Real-World Data as External Controls: Practical Experience from Notable Marketing Applications of New Therapies

Izem, Rima; Buenconsejo, Joan; Davi, Ruthanna; Luan, Jingyu Julia; Tracy, LaRee; Gamalo, Margaret

doi:10.1007/s43441-022-00413-0

Cited by 16 publications

(6 citation statements)

References 10 publications

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“…Purpura et al performed a review to quantify how many approved applications incorporated RWE in any form (i.e., for safety or efficacy) from January 2019 to June 2021 [ 14 ]. Izem et al reviewed RWD for only contextualization in oncology and RD applications since 2000 and discussed some of the approvals as case studies [ 15 ]. Similarly, Seifu et al assessed RWD for effectiveness in any indication and evaluated three applications in detail as case studies [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

“…This systematic review focused on the use of RWD for contextualization and/or comparison for efficacy outcomes in RD therapies. Arondekar [15]. Similarly, Seifu et al assessed RWD for effectiveness in any indication and evaluated three applications in detail as case studies [16].…”

Section: Discussionmentioning

confidence: 99%

“…Despite the FDA's willingness to accept RWE in drug approval assessment, there remains a lack of knowledge among stakeholders regarding the agency's acceptance of RWE for certain orphan indication approvals. While a limited number of prior published studies have reviewed the FDA's stance on RWE for safety and efficacy in the context of New Drug Applications (NDAs) and Biologic License Applications (BLAs) [13][14][15][16], no prior research has explicitly focused on RD therapies and their reliance on RWE to support efficacy outcomes. To address this gap, a systematic literature review (SLR) of NDAs and BLAs submitted to the FDA Post 21st Century Cures Act, was conducted aiming to evaluate the use of RWE in support of efficacy outcomes and approval within regulatory submissions for RD therapies.…”

Section: Introductionmentioning

confidence: 99%

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A systematic review of real-world evidence (RWE) supportive of new drug and biologic license application approvals in rare diseases

Vaghela,

Tanni,

Banerjee

et al. 2024

Orphanet J Rare Dis

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Background Real-world evidence (RWE) generated using real-world data (RWD) presents the potential to contextualize and/or supplement traditional clinical trials for regulatory approval of rare diseases (RDs). This systematic review evaluated the use of RWD for non-oncologic RD therapies with orphan drug designation (ODD) to support efficacy outcomes in regulatory application packages to the US Food and Drug Administration (FDA). New drug applications (NDAs) and biologic license applications (BLAs) submitted between January 2017 and October 2022 were obtained from publicly available FDA drug approval websites. NDAs and BLAs of non-oncologic RD therapies were screened, and manually reviewed using RWE-related keywords. Quantitative summary of number/proportion of study types was provided, whereas qualitative synthesis focused on key categories of output assessing the use of RWD in overall drug approval process, including agency’s feedback on its strengths and key challenges. Results A total of 868 NDAs and BLAs were identified, of which 243 were screened for non-oncologic RDs with ODD, and 151 were subsequently reviewed for the RWD used to support efficacy outcomes. Twenty (12 NDAs, 8 BLAs) applications met the review inclusion criteria. Most (19; 95%) applications used only retrospective RWD, while one (5%) collected RWD both retrospectively and prospectively. RWD studies included natural history including registry-based/retrospective historical controls (14; 70%), retrospective medical chart-reviews (4; 20%), and external RWD controls from other studies (2; 10%). The FDA generally accepted RWD studies demonstrating a large effect size despite the noted concerns and criticisms. However, the agency expressed concerns about overall quality and comparability of RWD with trial data for some applications, including RWD study designs with respect to differences in patients’ baseline characteristics, missing information, and potential bias and measurement errors. Conclusions This systematic review highlights potential benefits of appropriately conducted RWE studies in RD, which can strengthen the clinical evidence for efficacy comparison and contextualization to support product approval efforts, particularly when a large magnitude of effect is observed for the new intervention. Nonetheless, quality and completeness of RWD and its comparability with trial data remain areas of concern that can serve as valuable learnings for advancing future science and regulatory approvals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A systematic review of real-world evidence (RWE) supportive of new drug and biologic license application approvals in rare diseases

Vaghela,

Tanni,

Banerjee

et al. 2024

Orphanet J Rare Dis

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“…RW data can be leveraged to develop external control groups for single-arm studies. 30 Data from ECA studies complementing clinical trial data have been used in oncology and rare pediatric indications to support recent regulatory approvals. 31 – 33 The inclusion criteria for the ECA and the OLE PP6M study were aligned, and confounding covariates were carefully selected to help adjust potential differences between the cohorts.…”

Section: Discussionmentioning

confidence: 99%

Comparative effectiveness study of paliperidone palmitate 6-month with a real-world external comparator arm of paliperidone palmitate 1-month or 3-month in patients with schizophrenia

Turkoz,

Wong,

Chee

et al. 2023

Therapeutic Advances in Psychopharmacology

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Background: The paliperidone palmitate 6-month (PP6M) long-acting injectable formulation is currently the longest dosing interval available for schizophrenia treatment. Objective: To compare treatment outcomes between a real-world external comparator arm (ECA; NeuroBlu database) and the PP6M open-label extension (OLE) clinical trial arm. Methods: The ECA comprised patients receiving PP 1-month (PP1M) or PP 3-month (PP3M) for ⩾12 months without a relapse. The PP6M OLE arm included patients with PP1M treatment prior to randomization who completed the 12-month double-blind PP6M study on either PP3M or PP6M relapse-free. Inverse probability treatment weighting (IPTW) was used to study time-to-relapse (primary outcome) and change in Clinical Global Impressions-Severity (CGI-S) score (secondary outcome). Results: At 24 months, 3.9% (7/178) of patients in the PP6M cohort experienced a relapse versus 15.6% (26/167) in the ECA. Time-to-relapse was longer in the PP6M cohort versus the ECA at 12-, 18-, and 24-months across the different weighting methods; median time-to-relapse was not reached in both cohorts. Hazard ratio (HR) for relapse was significantly lower for the PP6M cohort versus the ECA throughout the duration of the study [HR at 24 months: 0.18 (95% CI: 0.08–0.42), p < 0.001]. At 24 months, change in CGI-S score for the PP6M cohort was 0.76 points lower than the ECA ( p < 0.001). Results were similar in a sensitivity analysis using propensity score matching (PSM); IPTW resulted in larger sample sizes in balanced dataset than PSM. Conclusion: Consistent findings across weighting and matching methods suggest PP6M efficacy in reducing and delaying relapses and long-term symptom control compared to PP1M/PP3M in usual-care settings. Additional confounds, such as greater illness severity and more frequent comorbidities and comedications in the ECA, were not fully controlled by the applied statistical methods. Future real-world studies directly comparing PP6M with PP3M/PP1M and adjusting for these confounders are warranted.

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“…22 In this review, the authors identified a need for additional collaboration across countries and groups, as well as continued guidance on the execution of innovative trials combining traditional methods with RWE designs. Other recent reviews have highlighted cohort comparability, data completeness, and data accuracy as essential elements to support the usability of RWE 28,29 and noted selection bias and confounding as key limitations. 30 Although these reviews provide useful frameworks for conceptualizing design and implementation of external controls, there is still a need for more practical, readily operationalized guidance for stakeholders seeking to conduct an RWD-derived external control study of their own.…”

Section: Evolving Guidance On External Controlsmentioning

confidence: 99%

Regulatory and HTA Considerations for Development of Real‐World Data Derived External Controls

Curtis

Solà-Morales

Heidt

et al. 2023

Clin Pharma and Therapeutics

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Regulators and Health Technology Assessment (HTA) bodies are increasingly familiar with, and publishing guidance on, external controls derived from real‐world data (RWD) to generate real‐world evidence (RWE). We recently conducted a systematic literature review (SLR) evaluating publicly available information on the use of RWD‐derived external controls to contextualize outcomes from uncontrolled trials submitted to the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and/or select HTA bodies. The review identified several key operational and methodological aspects for which more detailed guidance and alignment within and between regulatory agencies and HTA bodies is necessary. This paper builds on the SLR findings by delineating a set of key takeaways for the responsible generation of fit‐for‐purpose RWE. Practical methodological and operational guidelines for designing, conducting, and reporting RWD‐derived external control studies are explored and discussed. These considerations include: (i) early engagement with regulators and HTA bodies during the study planning phase; (ii) consideration of the appropriateness and comparability of external controls across multiple dimensions, including eligibility criteria, temporality, population representation, and clinical evaluation; (iii) ensuring adequate sample sizes, including hypothesis testing considerations; (iv) implementation of a clear and transparent strategy for assessing and addressing data quality, including data missingness across trials and RWD; (v) selection of comparable and meaningful endpoints that are operationalized and analyzed using appropriate analytic methods; and (vi) conduct of sensitivity analyses to assess the robustness of findings in the context of uncertainty and sources of potential bias.

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Real-World Data as External Controls: Practical Experience from Notable Marketing Applications of New Therapies

Cited by 16 publications

References 10 publications

A systematic review of real-world evidence (RWE) supportive of new drug and biologic license application approvals in rare diseases

A systematic review of real-world evidence (RWE) supportive of new drug and biologic license application approvals in rare diseases

Comparative effectiveness study of paliperidone palmitate 6-month with a real-world external comparator arm of paliperidone palmitate 1-month or 3-month in patients with schizophrenia

Regulatory and HTA Considerations for Development of Real‐World Data Derived External Controls

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