Optimizing benefit/risk in oncology: Review of post-marketing dose optimization and reflections on the road ahead

Soltantabar, Pooneh; Lon, Hoi‐Kei; Parivar, Kourosh; Wang, Diane D.; Elmeliegy, Mohamed

doi:10.1016/j.critrevonc.2023.103913

Cited by 8 publications

(20 citation statements)

References 66 publications

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“…This finding supported the FDA recommendation on conducting postmarketing trials to investigate whether higher dose increases trastuzumab C trough levels and increases OS. 4 In another study, case-control matching analysis was reported to compare the progression-free survival and OS of trastuzumab emtansine (T-DM1) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer using data from the EMILIA study. 14 Various exposure metrics including model-predicted C min and AUC as well as observed AUC and maximum plasma concentration were tested in this analysis.…”

Section: Discussionmentioning

confidence: 99%

“…The results indicated that the E-R relationships were most likely confounded by both the patients' baseline risk factors and the choice of exposure metrics that was used in the analysis. 4 In another work, the case-control matching was used to investigate the effect of time-varying clearance of nivolumab on disease dynamics and further E-R analysis. 23 To perform case-control analysis, patients in the treatment arm were divided into four quartiles by drug exposure which later were matched with the subjects extracted from the control arm.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 Still, a single dosing regimen, the MTD or the highest tested dose, has been traditionally evaluated in pivotal studies. 4,5 Exposure-response (E-R) characterization is at the heart of supporting dose selection. [6][7][8] The utility of E-R analysis for pivotal oncology studies is limited as they mainly utilize a single dosing regimen.…”

Section: Introductionmentioning

confidence: 99%

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Case–control matching‐guided exposure‐efficacy relationship for avelumab in patients with urothelial carcinoma

Soltantabar,

Alhadab,

Hibma

et al. 2023

CPT Pharmacom & Syst Pharma

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Exposure‐response (E‐R) analyses are an integral component of understanding the benefit/risk profile of novel oncology therapeutics. These analyses are typically conducted using data from the treatment arm to characterize the relationship between drug exposure (low vs. high) and efficacy or safety outcomes. For example, outcomes of patients with lower exposure in the treatment arm (e.g., Q1) might be compared to outcomes of those with higher drug exposure (Q2, Q3, and Q4). Outcomes from the lowest exposure quartile may be also compared to the control arm to evaluate whether the Q1 subgroup derived clinical benefit. However, the sample size and the distribution of patient baseline characteristics and disease risk factors are not balanced in such a comparison (Q1 vs. control), which may bias the analysis and causal interpretation of clinical benefit in the Q1 subgroup. Herein, we report the use of case–control matching to account for this bias and better understand the E‐R relationship for avelumab in urothelial carcinoma, a PD‐L1 inhibitor approved for the treatment of several cancers. Data from JAVELIN‐100 was utilized which is a phase III study of avelumab in first‐line maintenance treatment in patients with urothelial carcinoma; this clinical study demonstrated superiority of avelumab versus best‐supportive care leading to approval in the United States, Europe, and other countries. A post hoc case‐control matching method was implemented to compare the efficacy outcome between Q1 avelumab subgroup and matched patients extracted from the control arm with similar baseline characteristics, which showed a clinically relevant difference in overall survival in favor of the Q1 avelumab subgroup. This analysis demonstrates the importance of accounting for imbalance in important baseline covariates when comparing efficacy outcomes between subgroups within the treatment arm versus the control arm.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Case–control matching‐guided exposure‐efficacy relationship for avelumab in patients with urothelial carcinoma

Soltantabar,

Alhadab,

Hibma

et al. 2023

CPT Pharmacom & Syst Pharma

Self Cite

View full text Add to dashboard Cite

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“…A recent review of postmarketing studies leading to FDA label changes identifies several examples for which reduced doses were approved by the FDA without prospective randomized trials demonstrating similar efficacy. 76 For example, the approved niraparib dose was reduced to 200 mg daily in patients with low baseline platelet count due to retrospective evidence that these patients had higher adverse events. This is particularly notable because this would lead to reduced systemic niraparib exposure, unlike DPYDguided FP dose reduction to normalize systemic FP exposure, and presumably reduced niraparib efficacy.…”

Section: Lack Of Dosing Recommendation For Im or Pm Patientsmentioning

confidence: 99%

“…This novel proposal that FDA‐recommendation for dose‐adjustment should be based on randomized prospective clinical trials that demonstrate noninferior (or superior) clinical outcomes is not consistent with the FDA's prior statements or precedent. A recent review of postmarketing studies leading to FDA label changes identifies several examples for which reduced doses were approved by the FDA without prospective randomized trials demonstrating similar efficacy 76 . For example, the approved niraparib dose was reduced to 200 mg daily in patients with low baseline platelet count due to retrospective evidence that these patients had higher adverse events.…”

Section: Response To the Fda's Recent Decisions Regarding Dpyd Testin...mentioning

confidence: 99%

Response to the FDA Decision Regarding DPYD Testing Prior to Fluoropyrimidine Chemotherapy

Hertz

Smith

Scott

et al. 2023

Clin Pharma and Therapeutics

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Fluoropyrimidine (FP) chemotherapy is associated with severe, life‐threatening toxicities, particularly among patients who carry deleterious germline variants in the DPYD gene. Pretreatment DPYD testing is standard of care throughout most of Europe; however, it has not been recommended in clinical practice guidelines in the United States. Due to increased risk of severe toxicity, a Citizen's Petition asked the US Food and Drug Administration (FDA) to update language in FP drug labels to recommend DPYD testing as part of a boxed warning and recommend FP dose reduction in patients carrying deleterious germline variants. In response, the FDA updated the capecitabine package insert to inform patients about the toxicity risk and test availability and consider DPYD testing. However, the FDA did not include a testing recommendation or requirement, or a boxed warning. Additionally, the FDA did not recommend FP dose adjustment in DPYD variant carriers. This review provides a critical assessment of the DPYD‐FP pharmacogenetic association using the FDA's previously published Pharmacogenetic Pyramid, demonstrating that the evidence is compelling for recommending DPYD testing prior to FP treatment. Additionally, the FDA's stated concerns about recommending DPYD testing and DPYD‐guided FP dose adjustment are addressed and discussed in the context of the FDA's other genetic testing and dose adjustment recommendations. We call on the FDA to follow our European counterparts in recommending DPYD testing and genotype‐based dose adjustment to ensure patients with cancer receive safe and effective FP chemotherapy.

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A descriptive analysis of postmarketing requirement studies and clinical trials

Choi,

Etchey,

Billings

et al. 2023

Pharmacoepidemiology and Drug

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PurposeUnder the Food and Drug Administration Amendments Act of 2007 (FDAAA), the FDA has the authority to require applicants to conduct postmarketing studies or clinical trials. These postmarketing requirements (PMRs) provide additional data on the safety of the drug product. The purpose of the study was to conduct a descriptive analysis of FDAAA PMRs and the resulting regulatory actions.MethodsThis study evaluated FDAAA PMRs established between 2013 and 2019. We used the Medical Dictionary for Regulatory Activities (MedDRA) to map preferred terms (PTs) for serious risks associated with the PMRs. Relevant documents available in the FDA's document archiving, reporting, and regulatory tracking system (DARRTS), including but not limited to internal letters and reviews, documents submitted by applicants, and publicly available data sources were assessed for data collection of study elements.ResultsOf the 1079 new FDAAA PMRs established between January 01, 2013, and December 31, 2019, 82% (n = 884) were associated with new drug applications (NDAs) and 18% (n = 195) with biologic license applications (BLAs). Most PMRs were established at the time of drug approval (73%, n = 789) compared to post‐approval (27%, n = 290). The majority of PMRs had an open status (59%, n = 639) and 41% (n = 440) were closed. The median time from the PMR establishment date to submission of the results to the FDA was 690 days (interquartile range [IQR]: 748 days) for 167 completed clinical trials and 483 days (IQR: 603 days) for 241 completed studies. Approximately 53% (180/339) of fulfilled FDAAA PMRs resulted in labeling changes.ConclusionsFDAAA PMRs are useful in informing postmarket safety of drugs. Most FDAAA PMRs were established at the time of drug approval, reflecting safety signals identified during the review of the marketing application, and over half of fulfilled FDAAA PMRs resulted in regulatory action.

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Optimizing benefit/risk in oncology: Review of post-marketing dose optimization and reflections on the road ahead

Cited by 8 publications

References 66 publications

Case–control matching‐guided exposure‐efficacy relationship for avelumab in patients with urothelial carcinoma

Case–control matching‐guided exposure‐efficacy relationship for avelumab in patients with urothelial carcinoma

Response to the FDA Decision Regarding DPYD Testing Prior to Fluoropyrimidine Chemotherapy

A descriptive analysis of postmarketing requirement studies and clinical trials

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