Generic Formulations of Commonly-used Oral Drugs in Saudi Arabia:Interchangeability & Post-marketing Quality

Study Overview
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Brief Summary
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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
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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.

Official Title
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Generic Formulations of Commonly-Used, Immediate-Release, Solid, Oral, Drugs in Saudi Arabia: Interchangeability & Post-Marketing Quality

Conditions
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Generic Drug Quality, Generic Formulation Interchangeability

Intervention / Treatment
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* Drug: one of the 15 drugs listed below
* Drug: one of the 15 drugs listed below
* Drug: one of the 15 drugs listed below
* Drug: one of the 15 drugs listed below


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: No evidence of clinically important deviation from normal health as indicated by a recent physical examination, medical history, and clinical laboratory tests (complete blood count, renal and hepatic profiles, and routine urinalysis. Body Mass Index (BMI) should be less than 35 kg/m2. Acceptance to abstain from taking any medication (including over-the-counter [OTC] drugs) for at least 2 weeks prior to, and during the study; and from smoking and taking alcohol or caffeine or related xanthenes-containing beverages or food for 48 hours before taking the study drug and throughout each of the two blood sampling periods. Exclusion Criteria: any contraindication to use the drug. any history of hypersensitivity to the drug to be tested or related compounds.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Reference formulation of each drug<br>Innovator formulation | Drug: one of the 15 drugs listed below<br>* single, oral, immediate-release, non-combinational innovator formulation<br>|
| Active Comparator: generic formulation a<br>one of the several generic formulations in the market, randomly selected for each drug | Drug: one of the 15 drugs listed below<br>* single, oral, immediate-release, non-combinational generic formulation a<br>|
| Active Comparator: generic formulation b<br>second of the several generic formulations in the market, randomly selected for each drug | Drug: one of the 15 drugs listed below<br>* single, oral, immediate-release, non-combinational generic formulation b<br>|
| Active Comparator: generic formulation c<br>third of the several generic formulations in the market, randomly selected for each drug | Drug: one of the 15 drugs listed below<br>* single, oral, immediate-release, non-combinational generic formulation c<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| bioequivalence | Bioequivalence between marketed generic formulations and their corresponding innovator formulations and between 2 marketed generic formulations. Bioequivalence will be assessed by the ratio of the area under the curve (AUC) (drug level vs time)and maximum levels (cmax) of two formulations and analyzed by the 90% confidence interval method. The time is 3-5 plasma half-life of each drug. | ciprofloxacin 24hrs,ranitidine 14hrs,amoxicillin 10hrs,paracetamol 14hrs,atenolol 36hrs,cephalexin 6hrs,ibuprofen 10hrs,diclofenac 14hrs,metformin 32hrs,omperazole 12hrs,metronidazole 48hrs,enalapril 8hrs,clarithromycin 24hrs,amlodipine 240hrs | 
| Intra-subject variation despite average bioequivalence | Large intra-subject variation (a ratio of the test to reference formulation of AUC that is less than 80% or more than 120%) between innovator and generic formulation, despite showing average bioequivalence between the two formulations | ciprofloxacin 24hrs,ranitidine 14hrs,amoxicillin 10hrs,paracetamol 14hrs,atenolol 36hrs,cephalexin 6hrs,ibuprofen 10hrs,diclofenac 14hrs,metformin 32hrs,omperazole 12hrs,metronidazole 48hrs,enalapril 8hrs,clarithromycin 24hrs,amlodipine 240hrs | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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