Generic Formulations of Commonly-used Oral Drugs in Saudi Arabia:Interchangeability & Post-marketing Quality
Condition: Generic Drug Quality; Generic Formulation Interchangeability
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): one of the 15 drugs listed below; one of the 15 drugs listed below; one of the 15 drugs listed below; one of the 15 drugs listed below
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): single, oral, immediate-release, non-combinational innovator formulation; single, oral, immediate-release, non-combinational generic formulation a; single, oral, immediate-release, non-combinational generic formulation b; single, oral, immediate-release, non-combinational generic formulation c
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Keywords: innovator formulations; generic formulations; bioequivalence; interchangeability; inter-patch variation; quality of generic drug formulations on the market; Interchangeability between marketed generic formulations; prevalence of large intrasubject variability despite average bioequivalence; Causes of large intrasubject variability