Basket clinical trial design for targeted therapies for cancer: a French National Authority for Health statement for health technology assessment

Lengliné, Étienne; Péron, Julien; Vanier, Antoine; Gueyffier, François; Kouzan, S; Dufour, Patrick; Guillot, B.; Blondon, H.; Clanet, M.; Cochat, Pierre; Degos, Françoise; Chevret, Sylvie; Grande, Mathilde; Putzolu, J.

doi:10.1016/s1470-2045(21)00337-5

Cited by 33 publications

(16 citation statements)

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“…A further 31 papers were retrieved from other sources. Screening of titles and abstracts identified 109 papers for full-text review of which 23 papers were included for evidence synthesis22 29–50 (figure 1, online supplemental appendix 3).…”

Section: Resultsmentioning

confidence: 99%

Extrapolating evidence for molecularly targeted therapies from common to rare cancers: a scoping review of methodological guidance

et al. 2022

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ObjectivesCancer is increasingly classified according to biomarkers that drive tumour growth and therapies developed to target them. In rare biomarker-defined cancers, randomised controlled trials to adequately assess targeted therapies may be infeasible. Extrapolating existing evidence of targeted therapy from common cancers to rare cancers sharing the same biomarker may reduce evidence requirements for regulatory approval in rare cancers. It is unclear whether guidelines exist for extrapolation. We sought to identify methodological guidance for extrapolating evidence from targeted therapies used for common cancers to rare biomarker-defined cancers.DesignScoping review.Data sourcesWebsites of health technology assessment agencies, regulatory bodies, research groups, scientific societies and industry. EBM Reviews—Cochrane Methodology Register and Health Technology Assessment, Embase and MEDLINE databases (1946 to 11 May 2022).Eligibility criteriaPapers proposing a framework or recommendations for extrapolating evidence for rare cancers, small populations and biomarker-defined cancers.Data extraction and synthesisWe extracted framework details where available and guidance for components of extrapolation. We used these components to structure and summarise recommendations.ResultsWe identified 23 papers. One paper provided an extrapolation framework but was not cancer specific. Extrapolation recommendations addressed six distinct components: strategies for grouping cancers as the same biomarker-defined disease; analytical validation requirements of a biomarker test to use across cancer types; strategies to generate control data when a randomised concurrent control arm is infeasible; sources to inform biomarker clinical utility assessment in the absence of prospective clinical evidence; requirements for surrogate endpoints chosen for the rare cancer; and assessing and augmenting safety data in the rare cancer.ConclusionsIn the absence of an established framework, our recommendations for components of extrapolation can be used to guide discussions about interpreting evidence to support extrapolation. The review can inform the development of an extrapolation framework for biomarker-targeted therapies in rare cancers.

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Section: Resultsmentioning

confidence: 99%

Extrapolating evidence for molecularly targeted therapies from common to rare cancers: a scoping review of methodological guidance

et al. 2022

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“…Integration of evidence derived from clinical as well as real-world data sources [ 19 , 20 ], generating comparative evidence in small patient numbers, and ‘including specificities of new health technologies for which some data may not be readily available’ as outlined in §24 of the preamble of the EU HTA regulation [ 7 , 8 ] require innovative approaches to the management of uncertainty. Such could be the consideration of new clinical trial designs (e.g., basket trials) [ 21 ], the inclusion of data derived from interim analyses in rare e.g., genetic conditions requiring continuous data collection beyond marketing authorization, or the pre-specification of indirect treatment analysis plans. Consistency of the applied PICO scheme (Patient/ Intervention/Comparator/Outcomes) and in particular comparator selection and endpoint choice were identified in our survey as requiring specific attention in the context of EU HTA.…”

Section: Discussionmentioning

confidence: 99%

How can a joint European health technology assessment provide an ‘additional benefit’ over the current standard of national assessments?

et al. 2022

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Objectives We conducted a multi-stakeholder survey to determine key areas where a joint European health technology assessment (HTA) could provide ‘additional benefit’ compared to the status quo of many parallel independent national and subnational assessments. Methods Leveraging three iterative Delphi cycles, a semiquantitative questionnaire was developed covering evidence challenges and heterogeneity of value drivers within HTAs across Europe with a focus on hematology/oncology. The questionnaire consisted of five sections: i) background information; ii) value drivers in HTA assessments today; iii) evolving evidence challenges; iv) heterogeneity of value drivers across Europe; v) impact of Europe’s Beating Cancer Plan (EBCP). The questionnaire was circulated across n = 189 stakeholder institutions comprising HTA and regulatory bodies, clinical oncology associations, patient representatives, and industry associations. Results N = 30 responses were received (HTA bodies: 9; regulators: 10; patients’ and physicians’ associations: 3 each; industry: 5). Overall, 17 countries and EU level institutions were represented in the responses. Consistency across countries and stakeholder groups was high. Most relevant value drivers in HTAs today (scale 1, low to 5, high) were clinical trial design (mean 4.45), right endpoints (mean 4.40), and size of comparative effect (mean 4.33). Small patient numbers (mean 4.28) and innovative study designs (mean 4.1) were considered the most relevant evolving evidence challenges. Heterogeneity between regulatory and HTA evidence requirements and heterogeneity of the various national treatment standards and national HTA evidence requirements was high. All clinical and patient participants stated to have been with EBCP initiatives. Conclusions For a European HTA to provide an ‘additional benefit’ over the multitude of existing national assessments key methodological and process challenges need to be addressed. These include approaches to address uncertainty in clinical development; comparator choice; consistency in approaching patient-relevant endpoints; and a transparent and consistent management of both HTA and regulatory procedures as well as their interface, including all involved stakeholder groups.

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“…The Neurotrophic tyrosine receptor kinase (NTRK) inhibitors (NICE TA630 larotrectinib, NICE TA644 entrectinib) are good examples of likely future challenges. In these appraisals, the main clinical trials were basket trials, which is a novel trial design to evaluate the treatment effectiveness of TCT for one or more targets regardless of the pathology [ 28 ]. Also, companion diagnostic tests for this biomarker were absent [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring uncertainty and use of real-world data in the National Institute for Health and Care Excellence single technology appraisals of targeted cancer therapy

Kang

Cairns

2022

BMC Cancer

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Objectives Dealing with uncertainty is one of the critical topics in health technology assessment. The greater decision uncertainty in appraisals, the less clear the clinical- and cost-effectiveness of the health technology. Although the development of targeted cancer therapies (TCTs) has improved patient health care, additional complexity has been introduced in drug appraisals due to targeting more specific populations. Real-world data (RWD) are expected to provide helpful information to fill the evidence gaps in appraisals. This study compared appraisals of TCTs with those of non-targeted cancer therapies (non-TCTs) regarding sources of uncertainty and reviewed how RWD have been used to supplement the information in these appraisals. Methods This study reviews single technology appraisals (STAs) of oncology medicines performed by the National Institute for Health and Care Excellence (NICE) over 11 years up to December 2021. Three key sources of uncertainty were identified for comparison (generalisability of clinical trials, availability of direct treatment comparison, maturity of survival data in clinical trials). To measure the intensity of use of RWD in appraisals, three components were identified (overall survival, volume of treatment, and choice of comparators). Results TCTs received more recommendations for provision through the Cancer Drugs Fund (27.7, 23.6% for non-TCT), whereas similar proportions were recommended for routine commissioning. With respect to sources of uncertainty, the external validity of clinical trials was greater in TCT appraisals (p = 0.026), whereas mature survival data were available in fewer TCT appraisals (p = 0.027). Both groups showed similar patterns of use of RWD. There was no clear evidence that RWD have been used more intensively in appraisals of TCT. Conclusions Some differences in uncertainty were found between TCT and non-TCT appraisals. The appraisal of TCT is generally challenging, but these challenges are neither new nor distinctive. The same sources of uncertainty were often found in the non-TCT appraisals. The uncertainty when appraising TCT stems from insufficient data rather than the characteristics of the drugs. Although RWD might be expected to play a more active role in appraisals of TCT, the use of RWD has generally been limited.

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Basket clinical trial design for targeted therapies for cancer: a French National Authority for Health statement for health technology assessment

Cited by 33 publications

References 20 publications

Extrapolating evidence for molecularly targeted therapies from common to rare cancers: a scoping review of methodological guidance

Extrapolating evidence for molecularly targeted therapies from common to rare cancers: a scoping review of methodological guidance

How can a joint European health technology assessment provide an ‘additional benefit’ over the current standard of national assessments?

Exploring uncertainty and use of real-world data in the National Institute for Health and Care Excellence single technology appraisals of targeted cancer therapy

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