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

Generic Drug Quality Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01344070
• Other study ID #: RAC 2101100
• Secondary ID: project 10-BIO96
• Status: Completed
• Phase: N/A
• First received: April 3, 2011
• Last updated: August 31, 2015
• Start date: April 2011
• Est. completion date: April 2015

Study information

• Verified date: August 2015
• Source: King Faisal Specialist Hospital & Research Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Saudi Arabia: National Committee of Biological and Medical Research
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 500
• Est. completion date: April 2015
• Est. primary completion date: April 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Bio-equivalence Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Related Conditions & MeSH terms

• Generic Drug Quality
• Generic Formulation Interchangeability

Intervention

Drug:
• one of the 15 drugs listed below
single, oral, immediate-release, non-combinational innovator formulation
• one of the 15 drugs listed below
single, oral, immediate-release, non-combinational generic formulation a
• one of the 15 drugs listed below
single, oral, immediate-release, non-combinational generic formulation b
• one of the 15 drugs listed below
single, oral, immediate-release, non-combinational generic formulation c

Locations

Country	Name	City	State
Saudi Arabia	King Faisal Specialist Hospital & Research Center	Riyadh

Sponsors (2)

Lead Sponsor	Collaborator
King Faisal Specialist Hospital & Research Center	Saudi National Comprehensive Plan for Science & Technology

Country where clinical trial is conducted

Saudi Arabia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No