Clinical trial NCT01344070: Generic Formulations of Commonly-used Oral Drugs in Saudi Arabia:Interchangeability & Post-marketing Quality
Official title: Generic Formulations of Commonly-Used, Immediate-Release, Solid, Oral, Drugs in Saudi Arabia: Interchangeability & Post-Marketing Quality
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Generic Drug Quality
Generic Formulation Interchangeability
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
Lead sponsor: King Faisal Specialist Hospital & Research Center
Sponsor class: OTHER
Collaborators: name: Saudi National Comprehensive Plan for Science & Technology
First posted: 2011-04-28
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER

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.

Eligibility 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.

Primary outcomes:
measure: bioequivalence
timeFrame: 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
measure: Intra-subject variation despite average bioequivalence
timeFrame: 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
Secondary outcomes:
Other outcomes:
Locations:
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital & Research Center
Study officials:
affiliation: King Faisal Specialist Hospital & Research Center
name: Muhammad M Hammami, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.