Bioequivalence Approaches for Highly Variable Drugs and Drug Products

-Purpose. The FDA Working Group on Highly Variable (HV) Drugs recently presented procedures and conditions for determining the bioequivalence (BE) of HV drug products. They included analysis by the method of scaled average BE (SABE), a switching coefficient of variation of CV S = 30% and a regulatory standardized variation of CV 0 = 25% for applying SABE, and the use of a secondary regulatory criterion restricting to 0.80-1.25 the point estimate for the ratio of the estimated geometric means (GMR) of the two formulations. These conditions are scrutinized in the present communication. Methods. 3-period BE studies were simulated with various statistical and regulatory assumptions. Power curves, obtained by gradually increasing the true GMR, compared performances of the methods of SABE, a constrained point estimate of GMR (PE/GMR), and the composite of these two approaches. The consumer risk of each procedure was evaluated. Results. With CV 0 = 30% and PE/GMR = 0.80-1.25, the composite criterion of BE relied on the confidence limits of SABE. In contrast, with CV 0 = 25% and/or PE/GMR = 0.87-1.15, the composite criterion approached almost completely the features of the GMR point estimate, especially at high within-subject variation. The consumer risk was near 5% with CV 0 = 30% but about 15% when CV 0 = 25%. Conclusions. A constraint on GMR is difficult to justify scientifically. Still, if it is introduced then the condition of CV S = CV 0 = 30% and PE/GMR = 0.80-1.25 is recommended as a composite regulatory criterion. With alternative settings of the conditions, such as the recommended CV 0 = 25% and/or PE/GMR = 0.87-1.15, the composite criterion would reflect almost entirely the GMR point estimate. Also, with CV 0 = 25%, the BE limits are discontinuous at CV S = 30% and, as consequences, the consumer risk is substantially larger than 5%, and the regulatory uncertainty for making a decision about acceptance or rejection is enhanced. These would be undesirable outcomes.

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“…(19,20). The current proposals of FDA and their quantitative characteristics were published very recently (12,13).…”

Section: Scaled Average Bioequivalencementioning

confidence: 99%

“…At the meeting on October 6, 2006 the Working Group presented preferred regulatory and study conditions. These were recently published together with their quantitative rationale (12,13).…”

Section: Introductionmentioning

confidence: 99%

Regulatory and Study Conditions for the Determination of Bioequivalence of Highly Variable Drugs

Endrényi

Tóthfalusi

2009

J Pharm Pharm Sci

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“…1, because of this high variability, larger numbers of subjects may be needed in bioequivalence studies to give adequate statistical power to meet FDA bioequivalence limits (5)(6)(7)(8)(9). The FDA is currently investigating bioequivalence study design proposals that can reduce the number of subjects needed for a bioequivalence study (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Highly Variable Drugs: Observations from Bioequivalence Data Submitted to the FDA for New Generic Drug Applications

Davit

Conner

Fabian-Fritsch

et al. 2008

AAPS J

Self Cite

117

110

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Introduction. It is widely believed that acceptable bioequivalence studies of drugs with high withinsubject pharmacokinetic variability must enroll higher numbers of subjects than studies of drugs with lower variability. We studied the scope of this issue within US generic drug regulatory submissions. Materials and Methods. We collected data from all in vivo bioequivalence studies reviewed at FDA's Office of Generic Drugs (OGD) from [2003][2004][2005]. We used the ANOVA root mean square error (RMSE) from bioequivalence statistical analyses to estimate within-subject variability. A drug was considered highly variable if its RMSE for C max and/or AUC was ≥0.3. To identify factors contributing to high variability, we evaluated drug substance pharmacokinetic characteristics and drug product dissolution performance. Results and Discussion. In 2003-2005, the OGD reviewed 1,010 acceptable bioequivalence studies of 180 different drugs, of which 31% (57/180) were highly variable. Of these highly variable drugs, 51%, 10%, and 39% were either consistently, borderline, or inconsistently highly variable, respectively. We observed that most of the consistent and borderline highly variable drugs underwent extensive first pass metabolism. Drug product dissolution variability was high for about half of the inconsistently highly variable drugs. We could not identify factors causing variability for the other half. Studies of highly variable drugs generally used more subjects than studies of lower variability drugs. Conclusion. About 60% of the highly variable drugs we surveyed were highly variable due to drug substance pharmacokinetic characteristics. For about 20% of the highly variable drugs, it appeared that formulation performance contributed to the high variability.

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“…It is, however, believed that HVDs generally have a wide therapeutic window, such that despite high variability, these products have been demonstrated to be both safe and efficacious in human (28). Hence, applying the conventional BE criteria to these products may unnecessarily expose a large number of healthy subjects to a drug when this large number of subjects is not needed for assurance of BE.…”

Section: Highly Variable Drugsmentioning

confidence: 99%

Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products

Mitra

2012

AAPS J

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Abstract. Fixed-dose combination (FDC) products are becoming a popular treatment option because of increased patient compliance and convenience, improved clinical effectiveness, and reduced cost to the patient, among several other reasons. A commonly applied approach for approval of a FDC product is demonstrating bioequivalence between the FDC and co-administration of individual mono-products, provided that there is adequate safety and efficacy data for co-administration of the individual agents. However, achieving bioequivalence between the FDC and individual mono-products can be very challenging, and sometimes not possible since combining multiple active ingredients, especially insoluble molecules, in a single drug product could complicate its biopharmaceutical and pharmacokinetic behavior. In this review, some of the major challenges often encountered while assessing bioequivalence during FDC development will be presented along with discussion of future opportunities to facilitate FDC development and approval.

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Bioequivalence Approaches for Highly Variable Drugs and Drug Products

Cited by 176 publications

References 10 publications

Regulatory and Study Conditions for the Determination of Bioequivalence of Highly Variable Drugs

Regulatory and Study Conditions for the Determination of Bioequivalence of Highly Variable Drugs

Highly Variable Drugs: Observations from Bioequivalence Data Submitted to the FDA for New Generic Drug Applications

Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products

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