Common Deficiencies with Bioequivalence Submissions in Abbreviated New Drug Applications Assessed by FDA

Liu, Qing; Davit, Barbara M.; Cherstniakova, Svetlana A.; Dandamudi, Suman; Walters, Johnetta F.; Lee, Christina H.; Raines, Kimberly; Ren, Ke; Williamson, Leeh N.; Conner, Dale P.

doi:10.1208/s12248-011-9312-7

Cited by 17 publications

(5 citation statements)

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“…The PK and PD similarities between the licensed Xgeva ® products and those of the biosimilar substantiate the use of the biosimilars in phase III clinical studies ( Davit et al, 2008 ; Karalis et al, 2012 ). The inter-CV value of denosumab among Chinese subjects is high, and it is recommended that in future studies, the sample size of 152 to 180 subjects is sufficient to study the bioequivalence of denosumab biosimilar in each group, considering inter-CV (28.8–39.5%) ( Liu et al, 2012 ; Al-Sabbagh et al, 2016 ; Hammami et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects

Zhang

Zhu

et al. 2020

Front. Pharmacol.

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Objective This study was conducted to explore the tolerance, variability, pharmacokinetics (PK), and pharmacodynamics (PD) of denosumab biosimilar (QL1206) in healthy Chinese subjects. Methods This is a randomized, double-blind, two-arm, parallel study performed to examine the bioequivalence of denosumab biosimilar, QL1206, with that of Xgeva ® (Denosumab) as a reference drug. A single dose of 120 mg/kg of the denosumab biosimilar or Xgeva ® was administered to the subjects, who were followed up for 134 days. Results Similar PK properties as those of Xgeva ® were exhibited by QL1206. When compared to QL1206 with Xgeva ® , the 90% confidence intervals of the ratios for C max , AUC 0-t , and AUC 0-∞ were observed to be within 80–125%. The inter-subject variability (inter-CV) ranged from 29% to 39.5%. Six and three subjects in the QL1206 and Xgeva ® groups were found to be positive for the ADA and negative for the NAb, respectively. The CTX1 concentration-time profiles appeared similar (about 80% decrease from 48 hours to134 days) between the QL1206 and Xgeva ® groups. Adverse events (AEs) were observed in 92.6% and 93.4% of subjects in the QL1206 and Xgeva ® groups, respectively. Reduction in blood calcium level was found to be the most common AE recorded, with an incidence of 72.8% versus 72.4% in the QL1206 and Xgeva ® groups, respectively. Conclusion Similar PK and PD characteristics were exhibited by QL1206 as compared to those of Xgeva ® . The inter-CV was slightly large. The safety profiles of denosumab biosimilars and Xgeva ® were found to be similar.

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Section: Discussionmentioning

confidence: 99%

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects

Zhang

Zhu

et al. 2020

Front. Pharmacol.

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“…Figure 4 displays the statistics on these studies. Sixty-two of these studies met the RSABE acceptance criteria, although some studies were considered "incomplete" for other reasons, many due to questions relating to the bioanalytical method (48). Only two studies were unacceptable because they did not meet the acceptance criteria.…”

Section: Statistics On Be Study Designs In Recent Anda Submissions Ofmentioning

confidence: 99%

Implementation of a Reference-Scaled Average Bioequivalence Approach for Highly Variable Generic Drug Products by the US Food and Drug Administration

Davit

Chen

Conner

et al. 2012

AAPS J

Self Cite

110

122

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Abstract. Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration's Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.

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“…While the majority of the published literature focuses on the f 2 requirements in major markets (2,(7)(8)(9)(10), there exists limited literature comparing other global markets. Each country determines how to apply and enforce regulations to ensure the safety and efficacy of pharmaceutical products for sale in their jurisdiction, and the regulatory authorities in these markets are asking for more information about dissolution methods and dissolution profile comparisons.…”

Section: Regulatory Landscapementioning

confidence: 99%

Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations?

Diaz

Colgan

Langer

et al. 2015

AAPS J

154

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Abstract. The objective of this article is to compare and contrast the international expectations associated with the model-independent similarity factor approach to comparing dissolution profiles. This comparison highlights globally divergent regulatory requirements to meet local dissolution similarity requirements. In effect, experiments customized to meet the current international regulatory expectations for dissolution and drug release unnecessarily increase manufacturing costs, hinder science and risk-based approaches, increase collective regulatory burden, reduce continuous improvement and innovation, and potentially delay patient access to urgently needed medication. Comparative assessment of regulatory differences in applying dissolution to demonstrate product similarity is crucial to reduce non-scientifically justified experiments and foster collaborative harmonization among global regulatory health authorities and the pharmaceutical industry.

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Common Deficiencies with Bioequivalence Submissions in Abbreviated New Drug Applications Assessed by FDA

Cited by 17 publications

References 0 publications

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects

Implementation of a Reference-Scaled Average Bioequivalence Approach for Highly Variable Generic Drug Products by the US Food and Drug Administration

Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations?

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