Payer Perceptions of Nonclinical Value Drivers

Maximilian Hunt, BS, Ismail Ismailoglu, PhD, Grace Mock, BA, Helen Amata, MPH, Trinity Life Sciences, New York, NY, USA

Introduction to Nonclinical Value Drivers
Value assessment processes in Europe are designed to measure the benefit of an emerging therapy based on clinical efficacy, safety, and cost, but less transparent is how European decision makers consider nonclinical benefits that a therapy may offer (eg, route/frequency of administration or treatment setting). Nonclinical value drivers encompass a broad designation of factors that may not directly contribute to clinical or economic evaluation. Although possibly disregarded by health technology assessment (HTA) processes, these nonclinical factors may be meaningful to patients, caregivers, and providers. Nonclinical value drivers may directly or indirectly cause decreased treatment discontinuation rates, lower cost of care (eg, fewer visits to hospital provides savings for the health system, caregiver, and patient), improved patient quality of life, or time savings for caregivers.

Case Studies: Payer Perceptions of Nonclinical Value Drivers
Three recently approved therapies with significant nonclinical benefits were evaluated to provide insight into how these value drivers affect decision making in European HTAs.

Ixazomib (Ninlaro), approved by the European Medicines Agency (EMA) in November 2016, was the first oral proteasome inhibitor (indicated for relapsed/refractory multiple myeloma).¹ In addition to its clinical profile, this nonclinical value driver of an alternative route of administration (RoA) gave ixazomib considerable potential to improve patient convenience during long-term treatment. While payers may not perceive an oral RoA as a benefit, many patients prefer to take an oral pill over an injection or intravenous medication. Additionally, ixazomib’s oral RoA allows for it to be administered in the home rather than in the hospital, which can preserve time for the patient and caregiving team, increasing overall productivity.

Despite these benefits, a sample of European HTA assessments of ixazomib largely focused on clinical outcomes and did not consider the oral RoA as a value driver.^1-4 There was no mention of the oral RoA in any of the assessed European HTA decisions.

"Although possibly disregarded by health technology assessment processes, nonclinical factors may be meaningful to patients, caregivers, and providers."

Although outside of the scope of HTA decisions, one interesting impact of ixazomib’s oral RoA was the increased uptake of the regimen during the COVID-19 pandemic. At that time, ixazomib allowed immunocompromised patients with multiple myeloma to avoid visits to the hospital for treatment. This lowered COVID exposure for these patients. As a result, the reduction in use of hospitals during a time of overcrowding and resource allocation also provided an unexpected benefit to the healthcare system. This lowered COVID exposure for patients and reduced the use of hospitals during a time of overcrowding and resource allocation. While this kind of unexpected benefit to the healthcare system is challenging to account for in HTA evaluations, it provides evidence that nonclinical value drivers can have a positive impact on patients and healthcare systems. 

Ravulizumab (Ultomiris), approved by the EMA in July 2019, had potential value based on its less frequent administration versus the standard of care.^5-8 Ravulizumab was approved for treatment of paroxysmal nocturnal hemoglobinuria based on 2 noninferiority trials versus its predecessor, eculizumab, and is administered through infusion every 8 weeks while eculizumab requires infusions every 2 weeks.

HTA evaluations cited the less frequent administration for ravulizumab versus eculizumab as a minor advantage from the treatment cost and patient convenience perspectives in the United Kingdom and France.^5-6 The National Institute for Health and Care Excellence’s (NICE) “recommended with simple discount” decision noted the less frequent dosing schedule versus eculizumab as having the potential to create cost savings. The Haute de Autorité de Santé (HAS) decision of “SMR Important and ASMR IV” in France included mention of expected improvement in care conditions due to the infusion frequency reduction versus eculizumab. Ravulizumab has not yet been evaluated by Spanish or Italian authorities, and the G-BA in Germany did not reference nonclinical drivers in their decisions.^7-8

Onasemnogene abeparvovec (Zolgensma) was evaluated to determine the impact of its one-time administration schedule. Onasemnogene abeparvovec is the only one-time therapy available for spinal muscular atrophy and was approved by the EMA in 2020 based on a single-arm trial. The orphan-designated gene therapy is indicated for patients born with genetic mutations that cause severe spinal muscular atrophy and is administered via a one-time infusion lasting about 1 hour.

Onasemnogene abeparvovec received favorable HTA outcomes in the United Kingdom, France, and Italy; however, only NICE noted potential benefit from the one-time administration schedule.^9-12 Specifically, NICE highlighted the reduced need for constant care in the form of monitoring, at-home medical equipment, and invasive treatments, which can be overwhelming for parents and patients with spinal muscular atrophy, although this benefit was not quantified.⁹ HTA bodies in the remaining countries considered made no mention of nonclinical value drivers in their evaluations, although onasemnogene abeparvovec is not listed in Spain.

Key Trends Across Case Studies
These case studies demonstrate that assessments rarely mention nonclinical value drivers despite hypotheses that: (1) payers may be more likely to consider nonclinical value drivers in disease spaces with high treatment burden (eg, multiple myeloma), and that (2) new technologies which decrease frequency of administration may result in long-term clinical and economic benefits to patients. However, in the 3 instances that nonclinical value drivers were cited in the case-study HTA reports, cost-saving potential or improved quality of life for patient and caregiver were noted, showing that payers may consider nonclinical benefits if they are shown to improve economic or clinical outcomes indirectly. These trends illustrate the potential for nonclinical value drivers to become a greater consideration for European payers due to their potential for downstream impacts.

Impact of Nonclinical Value Drivers From the Patient Voice
One stakeholder group that may be able to increase consideration of nonclinical value drivers are patient advocacy organizations. Formally, patient advocacy organizations may only engage in the HTA process in the United Kingdom, France, and Germany.¹³ In the United Kingdom and Germany, patient advocates take part in the HTA evaluation meetings. In other markets, key opinion leaders included in the clinical review portion of the HTA process are tasked to provide the patient perspective indirectly and advocate on behalf of patients. There is some room for adjusting the HTA evaluation criteria if a nonclinical value driver is deemed important. In Germany, for instance, there is an exemption clause that can grant a therapy that has received a “no added benefit” outcome more flexibility in the reference pricing procedure if key opinion leaders convince the G-BA that it fills an unmet need.

"Considering patient input in HTA provides an opportunity for regulators to evaluate nonclinical value drivers on qualitative terms."

Outside of Germany and the United Kingdom, opportunity remains limited for patient advocacy organizations to provide a voice in the HTA process. Developing additional avenues for patients will facilitate access to valuable therapies and provide an avenue for pharmaceutical manufacturers to demonstrate value associated with nonclinical aspects—particularly those that are important to patients. Considering patient input in HTA provides an opportunity for regulators to evaluate nonclinical value drivers on qualitative terms as opposed to factoring them into quantitative clinical and economic analyses.

Conclusions and Future Outlook
This research shows how the current role for nonclinical value drivers in European HTA decisions is relatively minor—while they are often considered and acknowledged, they are rarely cited as driving decision outcomes. One solution to this oversight may come in the Joint Clinical Assessment, which could provide an opportunity for wider consideration of value drivers. Clinicians and patients will be able to provide input during the Joint Clinical Assessment and Joint Scientific Consultation processes, while patient advocacy organizations will also be able to offer their perspective on nonproduct-related matters, including methodological guidance documents. This is likely to increase the presence and weight of nonclinical value drivers in access decisions in the years to come.

References
1. National Institute for Health and Care Excellence (NICE). Ixazomib with lenalidomide and dexamethasone for treating relapsed or refractory multiple myeloma. Published February 7, 2018. Accessed June 10, 2022. https://www.nice.org.uk/guidance/ta505
2. Gemeinsamer Bundesausschuss (G-BA). Benefit assessment procedure for the active ingredient ixazomib (multiple myeloma at least 1 previous therapy, combination with lenalidomide and dexamethasone). Published April 18, 2017. Accessed June 10, 2022. https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/275/#beschluesse
3. Haute Autorite de Sante (HAS). NINLARO (ixazomib). Published September 9, 2020.  Accessed June 10, 2022. https://www.has-sante.fr/upload/docs/application/pdf/2021-03/ninlaro_09092020_summary_ct18381.pdf
4. Gazzetta Ufficiale della Republica Italiana. Ninlaro (ixazomib). Published February 19, 2019. Accessed June 10, 2022. https://www.gazzettaufficiale.it/atto/serie_generale/caricaDettaglioAtto/originario?atto.dataPubblicazioneGazzetta=2019-03-08&atto.codiceRedazionale=19A01444
5. National Institute for Health and Care Excellence (NICE). Ravulizumab for treating paroxysmal nocturnal haemoglobinuria. Published May 19, 2021. Accessed June 10, 2022. https://www.nice.org.uk/guidance/ta698 
6. Haute Autorite de Sante (HAS). ULTOMIRIS (ravulizumab). Published September 16, 2020. Accessed June 10, 2022. https://www.has-sante.fr/jcms/p_3202251/en/ultomiris-ravulizumab#smr 
7. Gemeinsamer Bundesausschuss (G-BA). Benefit assessment procedure for the active ingredient ravulizumab. Published February 6, 2020. Accessed June 10, 2022. https://www.g-ba.de/downloads/39-1464-4155ceb2181be9055025daa6b2b363fb64d3/2020-02-06_AM-RL-XII_Ravulizumab_D-463_EN.pdf
8. Gazzetta Ufficiale della Republica Italiana. Ultomiris (ravulizumab). Published March 8, 2021. Accessed June 10, 2022. https://www.gazzettaufficiale.it/atto/serie_generale/caricaDettaglioAtto/originario?atto.dataPubblicazioneGazzetta=2021-03-18&atto.codiceRedazionale=21A01525
9. National Institute for Health and Care Excellence (NICE). Onasemnogene abeparvovec for treating spinal muscular atrophy. Published July 7, 2021. Accessed June 10, 2022. https://www.nice.org.uk/guidance/hst15
10. Gemeinsamer Bundesausschuss (G-BA). Benefit assessment procedure for the active ingredient Onasemnogen-Abeparvovec (spinal muscular atrophy). Published December 3, 2020. Accessed June 10, 2022. https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/561/#beschluesse
11. Haute Authorité de Santé (HAS). SPINRAZA (nusinersen), antisense oligonucleotide. Published July 6, 2018. Accessed June 10, 2022. https://www.has-sante.fr/jcms/c_2826600/en/spinraza-nusinersen-antisense-oligonucleotide
12. Gazzetta Ufficiale della Republica Italiana. Zolgensma (onasemnogene abeparvovec). Published November 12, 2020. Accessed June 10, 2022. https://www.gazzettaufficiale.it/atto/serie_generale/caricaDettaglioAtto/originario?atto.dataPubblicazioneGazzetta=2020-11-17&atto.codiceRedazionale=20A06264
13. Scott AM, Wale JL, HTAi Patient and Citizen Involvement in HTA Interest Group, Patient Involvement and Education Working Group. Patient advocate perspectives on involvement in HTA: an international snapshot. Res Involv Engagem. 2017(3):2-17.