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

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by King Faisal Specialist Hospital & Research Center
Sponsor:
Collaborator:
Saudi National Comprehensive Plan for Science & Technology
Information provided by (Responsible Party):
Muhammad Maher Hammami, King Faisal Specialist Hospital & Research Center
ClinicalTrials.gov Identifier:
NCT01344070
First received: April 3, 2011
Last updated: December 10, 2013
Last verified: December 2013
  Purpose

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.


Condition Intervention
Generic Drug Quality
Generic Formulation Interchangeability
Drug: one of the 15 drugs listed below

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Official Title: Generic Formulations of Commonly-Used, Immediate-Release, Solid, Oral, Drugs in Saudi Arabia: Interchangeability & Post-Marketing Quality

Further study details as provided by King Faisal Specialist Hospital & Research Center:

Primary Outcome Measures:
  • bioequivalence [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Intra-subject variation despite average bioequivalence [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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


Estimated Enrollment: 500
Study Start Date: April 2011
Estimated Study Completion Date: May 2014
Estimated Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Reference formulation of each drug
Innovator formulation
Drug: one of the 15 drugs listed below
single, oral, immediate-release, non-combinational innovator formulation
Active Comparator: generic formulation a
one of the several generic formulations in the market, randomly selected for each drug
Drug: one of the 15 drugs listed below
single, oral, immediate-release, non-combinational generic formulation a
Active Comparator: generic formulation b
second of the several generic formulations in the market, randomly selected for each drug
Drug: one of the 15 drugs listed below
single, oral, immediate-release, non-combinational generic formulation b
Active Comparator: generic formulation c
third of the several generic formulations in the market, randomly selected for each drug
Drug: one of the 15 drugs listed below
single, oral, immediate-release, non-combinational generic formulation c

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.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01344070

Contacts
Contact: Muhammad M Hammami, MD, PhD 966 1 442 4537 muhammad@kfshrc.edu.sa

Locations
Saudi Arabia
King Faisal Specialist Hospital & Research Center Recruiting
Riyadh, Saudi Arabia, 11211
Contact: Muhammad M Hammami, MD, PhD    966 1 4424527    muhammad@kfshrc.edu.sa   
Sponsors and Collaborators
King Faisal Specialist Hospital & Research Center
Saudi National Comprehensive Plan for Science & Technology
Investigators
Principal Investigator: Muhammad M Hammami, MD, PhD King Faisal Specialist Hospital & Research Center
  More Information

No publications provided

Responsible Party: Muhammad Maher Hammami, Chairman, Department of Clinical Studies & Empirical Ethics, King Faisal Specialist Hospital & Research Center
ClinicalTrials.gov Identifier: NCT01344070     History of Changes
Other Study ID Numbers: RAC 2101100, project 10-BIO961-20
Study First Received: April 3, 2011
Last Updated: December 10, 2013
Health Authority: Saudi Arabia: National Committee of Biological and Medical Research

Keywords provided by King Faisal Specialist Hospital & Research Center:
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

ClinicalTrials.gov processed this record on August 01, 2014