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

NCT ID: NCT01344070

Last Updated: 2015-09-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 500 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-04-30
• Study Completion Date: 2015-04-30

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.

Conditions

Generic Drug Quality; Generic Formulation Interchangeability

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Blinding Strategy: QUADRUPLE

Study Groups

Reference formulation of each drug

Innovator formulation

Group Type: ACTIVE_COMPARATOR

one of the 15 drugs listed below

Intervention Type: DRUG

single, oral, immediate-release, non-combinational innovator formulation

generic formulation a

one of the several generic formulations in the market, randomly selected for each drug

Group Type: ACTIVE_COMPARATOR

one of the 15 drugs listed below

Intervention Type: DRUG

single, oral, immediate-release, non-combinational generic formulation a

generic formulation b

second of the several generic formulations in the market, randomly selected for each drug

Group Type: ACTIVE_COMPARATOR

one of the 15 drugs listed below

Intervention Type: DRUG

single, oral, immediate-release, non-combinational generic formulation b

generic formulation c

third of the several generic formulations in the market, randomly selected for each drug

Group Type: ACTIVE_COMPARATOR

one of the 15 drugs listed below

Intervention Type: DRUG

single, oral, immediate-release, non-combinational generic formulation c

Interventions

one of the 15 drugs listed below

single, oral, immediate-release, non-combinational innovator formulation

Intervention Type: DRUG

one of the 15 drugs listed below

single, oral, immediate-release, non-combinational generic formulation a

Intervention Type: DRUG

one of the 15 drugs listed below

single, oral, immediate-release, non-combinational generic formulation b

Intervention Type: DRUG

one of the 15 drugs listed below

single, oral, immediate-release, non-combinational generic formulation c

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Saudi National Comprehensive Plan for Science & Technology

UNKNOWN

Sponsor Role: collaborator

King Faisal Specialist Hospital & Research Center

OTHER

Sponsor Role: lead

Responsible Party

Muhammad Maher Hammami

Chairman, Department of Clinical Studies & Empirical Ethics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Muhammad M Hammami, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

King Faisal Specialist Hospital & Research Center

Locations

King Faisal Specialist Hospital & Research Center

Riyadh, , Saudi Arabia

Countries

Saudi Arabia

References

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.

Reference Type: DERIVED

PMID: 29216899 (View on PubMed)

Other Identifiers

project 10-BIO961-20

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

RAC 2101100

Identifier Type: -

Identifier Source: org_study_id