Value of innovation for hematologic malignancies

Abstract

Background:

Several novel drugs are dramatically improving both lifespan and quality-of-life of patients with blood cancers.

Aim:

Prolonged disease duration and increased treatment costs for hematologic malignancies impose a relevant economic burden onto healthcare services, despite the low incidence of blood cancers. Therefore, an appropriate paradigm for valuing ‘innovation’ is urgently required in order to refine pricing and reimbursement decisions. Cost-per-QALY-gained is still the standard metric for assessing the ‘incremental’ value of new drugs; however, the high number of ‘comparator’ therapies and the huge variety of treatment sequences make plain two-treatment comparisons sub-optimal, while multiple-treatment and multiple-sequence comparisons require complex and less-transparent decision models. A repository of standard backbones for decision models might allow benchmarking and comparability among cost-effectiveness analyses; however, an international effort is required to build it up.

Results:

Deontology recommends that hematologists act in optimizing healthcare resources while preserving patient–physician alliance, but clinical practice guidelines do not support doctors in balancing cost against clinical outcomes. Decision models of chronic blood cancers unexpectedly proved that cost might be an appropriate value for innovation if treatments avoided severe toxicity and further lines of treatments, despite the eventually long duration of treatment and the competing risk of death due to comorbidity and old age.

Conclusion:

The improved transparency of decision models allows sharing of relevant structural and analytic parameters (i.e., time horizon, comparator treatments, hierarchy of end-point, assumptions, source of data, sub-group analyses) by stakeholders, physicians and patients, making health economics a noble ‘translator’ of values for innovation.

Keywords::

• Cost-effectiveness
• Lymphoma
• Multiple myeloma
• Net benefit
• Health innovation

Blood cancers represent 8% of overall malignancies1 and most of blood cancers are ‘rare’ disorders. Despite that, EUROCARE-5 recently reported a net trend to increased 5-year survival in European patients affected with blood cancers: up to 10% improvement was shown in lymphoma, myeloma, and chronic myeloid leukemia2^,3. Indeed, despite the low incidence of lymphoid and myeloid malignancies, several novel molecules (TKIs, BTK inhibitors, PI3K inhibitors, proteasome inhibitors, bendamustine, anti-CD20 and anti-CD30 monoclonal antibodies, IMIDs, azacitidine, and so on) have been registered in the last 20 years for the treatment of hematologic malignancies, consistently leading to a more marked reduction of premature (before age 75) cancer mortality than solid cancers, proportionally, to the number of approved molecules and irrespective of the number of drug classes4^,5. Despite lead-time bias and classification changes possible also contributing to the estimates3, a survival amelioration was also reported by cancer registries after the introduction of anti-proteasome inhibitors and IMIDs for multiple myeloma6 and azacitidine for high-risk myelodysplastic syndromes7.

The enthusiasm for such amazing results questioned the concepts of ‘value’ and ‘innovative’, while further new drugs are being approved in the EU such as idelalisib, ibrutinib, pomalidomide, bosutinib, and daratumomab.

Prospect theory states that the reference point greatly influences judgments on a therapy impact; therefore, both the comparator of innovative therapies and the point of view might change the final assignment of value to such therapies. Both patients and physicians agree that survival and quality-of-life are the two major goals of therapy for blood cancers, but assign them different weights8^,9. The Value in Cancer Care Task Force measures the Net Health Benefit of new treatments, assigning 80 points to life prolongation, 20 points to toxicity, and 30 bonus points to significant amelioration of symptoms10, while lay citizens and blood cancer patients would probably assign opposite scores8^,11. Most of the novel molecules against blood cancers are administered orally or subcutaneously, have a fine safety profile, and are shown to markedly improve patients’ quality-of-life12. Therefore, the clinical value of such drugs is quite promising. Moreover, some of them faced unmet needs in patients for whom no treatment alternative holds or who are intolerant or refractory to alternative treatments, thus satisfying the ‘innovative drug’ definition used by the Italian Agency for Drug Authorization and ‘valuable drug’ definition proposed for the EU13. Nevertheless, some concerns on the relative effectiveness of some drugs derive from the poor comparators (under-efficient and often dismissed treatments) used in registrative trials and from the less stringent criteria for prescription as compared to trial eligibility criteria.

Innovation itself does not necessary hold a positive social value; therefore, the RAND recently recommended to estimate the incremental social value of innovation as the difference between expected improvements in population health and the social costs attributable to the innovation itself14. The QALY metric has been internationally adopted by regulatory institutions as the appropriate comparator for costs, in that it includes both the length and quality-of-life15, and the World Bank and WHO suggested that healthcare interventions may be considered cost-effective if they buy a year of healthy life for less than a multiple of the national Gross Domestic Product16. According to the cost-per-QALY paradigm, a group of researchers from the Tuft University recently reviewed all the economic evaluations of drug therapies for blood cancers included in the repository held by their institution: the nine reviewed hematologic cancer drugs provided good value for money in the US17. Opposite conclusions were reached by the MD Anderson University after a critical re-analysis of 20 out of the 29 retrieved studies, using current drug prices18. Of relevance is that none of the reviewed economic analyses assessed the social impact of the novel drugs. More insight is, thus, requested in order to assess the overall ‘value of innovation’ for blood cancers: until recently, pharmaceuticals made up less than one third of total healthcare19 and treatments that avoided allogeneic SCT proved very cost-effective, such as imatinib for young CML patients20. However, blood cancers that preferentially incur in the elderly, such as multiple myeloma and myelodysplastic syndromes, have a huge impact on healthcare expenditures, despite their low frequency: multiple myeloma is the bone-involving cancer with the highest budget impact and myelodysplastic syndromes incur yearly healthcare costs higher than the 17 most common solid cancers21^,22. Novel drugs for elderly populations still have the potential to be cost-effective, mainly by reducing healthcare expenditures related to toxicities and to further lines of treatments, despite the limited prolongation of life span, which is limited by comorbidities and age itself23–25. Unfortunately, pricing might not be proportional to the expected clinical benefit because company-driven pharmacoeconomic evaluations often target trial-like patients, model opportunistic treatments for subsequent lines, or adopt a biased median duration of treatment (for treatments ‘until progression’)26.

Appropriate pharmacoeconomic analyses provide a very attractive tool for assigning the adequate monetary value to innovative drugs for blood cancers. A list of unsolved problems jeopardizes a wide application of pharmacoeconomics in policy-making; however, sharing a common platform with companies27^,28 might in turn contribute to an effective dialogue with other stakeholders and patient representatives. Moreover, a repository of ‘reference’ cost-effectiveness decision models for the major blood cancers, fitted with a standard backbone, standard comparator treatments, patient sub-groups and post-progression events, might benchmark critical issues and improve comparability of cost-for value among different drugs29.

Hematologists daily need to quantify the value of innovative therapies as deontology suggests that ‘all physicians should aim at optimizing public and private resources, while safeguarding efficacy, safety and humanization of healthcare services’30, and the GRADE paradigm for developing clinical guidelines imposes costs to be considered as relevant outcomes31. Nevertheless, the relative weight physicians assign to outcomes, i.e., survival, progression, toxicity, quality-of-life, and costs, may differ from patients and policy-makers. Innovative therapies are a good opportunity to enhance the patient–physician alliance and to expand it to policy-makers and companies. In this process, pharmacoeconomics might play the role of ‘translator’ among different points of view.

Transparency

Declaration of funding

This manuscript has not received any funding.

Declaration of financial/other relationships

MM has received grants/funding from Novartis and Janssen, has consulted for Gilead, and has received speaker’s bureau for Celgene. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.