Advancing Biosimilar Development Using Pharmacodynamic Biomarkers in Clinical Pharmacology Studies

Li, Junyi; Florian, Jeffry; Campbell, Elizabeth; Schrieber, Sarah J.; Bai, Jane P. F.; Weaver, James L.; Hyland, Paula L.; Thway, Theingi M.; Matta, Murali K.; Lankapalli, Rachana H.; Narayanasamy, Suresh; Dancy, Jimena G.; Zusterzeel, Robbert; Tyson, Jessica Y.; Prentice, Kristin; Jackson, K.; Patel, Vikram; Rouse, Rodney; Wang, Yow‐Ming; Strauss, David G.

doi:10.1002/cpt.1653

Cited by 40 publications

(49 citation statements)

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“… 8 For different disease conditions, pharmacodynamic biomarkers are objectively measured and assessed as a sign of pharmacologic responses to therapeutic interventions. 9 TB biomarkers can either be in a two-dimensional matrix, according to the clinical outcome (failure vs relapse) and level of surrogacy (patient vs trial), 10 , 11 while other promising TB biomarkers are emerging. Such biomarkers, including time-to-positivity (TTP), sputum culture conversion, smear conversion, therapeutic drug monitoring (TDM), pharmacokinetics (PK), minimum inhibitory concentration (MIC), and whole blood bactericidal assay (WBA) could facilitate the development of alternative treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

Molecular bacterial load assay versus culture for monitoring treatment response in adults with tuberculosis

et al. 2021

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The lack of rapid, sensitive, and deployable tuberculosis diagnostic tools is hampering the early diagnosis of tuberculosis and early detection of treatment failures. The conventional sputum smear microscopy or Xpert MTB/RIF assay cannot distinguish between alive and dead bacilli and the culture method delays providing results. Tuberculosis molecular bacterial load assay is a reverse transcriptase real-time quantitative polymerase chain reaction that quantifies viable tuberculosis bacillary load as a marker of treatment response for patients on anti-tuberculosis therapy. However, results are not synthesized enough to inform its comparative advantage to tuberculosis culture technique which is yet the gold standard of care. With this review, we searched electronic databases, including PubMed, Embase, and Web of Science, from March 2011 up to February 2021 for clinical trials or prospective cohort studies that compared tuberculosis molecular bacterial load assay with tuberculosis culture in adults. We included eight studies that meet the inclusion criteria. Tuberculosis molecular bacterial load assay surpasses culture in monitoring patients with tuberculosis during the first few weeks of anti-tuberculosis treatment. It is more desirable over culture for its shorter time to results, almost zero rates of contamination, need for less expertise on the method, early rate of decline, lower running cost, and reproducibility. Its rapid and specific tuberculosis treatment monitoring competency benefits patients and healthcare providers to monitor changes of bacillary load among isolates with drug-susceptible or resistance to anti-tuberculosis regimens. Despite of the high installing cost of the tuberculosis molecular bacterial load assay method, molecular expertise, and a well-equipped laboratory, tuberculosis molecular bacterial load assay is a cost-effective method with comparison to culture in operational running. To achieve maximum utility in high tuberculosis burden settings, an intensive initial investment in nucleic acid extraction and polymerase chain reaction equipment, training in procedures, and streamlining laboratory supply procurement systems are crucial. More evidence is needed to demonstrate the potential large-scale and sustainable use of tuberculosis molecular bacterial load assay over culture in resource-constrained settings.

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Section: Introductionmentioning

confidence: 99%

Molecular bacterial load assay versus culture for monitoring treatment response in adults with tuberculosis

et al. 2021

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“…This approach aligns with US Food and Drug Administration (FDA) guidance, which suggests that healthy subjects are generally considered a more sensitive and homogeneous population with less likelihood of PK and/or PD variability and reduced potential for confounding factors compared with subjects who may have an unsuspected and/or concomitant disease, be heavily medicated, and/or myelosuppressed [ 13 , 14 ]. Furthermore, the choice of a single well-established, highly sensitive dose-dependent PD surrogate biomarker for clinical efficacy outcomes, or multiple PD measurements (e.g., area under the effect-versus-time curve [AUEC] for absolute neutrophil count [AUEC ANC ] for pegfilgrastim with a simultaneous measurement of the time of maximum value [ANC_ T max ]) of absolute neutrophil count (ANC) are recognized by the FDA as a streamlined method for reducing any residual uncertainty about clinically meaningful differences in the safety, purity, and potency between a proposed biosimilar and its reference product, albeit with the expectation that immunogenicity will still need to be adequately assessed [ 13 , 15 ]. The most recently (2018) revised draft regulatory guidelines from the European Medicines Agency’s Committee for Medicinal Product for Human Use (CHMP) propose that product quality and clinical pharmacology comparisons can be sufficient to demonstrate similarity between a proposed pegfilgrastim biosimilar and its reference product without the need for dedicated comparative efficacy trial data [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

PF-06881894, a Proposed Biosimilar to Pegfilgrastim, Versus US-Licensed and EU-Approved Pegfilgrastim Reference Products (Neulasta®): Pharmacodynamics, Pharmacokinetics, Immunogenicity, and Safety of Single or Multiple Subcutaneous Doses in Healthy Volunteers

Moosavi

Borema²,

Ewesuedo

et al. 2020

Adv Ther

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Introduction: PF-06881894 is a proposed biosimilar to pegfilgrastim (Neulasta Ò). This study evaluated the pharmacodynamic/pharmacokinetic (PD/PK) equivalence, immunogenicity, and safety of PF-06881894 vs pegfilgrastim reference products (US-and EU-Neulasta Ò) in healthy volunteers. Methods: A phase 1, open-label, randomized, crossover study was conducted to assess the pharmacologic equivalence and safety of a single 6-mg dose of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU. The primary PD endpoints were area under the effect-versus-time curve for absolute neutrophil count (ANC) from dose administration to 288 h postdose, and maximum observed ANC value among subjects confirmed negative for anti-pegfilgrastim antibodies. Primary PK variables included area under the serum pegfilgrastim-versus-time curve from the time of dose administration to time infinity and maximum observed serum pegfilgrastim concentration. A second phase 1, open-label, randomized (1:1), parallel-group, non-inferiority study was conducted to assess the immunogenicity and safety of multiple 6-mg doses of PF-06881894 versus pegfilgrastim-US. The primary endpoint for the immunogenicity study was the proportion of subjects with both negative baseline and confirmed positive postdose anti-pegfilgrastim antibodies at any time during the study. Results: Across the single-and multiple-dose studies (N = 153 and N = 420 treated subjects, respectively), demographics for age (18-65 years), male gender (n = 264/573), and white race (n = 423/573) were similar. Three-way PD/ PK equivalence of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU was demonstrated with the primary PD endpoints and primary PK variables being completely contained within the predefined 90% confidence interval acceptance limits (80-125%). The non-inferiority of PF-06881894 versus pegfilgrastim-US in terms of Digital Features To view digital features for this article go to

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“…The required extent of this clinical confirmation is subject to opinion and consequently regulators adopted a more flexible approach. Soon the EMA, followed by the US Food and Drug Administration (US-FDA), stated in their biosimilar guidelines that comparative efficacy studies could be waived under certain circumstances, specifically when suitable pharmacodynamic (PD) markers exist [9,10].…”

Section: Methodsmentioning

confidence: 99%

The Path Towards a Tailored Clinical Biosimilar Development

Schiestl¹,

Ranganna

Watson

et al. 2020

BioDrugs

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Since the first approval of a biosimilar medicinal product in 2006, scientific understanding of the features and development of biosimilar medicines has accumulated. This review scrutinizes public information on development programs and the contribution of the clinical studies for biosimilar approval in the European Union (EU) and/or the United States (US) until November 2019. The retrospective evaluation of the programs that eventually obtained marketing authorization and/or licensure revealed that in 95% (36 out of 38) of all programs, the comparative clinical efficacy studies confirmed similarity. In the remaining 5% (2 out of 38), despite meeting efficacy outcomes, the biosimilar candidates exhibited clinical differences in immunogenicity that required changes to the manufacturing process and additional clinical studies to enable biosimilar approval. Both instances of clinical differences in immunogenicity occurred prior to 2010, and the recurrence of these cases is unlikely today due to state-of-the-art assays and improved control of process-related impurities. Biosimilar candidates that were neither approved in the EU nor in the US were not approved due to reasons other than clinical confirmation of efficacy. This review of the development history of biosimilars allows the proposal of a more efficient and expedited biosimilar development without the routine need for comparative clinical efficacy and/or pharmacodynamic studies and without any compromise in quality, safety, or efficacy. This proposal is scientifically valid, consistent with regulation of all biologics, and maintains robust regulatory standards in the assessment of biosimilar candidates. Note: The findings and conclusion of this paper are limited to biosimilar products developed against the regulatory standards in the EU and the US.

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Advancing Biosimilar Development Using Pharmacodynamic Biomarkers in Clinical Pharmacology Studies

Cited by 40 publications

References 1 publication

Molecular bacterial load assay versus culture for monitoring treatment response in adults with tuberculosis

Molecular bacterial load assay versus culture for monitoring treatment response in adults with tuberculosis

PF-06881894, a Proposed Biosimilar to Pegfilgrastim, Versus US-Licensed and EU-Approved Pegfilgrastim Reference Products (Neulasta®): Pharmacodynamics, Pharmacokinetics, Immunogenicity, and Safety of Single or Multiple Subcutaneous Doses in Healthy Volunteers

The Path Towards a Tailored Clinical Biosimilar Development

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