The FDA and Gene Therapy for Duchenne Muscular Dystrophy.

This Viewpoint examines the appropriateness of FDA accelerated approval of novel gene therapies to treat boys with Duchenne muscular dystrophy following clinical trials with surrogate outcomes that did not demonstrate net benefits.

How do the Institute for Clinical and Economic Review's Assessments of Comparative Effectiveness Compare With the German Federal Joint Committee's Assessments of Added Benefit? A Qualitative Study.

OBJECTIVES: We compared the Institute for Clinical and Economic Review's (ICER) ratings of comparative clinical effectiveness with the German Federal Joint Committee's (G-BA) added benefit ratings, and explored what factors may explain the disagreement between the 2 organizations. METHODS: We included drugs if they were assessed by ICER under its 2020 to 2023 Value Assessment Framework and had a corresponding assessment by G-BA as of January 2024 for the same indication, patient population, and comparator drug. To compare assessments, we modified ICER's proposed crosswalk between G-BA and ICER benefit ratings to account for G-BA's certainty ratings. We also determined whether each pair was based on similar evidence. Assessment pairs exhibiting disagreement based on the modified crosswalk despite a similar evidence base were qualitatively analyzed to identify reasons for disagreement. RESULTS: Out of 15 drug assessment pairs matched on indication, patient subgroup, and comparator, none showed agreement in their assessments when based on similar evidence. Disagreement was attributed to differences in evidence evaluation, including evaluations of safety, generalizability, and study design, as well as G-BA's rejection of the available evidence in 4 cases as unsuitable. CONCLUSIONS: The findings demonstrate that even under conditions where populations and comparators are identical and the evidence base is consistent, different assessors may arrive at divergent conclusions about comparative effectiveness, thus underscoring the presence of value judgments within assessments of clinical effectiveness. To support initiatives that seek to facilitate the exchange of value assessments between countries, these value judgments should always be transparently presented and justified in assessment summaries.

Gene therapies for sickle cell disease: Effectiveness and value.

DISCLOSURES: Drs. Nikitin, McKenna, Rind, Nhan, and Pearson report grants from Arnold Ventures, grants from Blue Cross Blue Shield of MA, grants from California Healthcare Foundation, grants from The Commonwealth Fund, grants from The Patrick and Catherine Weldon Donaghue Medical Research Foundation, during the conduct of the study; other from America's Health Insurance Plans, other from Anthem, other from AbbVie, other from Alnylam, other from AstraZeneca, other from Biogen, other from Blue Shield of CA, other from CVS, other from Editas, other from Express Scripts, other from Genentech/Roche, other from GlaxoSmithKline, other from Harvard Pilgrim, other from Health Care Service Corporation, other from Kaiser Permanente, other from LEO Pharma, other from Mallinckrodt, other from Merck, other from Novartis, other from National Pharmaceutical Council, other from Premera, other from Prime Therapeutics, other from Regeneron, other from Sanofi, other from United Healthcare, other from HealthFirst, other from Pfizer, other from Boehringer-Ingelheim, other from uniQure, other from Envolve Pharmacy Solutions, other from Humana, other from Sunlife, outside the submitted work.

GRADE concept 6: a novel application of external indirect evidence into GRADE ratings of evidence certainty in network meta-analysis.

OBJECTIVES: We describe how consideration of external evidence may play an important role in judging certainty in the process of establishing the certainty of the evidence. Our example is a network meta-analysis (NMA) addressing treatment for Ebola virus disease, which informed a World Health Organization guideline. STUDY DESIGN AND SETTING: Through Grading of Recommendations Assessment, Development, and Evaluations (GRADE) project group iterative online, in-person and email discussions, we developed this GRADE concept and obtained approval from the GRADE working group. Using the null as a threshold, we rated our certainty for network estimates in mortality, including consideration of evidence external to the NMA (i.e., did not meet eligibility criteria) and formal logical construction. RESULTS: Based on the existing GRADE guidance, we rated the network estimate for one indirect comparison as low certainty. The formal logical construction that lead us reevaluate the certainty of the evidence is as follows: if A is superior to B, and B is not inferior to C, then A must be superior to C. After considering the logic and the external indirect evidence, we concluded at least moderate certainty for the comparison. CONCLUSION: Systematic review authors and guideline developers should apply the fundamental logical construction for indirect comparisons and consider compelling external evidence in NMA certainty ratings.

Grading of recommendations assessment, development, and evaluation concept article 5: addressing intransitivity in a network meta-analysis.

OBJECTIVES: This article describes considerations for addressing intransitivity when assessing the certainty of the evidence from network meta-analysis (NMA) using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Intransitivity is induced by effect modification, that is, when the magnitude of the effect between an intervention and outcome differs depending on the level of another factor. STUDY DESIGN AND SETTING: To develop this GRADE concept paper, the lead authors conducted iterative discussions, computer simulations, and presentations to the GRADE project group and at GRADE working group meetings. The GRADE Working Group formally approved the article in July 2022. RESULTS: NMA authors can have a higher or a lower threshold to rate down the certainty of the evidence due to intransitivity, which depends on the extent of their concerns regarding the trustworthiness of indirect comparisons, and their view of the relative problems with rating down excessively or insufficiently. NMA authors should consider three main factors when addressing intransitivity: the credibility of effect modification, the strength of the effect modification, and the distribution of effect modifiers across the direct comparisons. To avoid double counting limitations of the evidence, authors should consider the relationship between intransitivity and other GRADE domains. CONCLUSION: NMA authors face theoretic and pragmatic challenges and in most situations need to assess intransitivity without the availability of empirical data. Thus, explicitness regarding perspective is crucial.

The effectiveness and value of AMX0035 and oral edaravone for amyotrophic lateral sclerosis: A summary from the Institute for Clinical and Economic Review's Midwest Comparative Effectiveness Public Advisory Council.

DISCLOSURES: Funding for this summary was contributed by Blue Cross Blue Shield of MA, California Healthcare Foundation, The Patrick and Catherine Weldon Donaghue Medical Research Foundation, Arnold Ventures, and Kaiser Foundation Health Plan Inc., to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, AbbVie, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy Solutions, Express Scripts, Genentech/ Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health First, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer. Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, Sun Life Financial, uniQure, and United Healthcare. Mr Nikitin, Ms McKenna, Ms Richardson, and Drs Rind and Pearson are employed by ICER. Through their affiliated institutions, Drs Makam, Carlson, and Suh received funding from ICER for the work described in this summary.

Cost-Effectiveness of Nadofaragene Firadenovec and Pembrolizumab in Bacillus Calmette-Guérin Immunotherapy Unresponsive Non-Muscle Invasive Bladder Cancer.

OBJECTIVES: Nadofaragene firadenovec is a gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) undergoing Food and Drug Administration review. Pembrolizumab is approved for treating patients with BCG-unresponsive NMIBC with carcinoma in situ (CIS). We evaluated the cost-effectiveness of these treatments compared with a hypothetical therapeutic alternative, at a willingness-to-pay threshold of $150 000 per quality-adjusted life-year (QALY) gained, in CIS and non-CIS BCG-unresponsive NMIBC populations. METHODS: We developed a Markov cohort simulation model with a 3-month cycle length and lifetime horizon to estimate the total costs, QALYs, and cost per additional QALY from the health sector perspective. Clinical inputs were informed by results of single-arm clinical trials evaluating the treatments, and systematic literature reviews were conducted to obtain other model inputs. Sensitivity analyses were conducted to assess uncertainty in model results. RESULTS: Nadofaragene firadenovec, at a placeholder price 10% higher than the price of pembrolizumab, had an incremental cost-effectiveness ratio of $263 000 and $145 000 per QALY gained in CIS and non-CIS populations, respectively. Pembrolizumab had an incremental cost-effectiveness ratio of $168 000 per QALY gained for CIS. A 5.4% reduction in pembrolizumab's price would make it cost-effective. The model was sensitive to many inputs, especially to the probabilities of disease progression, initial treatment response and durability, and drug price. CONCLUSIONS: The cost-effectiveness of nadofaragene firadenovec will depend upon its price. Pembrolizumab, although not cost-effective in our base-case analysis, is an important alternative in this population with an unmet medical need. Comparative trials of these treatments are warranted to better estimate cost-effectiveness.

The estimated costs and benefits of a hypothetical supervised consumption site in Providence, Rhode Island.

BACKGROUND: Overdose deaths have increased dramatically in the United States, including in Rhode Island. In July 2021, the Rhode Island government passed legislation supporting a two-year pilot program authorizing supervised consumption sites (SCSs) in response to this crisis. We estimated the costs and benefits of a hypothetical SCS in Providence, Rhode Island. METHODS: We utilized a decision analytic mathematical model to compare costs and outcomes for people who inject drugs under two scenarios: (1) a SCS that includes syringe services provision, and (2) a syringe service program only (i.e., status quo). We assumed 0.95% of injections result in overdose, the SCS would serve 400 clients monthly and have a net cost of $783,899 annually, 46% of overdoses occurring outside of the SCS result in an ambulance run and 43% result in an emergency department (ED) visit, 0.79% of overdoses occurring within the SCS result in an ambulance run and ED visit, and the SCS would lead to a 25.7% reduction in fatal overdoses near the site. The model was developed from a modified societal perspective with a one-year time horizon. RESULTS: A hypothetical SCS in Providence would prevent approximately 2 overdose deaths, 261 ambulance runs, 244 ED visits, and 117 inpatient hospitalizations for emergency overdose care annually compared to a scenario that includes a syringe service program only. The SCS would save $1,104,454 annually compared to the syringe service program only, accounting only for facility costs and short-term costs of emergency overdose care and ignoring savings associated with averted deaths. Influential parameters included the percentage of injections resulting in overdose, the total annual injections at the SCS, and the percentage of overdoses outside of the SCS that result in an ED visit. CONCLUSION: A SCS in would result in substantial cost savings due to prevention of costly emergency overdose care.

The effectiveness and value of tezepelumab for severe asthma.

DISCLOSURES: Drs Rind, Campbell, Pearson, Ms Herce-Hagiwara, Ms Fluetsch, and Ms Herron-Smith report grants from Arnold Ventures; Kaiser Foundation Health Plan, Inc; The Patrick and Catherine Donaghue Medical Research Foundation; Blue Cross Blue Shield of Massachusetts; and California Healthcare Foundation during the course of this study.

The Cost-Effectiveness of Remdesivir for Hospitalized Patients With COVID-19.

OBJECTIVES: This study aimed to estimate the cost-effectiveness of remdesivir, the first novel therapeutic to receive Emergency Use Authorization for the treatment of hospitalized patients with COVID-19, and identify key drivers of value to guide future pricing and reimbursement efforts. METHODS: A Markov model evaluated the cost-effectiveness of remdesivir in patients hospitalized with COVID-19 from a US healthcare sector perspective. A lifetime time horizon captured potential long-term costs and outcomes. Model outcomes included discounted total costs, life-years, and quality-adjusted life-years (QALYs). Remdesivir was modeled as an addition to standard of care and compared with standard of care alone, including dexamethasone for patients requiring respiratory support. COVID-19 hospitalizations were assumed to be reimbursed through a single payment based on the respiratory support received alongside a remdesivir carveout payment in the base case. Sensitivity and scenario analyses identified key drivers. RESULTS: At a unit price of $520 per vial and assuming no survival benefit with remdesivir, the incremental cost-effectiveness was $298 200/QALY for patients with moderate to severe COVID-19 and $1 847 000/QALY for patients with mild COVID-19. Although current data do not support a survival benefit, if one was assumed, the cost-effectiveness estimate was $50 100/QALY for the moderate to severe population and $103 400/QALY for the mild population. Another key driver included the hospitalization payment structure (per diem vs bundled payment). CONCLUSIONS: With the current evidence available, remdesivir's price is too high to align with its expected health gains for hospitalized patients with COVID-19. Results from this study provide a rationale for iterative health technology assessment.

Mavacamten for hypertrophic cardiomyopathy: effectiveness and value.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Sun Life Financial, uniQure, and United Healthcare. Beinfeld, Nhan, Rind, and Pearson are employed by ICER. Through their affiliated institutions, Wasfy, Walton, and Sarker received funding from ICER for the work described in this summary. Walton also reports consulting fees from Second City Outcomes Research. Wasfy reports personal fees from Biotronik and Pfizer; grants from National Institutes of Health, National Football League Players Association and American Heart Association; and travel support from American College of Cardiology. Sarker has nothing additional to disclose.

JAK inhibitors and monoclonal antibodies for the treatment of atopic dermatitis: effectiveness and value.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Sun Life Financial, uniQure, and United Healthcare. Agboola, Herron-Smith, Nhan, Rind, and Pearson are employed by ICER. Through their affiliated institutions, Atlas, Brouwer, Carlson, and Hansen received funding from ICER for the work described in this summary.

The effectiveness and value of aducanumab for Alzheimer's disease.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Sun Life Financial, uniQure, and United Healthcare. Whittington, Rind, and Pearson are employed by ICER. Through their affiliated institutions, Synnott and Lin received funding from ICER for the work described in this summary. In addition, Synnott reports support from Biogen for the Tufts Medical Center Cost-Effectiveness Analysis Registry, which is maintained by the Center for the Evaluation of Value and Risk in Health.

The effectiveness and value of emicizumab and valoctocogene roxaparvovec for the management of hemophilia A without inhibitors.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Agboola, Rind, Herron-Smith, and Pearson are employed by ICER. Walton and Quach, through the University of Illinois at Chicago, received funding from ICER for development of the economic model described in this report.

Cost-effectiveness of oral semaglutide added to current antihyperglycemic treatment for type 2 diabetes.

BACKGROUND: Oral semaglutide is the first oral formulation of a glucagon-like peptide 1 (GLP-1) receptor agonist to be approved in the United States for glycemic control in people with type 2 diabetes mellitus (T2DM). While oral semaglutide is not indicated for reduction of cardiovascular event risk, its label does include evidence of no increase in cardiovascular risk in people who received oral semaglutide. OBJECTIVE: To estimate the incremental value of oral semaglutide added to existing antihyperglycemic treatment for people with T2DM with additional risk for cardiovascular disease. METHODS: We estimated the lifetime cost-effectiveness of oral semaglutide added to current antihyperglycemic treatment for T2DM using a microsimulation model based primarily on the UK Prospective Diabetes Study (UKPDS) Outcomes Model 2 (OM2) equations. Oral semaglutide added to current antihyperglycemic treatment was separately compared with (a) ongoing background antihyperglycemic treatment, (b) sitagliptin, (c) empagliflozin, and (d) liraglutide. Comparators sitagliptin, empagliflozin, and liraglutide were added to ongoing antihyperglycemic treatment. We applied hazard ratios derived from a network meta-analysis for cardiovascular and renal outcomes to the UKPDS OM2 estimated baseline rates. Health state utilities and costs were derived from the published literature. We estimated total costs, life-years (LYs), quality-adjusted life-years (QALYs), clinical events, and cost per major adverse cardiovascular event (MACE) avoided, over a lifetime time horizon using discount rates of 3% for costs and outcomes. RESULTS: The lifetime total cost for people treated with oral semaglutide was $311,300, with costs for the other comparators ranging from $262,800 (background treatment alone) to $287,800 (liraglutide). Oral semaglutide resulted in the fewest MACE, including the fewest cardiovascular deaths. Among the 5 modeled treatment strategies, oral semaglutide had the highest LYs gained (8.43 vs. 7.76 [background treatment alone] to 8.29 [empagliflozin and liraglutide]) and the highest QALYs gained (4.11 vs. 3.70 [background treatment alone] to 4.03 [empagliflozin]). Oral semaglutide would likely be considered cost-effective compared with liraglutide (incremental cost-effectiveness ratio [ICER] = $40,100), and moderately cost-effective versus background treatment alone ([ICER] = $117,500/QALY) and sitagliptin (ICER = $145,200/QALY). The ICER for oral semaglutide compared with empagliflozin was approximately $458,400 per QALY. CONCLUSIONS: As modeled, oral semaglutide as an add-on therapy to background antihyperglycemic treatment produced incremental benefits in MACE avoided, along with greater QALYs compared with background antihyperglycemic treatment alone. Oral semaglutide use resulted in better outcomes than background treatment alone or sitagliptin, and similar outcomes to liraglutide or empagliflozin with overlapping 95% confidence ranges for QALYs. Oral semaglutide was estimated to be cost-effective compared with liraglutide and to have incremental cost-effectiveness ratios between $100,000 and $150,000 per QALY versus sitagliptin and background therapy alone, but it did not meet these thresholds compared with empagliflozin. DISCLOSURES: Funding for this study was provided by the Institute for Clinical and Economic Review, an independent organization that evaluates the evidence on the value of health care interventions. ICER reports grants from Laura and John Arnold Foundation, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Rind, Fazioli, Chapman, and Pearson are employed by ICER. Guzauskas and Hansen have nothing to disclose. Study results were presented at the New England Comparative Effectiveness Public Advisory Council (New England CEPAC), November 14, 2019, at Brown University, Providence, RI.

The effectiveness and value of novel treatments for cystic fibrosis.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Seidner, Rind, and Pearson are employed by ICER. Tice reports contracts to his institution, University of California, San Francisco, from ICER during the conduct of this study. Wherry has nothing to disclose.