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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01344070
Recruitment Status : Completed
First Posted : April 28, 2011
Last Update Posted : September 1, 2015
Sponsor:
Collaborator:
Saudi National Comprehensive Plan for Science & Technology
Information provided by (Responsible Party):
Muhammad Maher Hammami, King Faisal Specialist Hospital & Research Center

Tracking Information
First Submitted Date  ICMJE April 3, 2011
First Posted Date  ICMJE April 28, 2011
Last Update Posted Date September 1, 2015
Study Start Date  ICMJE April 2011
Actual Primary Completion Date April 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 27, 2011)
  • 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 ]
    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 ]
    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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Generic Formulations of Commonly-used Oral Drugs in Saudi Arabia:Interchangeability & Post-marketing Quality
Official Title  ICMJE Generic Formulations of Commonly-Used, Immediate-Release, Solid, Oral, Drugs in Saudi Arabia: Interchangeability & Post-Marketing Quality
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Condition  ICMJE
  • Generic Drug Quality
  • Generic Formulation Interchangeability
Intervention  ICMJE
  • Drug: one of the 15 drugs listed below
    single, oral, immediate-release, non-combinational innovator formulation
  • Drug: one of the 15 drugs listed below
    single, oral, immediate-release, non-combinational generic formulation a
  • Drug: one of the 15 drugs listed below
    single, oral, immediate-release, non-combinational generic formulation b
  • Drug: one of the 15 drugs listed below
    single, oral, immediate-release, non-combinational generic formulation c
Study Arms  ICMJE
  • Active Comparator: Reference formulation of each drug
    Innovator formulation
    Intervention: Drug: one of the 15 drugs listed below
  • Active Comparator: generic formulation a
    one of the several generic formulations in the market, randomly selected for each drug
    Intervention: Drug: one of the 15 drugs listed below
  • Active Comparator: generic formulation b
    second of the several generic formulations in the market, randomly selected for each drug
    Intervention: Drug: one of the 15 drugs listed below
  • Active Comparator: generic formulation c
    third of the several generic formulations in the market, randomly selected for each drug
    Intervention: Drug: one of the 15 drugs listed below
Publications * Hammami MM, De Padua SJS, Hussein R, Al Gaai E, Khodr NA, Al-Swayeh R, Alvi SN, Binhashim N. Generic-reference and generic-generic bioequivalence of forty-two, randomly-selected, on-market generic products of fourteen immediate-release oral drugs. BMC Pharmacol Toxicol. 2017 Dec 8;18(1):78. doi: 10.1186/s40360-017-0182-1.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Estimated Enrollment  ICMJE
 (submitted: April 27, 2011)
500
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 2015
Actual Primary Completion Date April 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Saudi Arabia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01344070
Other Study ID Numbers  ICMJE RAC 2101100
project 10-BIO961-20 ( Other Grant/Funding Number: Saudi National Comprehensive Plan for Science & Technology )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Muhammad Maher Hammami, King Faisal Specialist Hospital & Research Center
Study Sponsor  ICMJE King Faisal Specialist Hospital & Research Center
Collaborators  ICMJE Saudi National Comprehensive Plan for Science & Technology
Investigators  ICMJE
Principal Investigator: Muhammad M Hammami, MD, PhD King Faisal Specialist Hospital & Research Center
PRS Account King Faisal Specialist Hospital & Research Center
Verification Date August 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP