ESMO 2017 Press Release: Study Shows ESMO Magnitude of Benefit Scale Can Be Used to Grade Orphan Drugs

  • Date: 10 Sep 2017

LUGANO-MADRID –The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a valid tool for grading orphan drugs, according to research presented at the ESMO 2017 Congress in Madrid. (1)

The ESMO-MCBS scales the clinical benefit that can be anticipated from new anti-cancer therapies for solid tumours. (2). This study used the ESMO-MCBS tool to determine how orphan and non-orphan drugs performed according to its established threshold for meaningful benefit.

The study included 63 drugs approved by the US Food and Drug Administration (FDA) between 2006 and 2016 for 118 solid tumour indications, of which 54 (46%) were given orphan designation. Compared to non-orphan drugs, trials supporting orphan drug approval included fewer patients, were less often randomised, were more likely to assess intermediate endpoints rather than overall survival, and were less likely to evaluate experimental cytotoxic chemotherapy or endocrine therapy than targeted therapy.

The ESMO-MCBS could be applied to 70% of trials supporting orphan designations. Less than half (48%) met the ESMO-MCBS clinically meaningful benefit threshold compared to 41% with non-orphan status. The difference was not statistically significant.

“Orphan drug designation did not influence the odds of meeting the ESMO-MCBS clinically meaningful benefit threshold,” said lead author Ms Consolación Molto Valiente, a researcher in the Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

“The ESMO-MCBS is applicable in most situations where randomised controlled trials are available, including those supporting approval for drugs granted orphan designation,” she said. “However, the practicability of applying the ESMO-MCBS is more limited for orphan drugs as in over a quarter of cases drug approval is supported by single-arm studies.”

Commenting on the results, ESMO President-Elect Professor Josep Tabernero, Head, Medical Oncology Department, Vall d’Hebron University Hospital, Director of the Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain, observed: “There were no major differences in the ability of the ESMO-MCBS to rank orphan and non-orphan drugs. This study used version 1.0 of the scale. Version 1.1 is now available and enables the scoring of single-arm studies in orphan diseases and for others with high unmet need. This will go even further to meet ESMO’s goal of sustainable cancer care.” (3)

Disparities in clinical added value between the ESMO-MCBS and the Health Technology Assessment (HTA) body in France will be discussed in another study presented during the same session. (4) “The aims and scope of the ESMO-MCBS differ from those of an HTA body,” said Tabernero.

“Some value-based assessment tools do not currently factor in considerations such as disease frequency or orphan designation,” he continued. “The ESMO-MCBS incorporates these criteria and many other important aspects. Collaboration between the ESMO-MCBS, HTAs and other major frameworks will help to further improve and fine-tune our respective evaluation platforms.”

“The ESMO-MCBS is a crucial component of ESMO’s sustainable cancer care agenda, which is centred around advocating for access to quality treatment and for cancer prevention,” concluded Tabernero.

Further studies on the ESMO-MCBS will be presented at ESMO 2017. (5,6)

-END-

Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress

References

  1. Abstract 1435O_PR ‘Comparison of the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) in Clinical Trials Supporting US Food and Drug Administration (FDA) Approval of Orphan vs. Non-orphan Drugs’ will be presented by Ms Consolación Molto Valiente during the Proffered Paper session Public health policy and economics on Monday, 11 September 2017, 16:30 to 18:00 (CEST) in the Alicante Auditorium.
  2. Cherny NI, et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol. 2015;26(8):1547–1573. doi: 10.1093/annonc/mdv249.
  3. Cherny N et al. ESMO-Magnitude of Clinical Benefit Scale version 1.1. Annals of Oncology 00: 1–27, 2017 doi:10.1093/annonc/mdx310
  4. Abstract 1436O_PR ‘How to assess a cancer therapy? Feedback from the French HTA body on the ESMO-MCBS’ will be presented by Ms Mathilde Grande during the Proffered Paper session Public health policy and economics on Monday, 11 September 2017, 16:30 to 18:00 (CEST) in the Alicante Auditorium.
  5. Abstract 1441PD ‘Magnitude of Clinical Benefit of Randomized Controlled Trials Supporting US Food and Drug Administration Approval of Drugs for Solid Tumours’ will be presented by Ms Consolación Molto Valiente during the Poster Discussion session Public health policy and health economics on Saturday, 9 September 2017, 16:30 to 17:45 (CEST) in the Tarragona Auditorium.
  6. Abstract 1437O_PR ‘Clinical Benefit of Randomized Controlled Trials (RCT) Supporting US Food and Drug Administration (FDA) Conversion from Accelerated to Full Approval‘ will be presented by Dr Maria Borrell Puy during the Proffered Paper session Public health policy and economics on Monday, 11 September 2017, 16:30 to 18:00 (CEST) in the Alicante Auditorium.

Disclaimer

This press release contains information provided by the authors of the highlighted abstracts and reflects the content of those abstracts. It does not necessarily reflect the views or opinions of ESMO who cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct .

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Abstract 1435O_PR

Comparison of the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) in Clinical Trials Supporting US Food and Drug Administration (FDA) Approval of Orphan vs. Non-orphan Drugs

C. Molto Valiente1, A. Tibau1, A. Ocana Fernandez2, A. Templeton3, L. del Carpio Huerta1, J. Del Paggio4, A. Barnadas1, C. Booth5, E. Amir6
1Oncology Department, Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona, Barcelona/SPAIN, 2Research Unit, Albacete University Hospital, Albacete/SPAIN, 3Department Of Oncology, St. Claraspital Basel, Basel/SWITZERLAND, 4Division Of Cancer Care And Epidemiology, Queen’s University Cancer Research Institute, Kingston/CANADA, 5Departments Of Oncology And Public Health Sciences, Queen’s University Cancer Research Institute, Kingston/CANADA, 6Dmoh, Princess Margaret Hospital, Toronto/CANADA

Background: The Orphan Drug Act provides incentives to manufacturers to develop drugs for rare diseases. The ESMO-MCBS is a validated tool, aimed at quantifying the clinical benefit for cancer drugs. Here, we compare the characteristics of clinical trials leading to approval by the FDA of orphan and non-orphan drugs and apply the ESMO-MCBS thresholds for meaningful clinical benefit.

Methods: We searched the Drugs@FDA website to identify anticancer drugs approved between January 2006 and December 2016. These were then categorized as orphan or non-orphan drugs as determined by the FDA. For each drug, we subsequently collected data on clinical trial design and methodology and compared these between orphan and non-orphan drugs. For drugs supported by randomized controlled trials (RCTs), we applied a ESMO-MCBS grade. Comparisons were performed using Mann Whitney U or Chi squared tests.

Results: Of the 137 studies included, 109 (80%) were RCTs. These led to the approval of 63 individual drugs for 118 indications. Among these indications, 54 (46%) received orphan drug designation. Compared to non-orphan drugs, trials supporting orphan drugs approval had a smaller sample size (median 369 vs 687, P=.001), were less likely to evaluate experimental cytotoxic chemotherapy or endocrine therapy than targeted therapy (8% vs 21%, P=.005) were less often randomized (73% vs 86%; P=.047) and were more likely to assess intermediate endpoints rather than overall survival (71% vs 51%, P=.01). A similar proportion of orphan and non-orphan drugs approved for palliative use met the ESMO-MCBS threshold for meaningful benefit (29% vs 27%; P=.86). There were too few studies performed in the curative setting (n=7) to perform statistical testing.

Conclusions: Compared with trials used to approve non-orphan cancer drugs, trials for orphan drugs are smaller, more likely to explore experimental biological therapies, use single-arm trials and intermediate end points. A similarly low proportion of approved orphan and non-orphan drugs meet the ESMO-MCBS threshold for meaningful benefit.

Clinical trial identification: Not applicable

Keywords: European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), US Food and Drug Administration (FDA) Approval, Orphan Drugs, clinical benefit

Disclosure: All authors have declared no conflicts of interest.

Abstract 1436O_PR

How to assess a cancer therapy? Feedback from the French HTA body on the ESMO-MCBS

M. Grande1, J. Fernandez1, B. Dahmani1, S. Stanel1, N. Albin2, L. Guillevin1, C. Belorgey1, A. D'ANDON1
1Medicine Assessment, National Authority for Health, St. Denis/FRANCE, 2Oncology, Clinique Mathilde, Rouen/FRANCE

Background: Concerns about cancer drug affordability explain the need to base reimbursement and pricing decisions on clinical added value (CAV). A special attention is given to the CAV assessment by Health Technology Assessment (HTA) bodies. In 2015, The European Society for Medical Oncology (ESMO) published the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), to assess CAV of drugs in solid tumors. For more than 20 years, the French National Authority for Health (HAS), which is responsible for HTA, assesses CAV on a 5-point scale from I (major CAV) to V (no CAV). While the HAS CAV scale is used for pricing, it is not used for reimbursement decision. The opportunity for HAS to use the ESMO scale should be further explored

Methods: To compare both the ESMO-MCBS CAV assessment and that done by HAS, we reviewed the 77 trials that were tested by the ESMO Task Force in its 2015 publication.

Results: Of the 77 trials tested using ESMO-MCBS, 59 were also appraised by HAS, 16 were not assessed and 2 are still under assessment by the HAS. In about 39% (23) of the 59 indications considered, the HAS CAV appraisal was consistent with the ESMO ranking. When an inconsistency was observed (36, 61%), the HAS CAV assessment was systematically more strict. No indication had a higher score than the ESMO evaluation under the HAS evaluation. In 37 indications (62%), the ESMO-MCBS indicated a substantial improvement in CAV. Of these, 48% (13/37) obtained a similar ranking by the HAS. Thirteen indications were downgraded for toxicity by the HAS while only two were downgraded for that criteria under the ESMO-MCBS. The HAS gave an unfavorable opinion for reimbursement for 4 indications that obtained the lowest scores on ESMO-MCBS.

Conclusions: In most cases, disparities between the ESMO-MCBS and the HAS assessment of CAV were observed. The HAS appears to be more demanding in its appraisals, which are mainly based on the level of evidence, comparator relevance, transposability of the results and safety. In the case of a health technology evaluation, the possibility of an unfavorable opinion for drug access should be added in the ESMO-MCBS. As CAV impacts drug prices, the use of the ESMO-MCBS might have led to an increase in French cancer expenses. Nevertheless, the ESMO-MCBS provides an objective tool for HTA bodies to rate CAV.

Keywords: health technology assessment, cancer therapy, pricing, ESMO-MCBS

Disclosure: All authors have declared no conflicts of interest.

Abstract 1441PD

Magnitude of clinical benefit of randomized controlled trials supporting US Food and Drug Administration approval of drugs for solid tumours

C. Molto Valiente1, E. Amir2, A. Ocana Fernandez3, A. Templeton4, L. del Carpio Huerta1, J. Del Paggio5, A. Barnadas1, C. Booth6, A. Tibau1
1Oncology Department, Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona, Barcelona/SPAIN, 2Dmoh, Princess Margaret Hospital, Toronto/CANADA, 3Research Unit, Albacete University Hospital, Albacete/SPAIN, 4Department Of Oncology, St. Claraspital Basel, Basel/SWITZERLAND, 5Division Of Cancer Care And Epidemiology, Queen’s University Cancer Research Institute, Kingston/CANADA, 6Departments Of Oncology And Public Health Sciences, Queen’s University Cancer Research Institute, Kingston/CANADA

Background: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated and reproducible tool to assess the magnitude of clinical benefit from drugs for solid tumors. Here, we evaluate characteristics and outcomes of clinical trials supporting approval by the FDA and their association with ESMO-MCBS.

Methods: We searched the Drugs@FDA website for applications of anticancer drugs from January 2006 to December 2016. Drug labels and reports of registration trials were reviewed and study characteristics, efficacy, toxicity and quality of life outcomes as well as regulatory pathways were collected. For randomized controlled trials (RCTs) ESMO-MCBS grades were applied. Meaningful clinical benefit was defined as a grade of A or B for trials of neo/adjuvant intent and 4 or 5 for those of palliative intent. Comparisons between groups were assessed using Logistic regression and the Mann Whitney U test.

Results: We identified 137 studies; 109 (80%) of which were RCTs. These led to the approval of 63 individual drugs for 118 licensed indications. Among the 105 RCTs for which the ESMO-MCBS could be applied, 7 (6%) were in the neo/adjuvant setting and 98 (94%) in the palliative setting. Only 46 (44%) met the ESMO-MCBS clinically meaningful benefit threshold (100% of neo/adjuvant trials and 41% of palliative trials). In multivariable analysis of palliative therapy trials, meaningful ESMO-MCBS grades were associated with phase III trials (compared to phase II; OR 38.45, P=0.004), those with overall survival as their primary endpoint (compared to intermediate endpoints; OR 8.28, P=0.001) and trials of targeted drugs with companion diagnostics (OR 11.62, P<0.001). Over time, there has been an increase in the number of trials meeting the ESMO-MCBS threshold (33% in 2006 vs. 67% in 2016, P for trend = 0.04). There was an insufficient number of neo/adjuvant studies to perform statistical analysis.

Conclusions: In patients with advanced solid tumours, fewer than half of RCTs supporting FDA approval meet the threshold for clinically meaningful benefit using validated scales.

Clinical trial identification: Not applicable

Keywords: clinical benefit, European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), US Food and Drug Administration Approval

Disclosure: All authors have declared no conflicts of interest.

Abstract 1437O_PR

Clinical Benefit Of Randomized Controlled Trials (RCT) Supporting US Food And Drug Administration (FDA) Conversion From Accelerated To Full Approval

M. Borrell Puy1, C. Molto Valiente2, A. Ocana Fernandez3, A. Templeton4, B. Seruga5, I. Gich6, A. Barnadas2, E. Amir7, A. Tibau2
1Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona/SPAIN, 2Oncology Department, Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona, Barcelona/SPAIN, 3Research Unit, Albacete University Hospital, Albacete/SPAIN, 4Department Of Oncology, St. Claraspital Basel, Basel/SWITZERLAND, 5Department Of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana/SLOVENIA, 6Epidemiology, Hospital de la Santa Creu i Sant Pau, Barcelona/SPAIN, 7Dmoh, Princess Margaret Hospital, Toronto/CANADA

Background: Accelerated approval (AA) regulations were established by the US FDA to improve access to drugs for life-threatening diseases. Pharmaceutical companies must confirm efficacy in post-approval trials as predicted by the surrogate endpoint. The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated and reproducible tool to assess the magnitude of clinical benefit from drugs for solid tumors. Here, we evaluate confirmatory RCTs supporting conversions from AA to regular approval (RA) and their association with ESMO defined thresholds for meaningful clinical benefit.

Methods: We searched the Drugs@FDA website to identify anticancer drugs that had received AA from January 2000 to December 2016 and to assess the status regarding conversion to full approval. Drug labels and reports of post-approval trials supporting conversion to RA were reviewed and study characteristics, efficacy, toxicity and quality of life outcomes were collected. For RCTs ESMO-MCBS grades were applied. Meaningful clinical benefit was defined as a grade of A or B for trials of curative intent and 4 or 5 for those of palliative intent.

Results: Of the 37 new indications granted AA, 17 (46%) were subsequently converted to RA based on 17 RCTs. The median time between AA and RA of oncology drugs was 3.1 years (range = 1.02–7.6). Two confirmatory trials (5%) failed to show clinical benefit. Confirmatory trials were still not completed for 18 (49%) indications; among these, the three longest intervals since AA up to the December 2016 cut-off date were 6.6, 5.9 and 2.3 years. ESMO-MCBS could be applied to 16 RCTs and 11 (69%) met the ESMO-MCBS clinically meaningful benefit threshold (100% of adjuvant trials and 58% of palliative trials).

Conclusions: Two thirds of RCTs supporting FDA conversion from accelerated to full approval of anticancer therapies meet the threshold for clinically meaningful benefit. AA indications should not be on the market for unacceptably prolonged intervals before confirmatory trials are completed.

Clinical trial identification: Not applicable

Keywords: Confirmatory Randomized Controlled Trials, European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), Accelerated approval, clinical benefit

Disclosure: All authors have declared no conflicts of interest.