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)

N. I. Cherny; R. Sullivan; U. Dafni; J. M. Kerst; A. Sobrero; C. Zielinski; E. G. E. de Vries; M. J. Piccart

Disclosures

Ann Oncol. 2015;26(8):1547-1573. 

In This Article

Abstract and Introduction

Abstract

The value of any new therapeutic strategy or treatment is determined by the magnitude of its clinical benefit balanced against its cost. Evidence for clinical benefit from new treatment options is derived from clinical research, in particular phase III randomised trials, which generate unbiased data regarding the efficacy, benefit and safety of new therapeutic approaches. To date, there is no standard tool for grading the magnitude of clinical benefit of cancer therapies, which may range from trivial (median progression-free survival advantage of only a few weeks) to substantial (improved long-term survival). Indeed, in the absence of a standardised approach for grading the magnitude of clinical benefit, conclusions and recommendations derived from studies are often hotly disputed and very modest incremental advances have often been presented, discussed and promoted as major advances or 'breakthroughs'. Recognising the importance of presenting clear and unbiased statements regarding the magnitude of the clinical benefit from new therapeutic approaches derived from high-quality clinical trials, the European Society for Medical Oncology (ESMO) has developed a validated and reproducible tool to assess the magnitude of clinical benefit for cancer medicines, the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). This tool uses a rational, structured and consistent approach to derive a relative ranking of the magnitude of clinically meaningful benefit that can be expected from a new anti-cancer treatment. The ESMO-MCBS is an important first step to the critical public policy issue of value in cancer care, helping to frame the appropriate use of limited public and personal resources to deliver cost-effective and affordable cancer care. The ESMO-MCBS will be a dynamic tool and its criteria will be revised on a regular basis.

Introduction

The value of any new therapeutic strategy or treatment is determined by the magnitude of its clinical benefit balanced against its cost.[1] Value considerations have become increasingly important in an era of rapid expansion of new, expensive cancer medicines and other technologies such as advanced radiotherapy techniques or robotic surgery which provide small incremental benefits[2–5] within the context of cost-constrained health care systems.[6] This is especially true in Europe where the costs of care delivery[6] and cancer outcomes[7–9] vary substantially across Europe with the latter being influenced by the level of economic development.[9,10] In some instances, discrepant outcomes between countries in Europe can be attributed to inordinate delays, sometimes of years, in making highly effective treatments available at an affordable cost to the patient.[11,12]

Whereas costs of procurement and out of pocket expenditures vary from country to country, the magnitude of clinical benefit, as derived from well-designed clinical trials, is a relative constant. Consequently, meaningful discussion of value and relative value are predicated on an understanding of the magnitude of clinical benefit.[1] Clinical benefit in this context refers to the added benefit compared with a control which, in most cases, is the best current standard care.

Evidence for clinical benefit from new treatment approaches is derived from comparative outcome studies, most commonly phase III randomised clinical trials, which generate ostensibly unbiased data regarding the efficacy, benefit and safety of new therapeutic approaches. The potential benefits of a new treatment can be summarised as either living longer and/or living better, evaluated in clinical studies through the treatment effect on overall survival (OS) and/or quality of life (QoL), and their surrogates (Table 1). In studies of interventions with curative intent in which mature survival data are not yet available disease-free survival (DFS), recurrence-free survival (RFS), event-free survival (EFS), distant disease-free survival and time to recurrence (TTR), are used as surrogate measures. The validity of this approach, though not uncontroversial,[13] is relatively well supported by data derived from a wide range of solid tumour settings including in colon,[14] gastric,[15] lung[16] and breast[17] cancers. In studies evaluating therapies in non-curative settings, progression-free survival (PFS), and time to progression (TTP) provide information about biological activity and may indicate benefit for some patients;[18,19] however, they are not reliable surrogates for improved survival[18,20–23] or QoL.[23,24]

To date, there is no standard tool for grading the magnitude of clinical benefit of cancer therapies,[25,26] which may range from trivial (median PFS advantage of only a few weeks) to substantial (improved long-term survival). Indeed, in the absence of a standardised approach for grading, the magnitude of clinical benefit, conclusions and recommendations derived from studies are often hotly disputed[25] and very modest incremental advances have often been presented, discussed and promoted as major advances or 'breakthroughs'.[5,25–29] Overestimating or overstating the benefits from new intervention can cause harm: it confounds public policy decision making,[29] undermines the credibility of oncology research reporting,[26,29,30] harms patients who choose to undertake treatments based on exaggerated expectations that may subject them to either risk of adverse effects, inconvenience or substantial personal costs[26,28] and, in the public domain, they fuel sometimes inappropriate hype or disproportionate expectations about novel treatments[31,32] and the need to allocate public or personal funds to provide them.

It is important for the Oncology Community to present clear and unbiased statements regarding the magnitude of clinical benefit from new therapeutic approaches supported by credible research. ESMO aims to emphasize those treatments which bring substantial improvements to the duration of survival and/or the QoL of cancer patients which need to be distinguished from those whose benefits are more modest, limited or even marginal. To this end, ESMO has undertaken the development of a validated and reproducible tool to assess the magnitude of clinical benefit of anti-cancer interventions, the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). ESMO intends to apply this scale prospectively to each new anti-cancer drug/intervention that will be European Medicines Agency (EMA) approved. Drugs or treatment interventions that obtain the highest scores on the scale will be emphasized in the ESMO guidelines, with the hope that they will be rapidly endorsed by health authorities across the European Union.

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