatment partially replicated cross-over BE studies were simulated in S-Plus. Average BE criteria, using 80-125% limits on the 90% confidence intervals for C (max) and AUC geometric mean ratios, as well as scaled average BE were applied to the results. The percent of studies passing BE was determined under different conditions. Variables tested included within subject variability, point estimate constraint, and different values for sigma(w0), which is a constant set by the regulatory agency. The simulation results demonstrated higher study power with scaled average BE, compared to average BE, as within subject variability increased. At 60% CV, study power was more than 90% for scaled average BE, compared with about 22% for average BE. A sigma(w0) value of 0.25 appears to work best. The results of this research project suggest that scaled average BE, using a partial replicate design, is a good approach for the evaluation of BE of highly variable drugs.
  The AAPS Journal 09/2008; 10(3):450-4. · 5.09 Impact Factor
• Article: Bioequivalence approaches for highly variable drugs and drug products.

  Sam H Haidar, Barbara Davit, Mei-Ling Chen, Dale Conner, LaiMing Lee, Qian H Li, Robert Lionberger, Fairouz Makhlouf, Devvrat Patel, Donald J Schuirmann, Lawrence X Yu
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  ABSTRACT: Over the past decade, concerns have been expressed increasingly regarding the difficulty for highly variable drugs and drug products (%CV greater than 30) to meet the standard bioequivalence (BE) criteria using a reasonable number of study subjects. The topic has been discussed on numerous occasions at national and international meetings. Despite the lack of a universally accepted solution for the issue, regulatory agencies generally agree that an adjustment of the traditional BE limits for these drugs or products may be warranted to alleviate the resource burden of studying relatively large numbers of subjects in bioequivalence trials. This report summarizes a careful examination of all the statistical methods available and extensive simulations for BE assessment of highly variable drugs/products. Herein, the authors present an approach of scaling an average BE criterion to the within-subject variability of the reference product in a crossover BE study, together with a point-estimate constraint imposed on the geometric mean ratio between the test and reference products. The use of a reference-scaling approach involves the determination of variability of the reference product, which requires replication of the reference treatment in each individual. A partial replicated-treatment design with this new data analysis methodology will thus provide a more efficient design for BE studies with highly variable drugs and drug products.
  Pharmaceutical Research 02/2008; 25(1):237-41. · 4.09 Impact Factor