Harmonization of Regulatory Approaches for Evaluating Therapeutic Equivalence and Interchangeability of Multisource Drug Products: Workshop summary report

Chen, Mei‐Ling; Shah, Vinod P.; Crommelin, Daan J.A.; Shargel, Leon; Bashaw, Dennis; Bhatti, Masood; Blume, Henning; Dressman, Jennifer B.; Ducharme, Murray P.; Fackler, Paul; Hyslop, Terry; Lutter, Lorelei; Morais, José; Ormsby, Eric; Thomas, Saji; Tsang, Yu Chung; Velagapudi, Raja; Yu, Lawrence X.

doi:10.1016/j.ejps.2011.09.010

Cited by 22 publications

(18 citation statements)

References 6 publications

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“…However, the sample size of 32 subjects exceeded the minimum requirement of typical ABE studies of 12-24. [4][5][6][7] Outcome measures and analysis…”

Section: Sample Sizementioning

confidence: 99%

“…Throughout the world, an application for marketing approval of a generic drug product must reference a corresponding product that was approved on the basis of clinical trials. [4][5][6][7] Drug products that are both pharmaceutically equivalent and bioequivalent are considered therapeutically equivalent. The rate and extent of drug bioavailability are commonly evaluated by maximum concentration (C max ) and area-under-time-concentration curve (AUC) to last measured concentration (AUC T ) or extrapolated to infinity (AUC I ), respectively, using the non-compartmental method.…”

Section: Introductionmentioning

confidence: 99%

“…[6] Bioequivalence approaches of several regulatory agencies including the US Food and Drug Administration (FDA), European Medicines Agency (EMA), Health Canada (HC), and WHO have been recently reviewed. [4,5,7] For immediate-release drugs, ABE testing is commonly performed in a single-dose, cross-over study on healthy volunteers under fasting conditions, with measurement of parent drug plasma level, non-compartmental pharmacokinetic analysis of logarithmically transformed AUC and C max data, and computation of the 90 % confidence interval (CI) on the test/reference geometric mean ratio, which should generally fall within the 80-125 % bioequivalence limits. [4,5,7] Several concerns have been raised regarding current ABE standards, including, focusing on average difference and relatively ignoring intra-subject variation; thus being unable to ensure therapeutic equivalence in all subjects.…”

Section: Introductionmentioning

confidence: 99%

“…[4,5,7] For immediate-release drugs, ABE testing is commonly performed in a single-dose, cross-over study on healthy volunteers under fasting conditions, with measurement of parent drug plasma level, non-compartmental pharmacokinetic analysis of logarithmically transformed AUC and C max data, and computation of the 90 % confidence interval (CI) on the test/reference geometric mean ratio, which should generally fall within the 80-125 % bioequivalence limits. [4,5,7] Several concerns have been raised regarding current ABE standards, including, focusing on average difference and relatively ignoring intra-subject variation; thus being unable to ensure therapeutic equivalence in all subjects. [8] Large intra-subject variability despite ABE can be due to intra-drug variability (first-pass or metabolic variability), intra-product variability (unit to unit or batch to batch), or subject-by-product interaction (which means that the difference between products is not the same across subjects).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Large Intra-subject Variability in Caffeine Pharmacokinetics: Randomized Cross-over Study of Single Caffeine Product

Hammami

Alvi

2017

Drug Res (Stuttg)

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Average bioequivalence has been criticized for not adequately addressing individual variations. Importance of subjects' blinding in bioequivalence studies has not been well studied. We explored the extent of intra-subject pharmacokinetic variability and effect of drug-ingestion unawareness in subjects taking single caffeine product. A single-dose randomized cross-over design was used to compare pharmacokinetics of 200 mg caffeine, described as caffeine (overt) or as placebo (covert). Maximum concentration (C), C first time (T), area-under-the-concentration-time-curve, to last measured concentration (AUC), extrapolated to infinity (AUC), or to T of overt caffeine (AUC), and C/AUC were calculated blindly using standard non-compartmental method. Percentages of individual covert/overt ratios that are outside the ±25% range were determined. Covert-vs-overt effect on caffeine pharmacokinetics was evaluated by 90% confidence interval (CI) and 80.00-125.00% bioequivalence range. 32 healthy subjects (6% females, mean (SD) age 33.3 (7.2) year) participated in the study (28 analysed). Out of the 28 individual covert/overt ratios, 23% were outside the ±25% range for AUC, 30% for AUC, 20% for AUC, 30% for C, and 43% for T. There was no significant covert-vs-overt difference in any of the pharmacokinetic parameters studied. Further, the 90% CIs for AUC, AUC, C, AUC, and C/AUC were all within the 80.00-125.00% bioequivalence range with mean absolute deviation of covert/overt ratios of 3.31%, 6.29%, 1.43%, 1.87%, and 5.19%, respectively. Large intra-subject variability in main caffeine pharmacokinetic parameters was noted when comparing an oral caffeine product to itself. Subjects' blinding may not be important in average bioequivalence studies.

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“…However, the sample size of 32 subjects exceeded the minimum requirement of typical ABE studies of 12-24. [4][5][6][7] Outcome measures and analysis…”

Section: Sample Sizementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Large Intra-subject Variability in Caffeine Pharmacokinetics: Randomized Cross-over Study of Single Caffeine Product

Hammami

Alvi

2017

Drug Res (Stuttg)

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“…This guideline incorporated several new aspects, like a scaled BE approach for highly variable drugs, the introduction of two-stage designs in BE testing, and the possibility for biowaivers based on the biopharmaceutics classification scheme (BCS) (19)(20)(21)(22)(23). Since then, the EMA committee for Human Medicinal Products has published several clarifications of the 2010 guideline in the form of the 'Questions & Answers' (24).…”

Section: Introductionmentioning

confidence: 99%

Bioequivalence studies in Europe before and after 2010

Daousani

Karalis

2014

Clinical Research and Regulatory Affairs

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Regulatory guidelines are necessary to standardize the evaluation procedure in bioequivalence. Revisions in the guidelines occur in order to resolve any previously unclear issues and to address new needs. In this paper, the authors discuss the major regulatory requirements for bioequivalence assessment before and after the EMA guidelines of 2010 and unveil their differences. The authors compiled this review following the critical exploration of literature articles and regulatory guidance documents. This was achieved through searching MEDLINE, Scopus, and the official EMA site. The authors found, in the post-2010 era, that the major differences in the regulatory framework refer to: the choice of clinical designs, the assessment of highly variable drugs, biowaivers, the pharmacokinetics parameters used, and the explicit definition for the use of metabolite data, enantiomers, and endogenous substances. Also, product-specific guidelines have started to be issued, while recommendations are now provided for some special formulations like orodispersible tablets. Other issues were elucidated like studies in the fasting or fed state and the dissolution assessment. The EMA regulatory framework on bioequivalence changed significantly in the post-2010 era. Many issues are now defined more explicitly, while others are newly introduced. However, some issues remain unresolved.

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Barriers to generic antiseizure medication use: Results of a global survey by the International League Against Epilepsy Generic Substitution Task Force

Niyongere¹,

Welty

Bell

et al. 2022

Epilepsia Open

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The objective of this study was to identify and quantify barriers to generic substitution of antiseizure medications (ASM). A questionnaire on generic ASM substitution was developed by the International League Against Epilepsy (ILAE) Task Force on Generic Substitution. Questions addressed understanding of bioequivalence, standards for generic products, experiences with substitution, and demographic data. The survey was web‐based and distributed to ILAE chapters, their membership, and professional colleagues of task force members. Comparisons in responses were between ILAE regions and country income classification. A total of 800 individuals responded, with 44.2% being from the Asia‐Oceania ILAE Region and 38.6% from European Region. The majority of respondents had little or no education in generic substitution or bioequivalence. Many respondents indicated lack of understanding aspects of generic substitution. Common barriers to generic substitution included limited access, poor or inconsistent quality, too expensive, or lack of regulatory control. Increase in seizures was the most common reported adverse outcome of substitution. Of medications on the World Health Organization Essential Medication list, problems with generic products were most frequent with carbamazepine, lamotrigine, and valproic acid. Several barriers with generic substitution of ASM revolved around mistrust of regulatory control and quality of generic ASM. Lack of education on generic substitution is also a concern. Generic ASM products may be the only option in some parts of the world and efforts should address these issues. Efforts to address these barriers should improve access to medications in all parts of the world.

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Harmonization of Regulatory Approaches for Evaluating Therapeutic Equivalence and Interchangeability of Multisource Drug Products: Workshop summary report

Cited by 22 publications

References 6 publications

Large Intra-subject Variability in Caffeine Pharmacokinetics: Randomized Cross-over Study of Single Caffeine Product

Large Intra-subject Variability in Caffeine Pharmacokinetics: Randomized Cross-over Study of Single Caffeine Product

Bioequivalence studies in Europe before and after 2010

Barriers to generic antiseizure medication use: Results of a global survey by the International League Against Epilepsy Generic Substitution Task Force

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