Clinical Evidence Supporting FDA Approval of Gene and RNA Therapies for Rare Inherited Conditions.

BACKGROUND: Gene and RNA therapies have potential to transform the treatment of rare inherited diseases, but there are concerns about the evidence supporting their use and high costs. OBJECTIVE: We analyze the evidence supporting Food and Drug Administration (FDA) approval of gene and RNA therapies for rare inherited diseases and discuss implications for clinical practice and policy. METHODS: We conducted a qualitative analysis of FDA documents outlining the basis of approval for gene and RNA therapies approved for rare inherited diseases between 2016 and 2023. For each drug, we gathered five characteristics of the evidence supporting FDA approval (no phase 3 trial, nonrandomized, no clinical endpoint, lack of demonstrated benefit, and significant protocol deviation) and four characteristics of the FDA approval process (prior rejection or complete response, negative committee vote, discrepancy between label and trial population, and boxed warning). The main outcome was the number of drugs with each characteristic. RESULTS: Between 2016 and 2023, 19 gene and RNA therapies received FDA approval to treat rare inherited diseases. The most common limitations in the evidence supporting approval of these drugs were nonrandomized studies (8/19, 42%), no clinical endpoint (7/19, 37%), lack of demonstrated benefit or inconsistent results (4/19, 21%), and no phase 3 trial (4/19, 21%). Half (3/6) of accelerated approvals and 57% (5/9) of drugs with breakthrough designation had nonrandomized trials, and gene therapies with one-time dosing were overrepresented (5/7, 71%) among the drugs with nonrandomized trials. Five of six accelerated approvals (83%) and five of nine pediatric drugs (56%), most of which were indicated for Duchenne muscular dystrophy, had no clinical endpoint. Four of nine (44%) pediatric drugs and four of six (67%) accelerated approvals failed to demonstrate benefit compared with none of the nonpediatric drugs and none of the traditional approvals. Five drugs, which all had different indications and represented a mix of RNA and gene therapies, did not have any of these evidence characteristics. Among drugs that received prior rejections or negative committee opinions, all four had nonrandomized trials and lacked a clinical endpoint, and 75% (3/4) lacked demonstrated benefit. Five of nine (56%) pediatric drugs were indicated for broader age groups according to the drug label compared with the trial populations. Of the three drugs with boxed warnings, two had pediatric indications and nonrandomized studies, and one had no phase 3 trial. CONCLUSIONS: Issues related to trial design, outcome, and data integrity in the evidence supporting FDA approval of rare inherited disease gene and RNA therapies raise questions about whether this evidence is adequate to inform prescribing decisions. Gene and RNA therapies with accelerated approval and pediatric indications were overrepresented among drugs lacking clinical endpoints or demonstrated benefit and should be the focus of efforts to reduce uncertainty in the evidence.

Medicaid spending and utilization of gene and RNA therapies for rare inherited conditions.

Gene and RNA therapies are promising treatments for many rare diseases. Pediatric populations that could benefit from these drugs are overrepresented among state Medicaid programs. Using Medicaid State Drug Utilization Data, we examined Medicaid spending and utilization of rare disease gene and RNA therapies. Between 2017 and 2022, the number of available gene and RNA therapies increased from 3 to 13, yearly Medicaid spending increased from $148.3 million to $879.7 million, and the number of yearly treatments (a proxy for number of patients) increased from 327 to 1638. Nearly all spending was attributed to spinal muscular atrophy (SMA) and Duchenne muscular dystrophy drugs. States participating in Medicaid pooled purchasing initiatives had 39% higher treatments per 100 000 enrollees with no differences in spending. Compared to states without a carve-out, states that carved SMA drugs out of managed Medicaid contracts had higher utilization (54%). Spending among carve-out states varied according to managed care enrollment, being higher for those with <80% of enrollees in managed care as compared with those with ≥80% of enrollees in managed care. This suggests that multi-state purchasing initiatives and managed care carve-outs can help increase access to gene and RNA therapies among Medicaid beneficiaries, but it is unclear if these strategies are effective at managing spending.

Global Production of Active Pharmaceutical Ingredients for US Generic Drugs Experiencing Shortages.

This study evaluates the characteristics of generic active pharmaceutical ingredients (APIs) used to manufacture drugs with shortages in the US and facilities producing APIs worldwide.

Exploring the Influence of Health Insurance Plans on Biosimilar Adoption Rates.

BACKGROUND: We conducted a study to investigate the role of health insurance plans on biosimilar adoption among commercially insured patients in the USA. Flexible and rigid health plans may exhibit differing biosimilar coverage due to variations in cost considerations, formulary design, and provider networks. OBJECTIVE: To identify the characteristics of switchers and biosimilar initiators for six biologic-biosimilar pairs. METHODS: Using claims data from 2015 to 2019, we implement sequential regression models to assess the role of health plans on biosimilars adoption. FINDINGS: We found that low-flexibility plans, such as Health Maintenance Organization (HMOs) and Exclusive Provider Organization (EPOs), are more likely to have patients who are switchers and/or biosimilar initiators. CONCLUSION: Our findings highlight the importance of health insurance plan design in promoting biosimilar uptake.

Ownership and Interoperability Challenges of Alzheimer Monoclonal Antibody Registries.

This Viewpoint addresses the challenges that the Centers for Medicare and Medicaid Services faces to collect real-world data on the effectiveness and safety of lecanemab from external registries to achieve its coverage with evidence development objectives.

Spending on Dual Over-the-Counter and Prescription Drugs in the Medicare Part D Program.

This study compares Medicare and patient spending for dual over-the-counter and prescription drugs with their over-the-counter cash prices.

Role of Registries in Medicare Coverage of New Alzheimer Disease Drugs.

This Viewpoint discusses how the design of the Centers for Medicare & Medicaid Services (CMS) registry could impact Medicare's ability to evaluate whether monoclonal antibodies are reasonable and necessary for patients with Alzheimer disease and help physicians understand when the drug is most beneficial.

Incorporating Added Therapeutic Benefit and Domestic Reference Pricing Into Medicare Payment for Expensive Part B Drugs.

OBJECTIVES: Identify expensive Part B drugs and evidence for each drug's added benefit and model a reimbursement policy for Medicare that integrates added benefit assessment and domestic reference pricing. METHODS: A retrospective analysis using a 20% nationally representative sample of 2015 to 2019 traditional Medicare Part B claims. Expensive drugs were defined as having average annual spending per beneficiary exceeding the average annual social security benefit ($17 532 in 2019). For expensive drugs identified in 2019, added benefit assessments conducted by the French Haute Autorité de Santé were collected. For expensive drugs with a low added benefit rating, comparator drugs were identified in French Haute Autorité de Santé reports. For each comparator, average annual spending per beneficiary in Part B was computed. Potential savings from 2 reference pricing scenarios were calculated: reimbursing expensive Part B drugs with low added benefit at the level of each drug's (1) lowest cost comparator and (2) beneficiary-weighted-average cost of all comparators. RESULTS: The number of expensive Part B drugs grew from 56 in 2015 to 92 in 2019. Of the 92 expensive drugs in 2019, 34 offer low added benefit. Implementing reference pricing for these expensive drugs with low added benefit could have saved an estimated $2.1 billion if prices were set based on spending for their lowest cost comparator, or $1 billion if prices were set based on the weighted average of spending for comparators. CONCLUSION: Reference pricing based on added benefit assessment could be used to address the launch prices for expensive Part B drugs with low added benefit.

Estimating Changes in Medicare Part D and Commercial Insurer Insulin Spending Amid Planned State-Led Biosimilar Insulin Production in California.

This cross-sectional study evaluates the cost savings of state-led manufacturing and selling of biosimilar insulin.

Cancer Outcomes Among Prediabetes and Type 2 Diabetes Populations With Dietary and Physical Activity-based Lifestyle Interventions.

CONTEXT: People with type 2 diabetes (T2D) have higher risks of cancer incidence and death. OBJECTIVE: We aimed to evaluate the relationship between dietary and physical activity-based lifestyle intervention and cancer outcomes among prediabetes and T2D populations. METHODS: We searched for randomized controlled trials with at least 24 months of lifestyle interventions in prediabetes or T2D populations. Data were extracted by pairs of reviewers and discrepancies were resolved by consensus. Descriptive syntheses were performed, and the risk of bias was assessed. Relative risks (RRs) and 95% CIs were estimated using a pairwise meta-analysis with both a random-effects model and a general linear mixed model (GLMM). Certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation framework, and trial sequential analysis (TSA) was conducted to assess if current information is enough for definitive conclusions. Subgroup analysis was performed by glycemic status. RESULTS: Six clinical trials were included. Among 12 841 participants, the combined RR for cancer mortality comparing lifestyle interventions with usual care was 0.94 (95% CI, 0.81-1.10 using GLMM and 0.82-1.09 using random-effects model). Most studies had a low risk of bias, and the certainty of evidence was moderate. TSA showed that the cumulative Z curve reached futility boundary while total number did not reach detection boundary. CONCLUSION: Based on the limited data available, dietary and physical activity-based lifestyle interventions had no superiority to usual care on reducing cancer risk in populations with prediabetes and T2D. Lifestyle interventions focused on cancer outcomes should be tested to better explore their effects.

Competition And Vulnerabilities In The Global Supply Chain For US Generic Active Pharmaceutical Ingredients.

The US supply of generic drugs is heavily dependent on the global supply chain for sources of generic active pharmaceutical ingredients (APIs) for the US pharmaceutical market. Data from Clarivate Analytics' Cortellis Generics Intelligence database were analyzed to perform a systematic examination of generic APIs produced globally for the US market during 2020-21. We identified a total of 565 facilities producing 1,379 unique generic APIs across forty-two countries. India, China, and Italy were the top producers; 14 percent of APIs were manufactured in the US. About a third of APIs were manufactured by a single facility, and another third were manufactured by two or three facilities. More than one in every five APIs reflected markets in which current Food and Drug Administration standards would have failed to detect low competition because there were three or fewer API manufacturers despite there being four or more manufacturers of finished generic drugs. Monitoring the API supply is crucial to identifying vulnerabilities in the US pharmaceutical supply chain and identifying drugs that could represent potential priorities for domestic production. Incentives in the US may be needed to support API production to safeguard against supply-chain disruptions.

Developing Prioritization Criteria to Identify Target Drugs for CalRx, the California Generic Drugs Initiative.

OBJECTIVES: This study aimed to establish criteria to identify priority drugs for CalRx, a California-sponsored initiative to support the manufacture and distribution of affordable generic drugs. METHODS: A web-based ranking exercise was implemented with key stakeholders in August 2020, using pricing, spending, and public health criteria identified through a review of academic literature and public health agency reports. A total of 39 of 40 invited stakeholders in 4 different categories-patient advocates, healthcare providers, health insurers, and health policy and economic experts-participated in this study (98% response rate). RESULTS: Drugs that treat large populations, drugs that represent high cost to payors, and drugs that represent high cost to consumers were ranked a priority, receiving > 10% of ranking weights. Drugs that treat conditions with high morbidity or mortality, drugs without therapeutic alternatives, and drugs treating vulnerable populations represented criteria of further interest (9%-10% of weights). Shortage risk and curative effect (8%-9% of the weights), high price increases, communicable disease treatments, and high unit prices (< 8% of the weights) represented the bottom of the priority distribution. CONCLUSIONS: This study suggests that drugs that treat large populations, drugs that represent large costs to payors, and drugs that represent large costs to consumers should be the priority for California's CalRx generic drug initiative. A prioritizing algorithm will assist California in determining top drugs to target from a public health and spending perspective as it plans the rollout of the CalRx initiative and negotiates with drug manufacturers.

Estimating Savings Opportunities From Therapeutic Substitutions of High-Cost Generic Medications.

Importance: Use of generics is generally understood as a cost-saving practice. However, pharmacy benefit managers have an incentive to place higher-priced generic drugs on insurers' drug formularies to profit by creating a large difference between the price negotiated with pharmacies and the price paid by insurers (what is known as spread pricing). Objective: To examine price differentials and savings potential between high-cost generics and corresponding therapeutic alternatives of same clinical value and lower cost. Design, Setting, and Participants: This cross-sectional analysis examined the top 1000 generics in Colorado's all-payer claims database (CO-APCD) in 2019. High-cost generics and lower-cost generic therapeutic alternatives of same clinical value constituted the study sample. Data were analyzed from January 2019 to December 2019. Exposures: Generic drug prices measured by transaction prices, average wholesale price (AWP), and national drug acquisition average cost (NADAC). Main Outcomes and Measures: Price differentials between the high-cost generics and the corresponding therapeutic alternatives. Levels of discounts and savings that could be achieved if the high-cost generics had been substituted by their therapeutic alternatives. Results: This cross-sectional study of the top 1000 CO-APCD generics identified 45 high-cost products that had lower-cost therapeutic alternatives of same clinical value. Overall, high-cost generics were 15.6 times more expensive than their therapeutic alternatives (median values). If the lower-cost alternatives had been used, total spending would have been reduced from $7.5 million to $873 711, resulting in 88.3% savings. Most substitutions (28 of 45 [62.2]%) involved different dosage forms or different strengths of the same drug and provided mean (SD) discounts of 94.9% (3.8%) and 77.1% (19.9%), respectively. Conclusions and Relevance: In this study, replacing high-cost generics with lower-cost alternatives of same clinical value would produce savings of nearly 90%. Plan sponsors should be aware that some generics are associated with higher spending and should periodically review the specific products driving their generic drug spending. Substitution of high-cost generics may provide a simple pathway to offer the same therapeutic benefit at lower cost to patients and insurers.

The price paradox of biosimilar-like long-acting insulin.

OBJECTIVES: To describe the uptake and out-of-pocket (OOP) costs of Basaglar, the first long-acting insulin biosimilar, in a commercially insured population in the United States. STUDY DESIGN: Retrospective analysis of commercial pharmacy claims and pharmacy co-payment offsets. METHODS: We assessed Basaglar uptake by examining trends in the composition of the long-acting insulin market in the United States from 2014 to 2018. As patient demographics and plan type may be important determinants of biosimilar uptake, we also assessed characteristics of all long-acting insulin users by drug. We examined Basaglar OOP costs by assessing mean OOP costs per claim for users of Basaglar and other long-acting insulins, overall and by plan type, and the number and source of co-payment offsets for Basaglar and other insulin glargine products from Basaglar market entry through 2018. We used multivariate linear models to examine the relationship between Basaglar OOP expenditures and insurer-negotiated amounts, overall and by plan type. RESULTS: Basaglar experienced a rapid uptake. However, there was no evidence that Basaglar users had lower OOP costs than reference product (Lantus) users. CONCLUSIONS: Given our results and the approval of the first interchangeable biosimilar, we recommend the empirical evaluation of biosimilar cost savings to patients and insurers prior to promoting their automatic substitution.

Trends of Prescription Drug Manufacturer Rebates in Commercial Health Insurance Plans, 2015-2019.

This economic evaluation examines the magnitude and trend of prescription drug rebates in commercial markets from 2015 to 2019 and identifies insurance plan factors associated with rebates.