Generic Drug Quality Clinical Trial
Official title:
Generic Formulations of Commonly-Used, Immediate-Release, Solid, Oral, Drugs in Saudi Arabia: Interchangeability & Post-Marketing Quality
Generic formulations of prescription drugs can, through their relatively lower cost, improve
healthcare as long as they maintain their registration-quality and public trust. On the
other hand, the market availability of several generic formulations raises a concern
regarding their interchangeability, despite being proven to be individually therapeutically
interchangeable with their corresponding innovator formulation.
The investigators propose to assess the quality and therapeutic interchangeability of
generic formulations in the drug market of Saudi Arabia, using fifteen, commonly-used, oral,
solid, immediate-release, and non-combinational drugs.
Generic formulations of prescription drugs can, through their relatively lower cost, improve
healthcare as long as they maintain their registration-quality and public trust. On the
other hand, the market availability of several generic formulations raises a concern
regarding their interchangeability, despite being proven to be individually therapeutically
interchangeable with their corresponding innovator formulation.
The investigators propose to assess the quality and therapeutic interchangeability of
generic formulations in the drug market of Saudi Arabia, using fifteen, commonly-used, oral,
solid, immediate-release, and non-combinational drugs.
The following drugs have been identified from the Saudi National Formulary (September 2006)
as having, among oral, immediate-release, non-combinational drugs, the highest number of
formulations (they have each 15 to 47): ciprofloxacin, ranitidine, amoxicillin, paracetamol,
atenolol, cephalexin, ibuprofen, diclofenac, metformin, omeprazole, metronidazole,
enalapril, clarithromycin, amlodipine, and fluconazole. In the first set of studies and for
each drug, a four-treatment, four-period, four-sequence, crossover bioequivalence study will
be conducted on the innovator and three randomly-selected generic formulations. Each study
will be designed to have a power of 0.9 to detect bioequivalence, and sampling and wash-out
periods of at least 5 and 7 half lives, respectively. Individuals who are identified in the
first set of studies as having the large intra-subject variation (bioequivalence parameters
ratios of less the 80% or more than 120% for AUC) will be subjected to a second set of
studies, in which 2 batches of the reference formulation (including the batch used in the
first set of studies) and the generic formulation will be compared in a two-treatment,
four-period, two-sequence, replicate design crossover bioequivalence study. Drug levels will
be determined by an HPLC or LC-MS-MS method, locally-validated according to international
guidelines. After log transformation, AUC and Cmax (non-compartmental model) of the
formulations will be compared pair-wise by ANOVA. Pair-wise bioequivalence will be tested by
90% (and 95%) confidence interval of ratios and Schuirmann's two one sided t-tests for the
70-143, 80-125%, and 90-112% ranges. The following will be determined: 1) the prevalence of
generic formulations that are not bioequivalent to their innovator formulation, 2) the
prevalence of the phenomena that two generics of the same innovator formulation are not
bioequivalent to each other, 3) the percentage of individuals with large intra-subject
variation despite the presence of average bioequivalence between the two formulations, and
4) how much of the large intra-subject variation in 3 above is true or related, in part, to
product failure, random error, or subject-by-formulation interaction; and how it compares to
intra-subject variability when two batches of the innovator formulation are compared.
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Allocation: Randomized, Endpoint Classification: Bio-equivalence Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)