— Independent appraisal committee determines current evidence is adequate to demonstrate that nadofaragene firadenovec and oportuzumab monatox provide a net health benefit over best supportive care, but that the evidence is inadequate to enable a clear comparison of these treatments to each other or to other active treatments —

— While no US price is known at this time, based on the estimates derived from single-arm trials of patient benefits from delay of metastasis and need for cystectomy, ICER calculates annual health-benefit price benchmark ranges of approximately $121,000-$201,000* for nadofaragene firadenovec and $93,000-$162,000 for oportuzumab monatox —

— Experts at policy roundtable debated the prospects for step therapy with less expensive chemotherapy regimens and highlighted the urgent need for more rigorous studies that compare how well multiple active regimens achieve patient-relevant outcomes —

BOSTON, December 17, 2020 – The Institute for Clinical and Economic Review (ICER) today released a Final Evidence Report* and Report-at-a-Glance* assessing the comparative clinical effectiveness and value of nadofaragene firadenovec (Adstiladrin®, FKD Therapies Oy and FerGene) and oportuzumab monatox (Vicineum™, Sesen Bio) for the treatment of non-muscle invasive bladder cancer (NMIBC) that is unresponsive to Bacillus Calmette-Guerin (BCG) intravesical therapy.

“For many patients with BCG-unresponsive NMIBC, there are limited interventions available that preserve the bladder,” said David Rind, MD, ICER’s Chief Medical Officer. “While our review of the evidence suggests that both nadofaragene firadenovec and oportuzumab monatox may provide benefits for patients, more rigorous trials are needed. The lack of a placebo or active comparator in pivotal trials, though meeting FDA guidance, leaves clinicians, patients, and other stakeholders with significant uncertainty around comparative benefits and the magnitude of those benefits. Even if the therapies are approved based on the current evidence, prospective head-to-head trials are needed that compare treatments and assess patient-important outcomes. Manufacturers should commit to setting prices that are commensurate with the added benefits of these new therapies compared to lower-cost clinically appropriate regimens.”

ICER’s report on these therapies was reviewed at the November 2020 public meeting of the Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC), one of ICER’s three independent evidence appraisal committees.

Voting on Clinical Effectiveness and Contextual Considerations

During the public meeting, the Midwest CEPAC panelists evaluated the clinical evidence for these treatments across two patient populations:

  • Population 1: adults with BCG-unresponsive NMIBC, with carcinoma in situ (and who may or may not also have papillary disease and superficial invasion)
  • Population 2: adults with BCG-unresponsive NMIBC with high-grade papillary disease or superficial invasion, but who do not have carcinoma in situ

For populations 1 and 2, a majority of the panelists found that the evidence is adequate to demonstrate that both nadofaragene firadenovec and oportuzumab monatox provide a net health benefit over best supportive care. However, they also found that the evidence is not adequate to compare each of these treatments to each other, nor is it adequate to demonstrate that either provides a superior net health benefit over gemcitabine (with or without docetaxel).

For population 2, a majority of the panelists found that the evidence was not adequate to demonstrate that either nadofaragene firadenovec or oportuzumab monatox provides a net health benefit over systemic pembrolizumab.

During their deliberations, panel members also weighed these treatments’ other potential benefits, disadvantages, and contextual considerations. A majority affirmed that both treatments offer a new mechanism of action compared to that of other treatments, and that nadofaragene firadenovec’s relative simplicity of regimen is likely to result in higher real-world adherence and better outcomes relative to other treatment options that require more frequent clinician visits.

A majority of the panelists also voted that ICER’s economic model assumptions for both treatments were neither too optimistic nor too pessimistic.

Cost-Effectiveness Findings and Voting on Long-Term Value for Money

Because neither drug has received FDA approval yet, and there is no known US market price, the Midwest CEPAC did not conduct a vote on the treatments’ long-term value for money.

Based on the available data from single-arm trials suggesting delay in metastasis and requirement for cystectomy compared to historical estimates of outcomes with best supportive care, ICER’s recommended health-benefit price benchmark (HBPB) ranges are $158,600-$262,000* per year for nadofaragene firadenovec and $93,000-$162,000 per year for oportuzumab monatox. NOTE: These recommendations have been updated since the publication of ICER’s earlier Evidence Report due to revisions in data used to model longer-term outcomes.

These HBPB ranges should be viewed as an upper bound on pricing, because ICER’s cost-effectiveness model is comparing these therapies to best supportive care. Most clinicians caring for patients with BCG-unresponsive NMIBC who choose not to have cystectomy would likely use treatments with at least some short-term efficacy.

The HBPB is a price range suggesting the highest US price a manufacturer should charge for a treatment, based on the amount of improvement in overall health patients receive from that treatment, when a higher price would cause disproportionately greater losses in health among other patients in the health system due to rising overall costs of health care and health insurance. In short, it is the top price range at which a health system can reward innovation and better health for patients without doing more harm than good.

Key Policy Recommendations  

Following the voting session, a policy roundtable of experts — including clinical experts, patient advocates, and representatives from US payers and both relevant pharmaceutical companies — convened to discuss the implications of the evidence for policy and practice. Key recommendations stemming from the roundtable discussion include:

  • Manufacturers should acknowledge that single-arm trials usually fail to provide the kind of evidence that is needed to help patients, clinicians, and insurers understand the comparative clinical effectiveness and value of new treatments. Therefore, manufacturers developing new treatments for BCG-unresponsive NMIBC should use randomized trials as the basis for regulatory approval; where this has not been done, manufacturers should sponsor real-world comparative studies of their therapies that can help evaluate a broad set of patient-relevant outcomes including quality of life, work and disability status, and overall mortality.
  • Regulators have an important role to play in how new therapeutics enter clinical practice. The lack of a clear consensus on “standard care” for BCG-unresponsive NMIBC provides no justification for the FDA’s failure to require randomized trials comparing emerging therapies to active regimens.
  • Providers should engage in a shared decision-making process with their patients and not let their treatment recommendations be unduly swayed by the perverse incentives that often pay clinicians more for administering more expensive treatment options. In bladder cancer, this is particularly relevant given the dramatic price difference between chemotherapy and the prices expected for the emerging agents nadofaragene firadenovec and oportuzumab monatox.
  • Patient groups advocating for bladder cancer research and for patients with bladder cancer have played an essential role in bringing forward important new advances in care. These groups should continue their efforts to encourage innovation while pushing life science companies to generate better evidence to guide patient and clinician decision-making. They should also fully embrace their power to speak explicitly about the impact of the high US prices that are anticipated for new treatments for BCG-unresponsive NMIBC.

ICER’s detailed set of policy recommendations, including considerations for establishing prior authorization criteria, is available in the Final Evidence Report* and in the standalone Policy Recommendations document.

* CORRECTION: Originally published on December 17 2020, this report was updated on January 15, 2021. A data entry error affected model results regarding nadofaragene firadenovec when used in the Ta/T1 population. Results have been corrected in this press release and in its hyperlinked documents, including a revised health-benefit price benchmark for nadofaragene firadenovec. ICER issued a new press release on January 15, 2021 to announce and explain this correction.

About ICER

The Institute for Clinical and Economic Review (ICER) is an independent non-profit research institute that produces reports analyzing the evidence on the effectiveness and value of drugs and other medical services. ICER’s reports include evidence-based calculations of prices for new drugs that accurately reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall health care system.

ICER’s reports incorporate extensive input from all stakeholders and are the subject of public hearings through three core programs: the California Technology Assessment Forum (CTAF), the Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC), and the New England Comparative Effectiveness Public Advisory Council (New England CEPAC). These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of health care. For more information about ICER, please visit ICER’s website.