Adjusting starting points for initial price offers: the example of ibrutinib.

The Inflation Reduction Act of 2022 (IRA) allows the Medicare program to negotiate drug prices beginning in 2024. Based on the guidance in the statute, CMS has selected specific data items to use to adjust initial price offers for 10 drugs in the decision-making process. Although much of the data are publicly available, some of these data items will need to be collected directly from drug companies. A 2019 US House of Representatives Committee on Oversight and Accountability investigative report collected a wide range of data from manufacturers of 12 high-revenue drugs that show what is available from the drug companies, including development costs, marketing, pricing, competition, and patent status. This article focuses on the data obtained for ibrutinib, an oral medication for treating hematologic malignancies, which is one of the only drugs reviewed by the committee that also has been selected for Medicare price negotiation. We examine data that can be obtained only from the drug manufacturer that the IRA has explicitly identified as being used to determine the price and suggest potential negotiation strategies for CMS in response.

Humira: the first $20 billion drug.

AbbVie's adalimumab (Humira) is the top-selling pharmaceutical in the world. Due to concerns about government health program spending on Humira, the US House Committee on Oversight and Accountability opened an investigation in 2019 to investigate AbbVie's pricing and marketing practices. We review these reports and describe policy debates surrounding the highest-grossing drug to highlight how the legal landscape enables incumbent manufacturers to block competition in the pharmaceutical market. Tactics include patent thickets, evergreening, Paragraph IV settlement agreements, product hopping, and linking executive compensation to sales growth. These strategies are not unique to AbbVie and shed light on pharmaceutical market dynamics that may be hindering a competitive market. Policy reform and legal initiatives may help reduce anticompetitive behaviors by pharmaceutical manufacturers and increase access to competitive therapeutic options such as biosimilars.

Policing of Drug Safety Information Dissemination Under the False Claims Act.

On July 25, 2017, the second largest multi-million dollar settlement was pursued with the assistance of the Department of Justice and alleging inappropriate marketing strategies utilized by the pharmaceutical industry came to an end.

Medicare Spending on Drugs With Accelerated Approval.

BACKGROUND: The U.S. Food and Drug Administration provides accelerated approval to drugs on the basis of surrogate end points deemed to be "reasonably likely" to predict clinical benefit. To receive full approval, drugs must complete a confirmatory trial. Although most accelerated approved drugs ultimately receive full approval, others remain on the market without full approval for many years, and some are withdrawn before full approval is granted. Until confirmatory trials are completed and full approval is granted, there is uncertainty surrounding each drug's clinical benefits. OBJECTIVE: To estimate fee-for-service Medicare payments on accelerated approved drugs without full approvals. DESIGN: Cross-sectional analysis. SETTING: Fee-for-service Medicare Part B and Part D drug claims in 2019. PARTICIPANTS: Beneficiaries enrolled in Medicare Part B and Part D plans. MEASUREMENTS: Medicare spending for drugs treating accelerated approved indications without full approval, beneficiary spending, and drug characteristics. RESULTS: In 2019, 45 drugs associated with 69 accelerated approved indications lacked full approval. Of those, the fee-for-service Medicare program spent $1.2 billion on 36 drugs across 55 indications. Medicare beneficiaries had $209 million in out-of-pocket spending on these drugs. Oncology drugs represented 82% of these indications and 72% of the Medicare spending. Extrapolating to Medicare Advantage, total Medicare spending on these drugs in 2019 was $1.8 billion. LIMITATIONS: The study drugs may have clinical benefit and may come to receive full approval after this analysis. The algorithm used to identify accelerated approved indications is novel. Generalizability to other years is unclear. CONCLUSION: In 2019, fee-for-service Medicare spent $1.2 billion on accelerated approved drugs without full approval. Medicare should adjust incentives to encourage sponsors to complete confirmatory trials as soon as possible. PRIMARY FUNDING SOURCE: Laura and John Arnold Foundation.

A spatial assessment of prostate cancer mortality-to-incidence ratios among South Carolina veterans: 1999-2015.

PURPOSE: To assess veteran-specific prostate cancer (PrCA) mortality-to-incidence ratios (MIR) in South Carolina's (SC) veteran population. METHODS: U.S. Veterans Health Administration electronic medical records from January 1999 to December 2015 identified 3,073 PrCA patients residing in 345 ZIP code tabulation areas (ZCTA) within SC. MIRs were calculated for all SC ZCTAs and by key patient- and neighborhood-level risk factors for PrCA. Comparisons between ZCTAs identified as part of a spatial cluster were compared with non-significant ZCTAs using t tests. RESULTS: The MIR was 0.17 overall, ranging from a low of 0.15 among Black men to 0.20 among White men. Among metropolitan ZCTAs, the MIR was 0.18 compared to 0.16 in non-metropolitan ZCTAs. Two clusters of higher-than-expected MIRs were found in the Upstate region. CONCLUSIONS: Identification of spatial clusters of higher- or lower-than-expected MIRs allows for further testing of possible explanatory factors, and the capacity to target resources and policies according to greatest need.

The First 2 Years of Biosimilar Epoetin for Cancer and Chemotherapy-Induced Anemia in the U.S.: A Review from the Southern Network on Adverse Reactions.

Biosimilars are biologic drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety, and efficacy. Biosimilar epoetin received Food and Drug Administration (FDA) approval in 2018. The manufacturer received an FDA nonapproval letter in 2017, despite receiving a favorable review by FDA's Oncologic Drugs Advisory Committee (ODAC) and an FDA nonapproval letter in 2015 for an earlier formulation. We discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review, and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labeling, substitution, interchangeability, and pharmacovigilance; review European and U.S. oncology experiences with biosimilar epoetin; and review the safety of erythropoiesis-stimulating agents. In 2020, policy statements from AETNA, United Health Care, and Humana indicated that new epoetin oncology starts must be for biosimilar epoetin unless medical need for other epoetins is documented. Empirical studies report that as of 2012, reference epoetin use decreased from 40%-60% of all patients with cancer with chemotherapy-induced anemia to <5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer's patients covered by Medicare whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer's patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California, and with yet-to-be-reported data from most oncology settings. We conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the U.S. is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake. IMPLICATIONS FOR PRACTICE: Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market, and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists.

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions.

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.

Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada.

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

Why Biologics and Biosimilars Remain So Expensive: Despite Two Wins for Biosimilars, the Supreme Court's Recent Rulings do not Solve Fundamental Barriers to Competition.

Biologics and biosimilars are medicines made from living cells that treat common and serious diseases such as cancer, diabetes, rheumatoid arthritis, and other inflammatory diseases. They are highly targeted, efficacious, and represent an increasingly important part of physicians' armamentaria in the combat against these medical conditions. Yet they are extremely expensive, costing on average $10,000-$30,000 per year and exceed $500,000 for the most expensive biologics. The advent of biosimilar drugs, or high similar copies of biologics, was supposed to help reduce costs, but thus far the cost of treatment with biologics or biosimilars has not fallen sharply in the USA. We argue that a primary hurdle is the extent of patent protection for the reference biologics that impedes greater numbers of biosimilars entering into the market. To date, of the 12 biosimilars approved for marketing by the US Food and Drug Administration (FDA), only five are commercially available. All but one of the remaining biosimilars are withheld from commercialization due to patent disputes. We argue that the market for biologics and biosimilars will become price competitive only if more biosimilars are available to patients. To this end, the process to eliminate marginally inventive patents held by the reference drug makers must be streamlined and improved. In this perspective article, we suggest actions to improve the pre-FDA approval patent resolution process known as the patent dance, the streamlined patent invalidation process known as Inter Partes Reviews, and the process of granting patents.

Tale of Two Erythropoiesis-Stimulating Agents: Utilization, Dosing, Litigation, and Costs of Darbepoetin and Epoetin Among South Carolina Medicaid-Covered Patients With Cancer and Chemotherapy-Induced Anemia.

PURPOSE: The US Food and Drug Administration (FDA) has approved epoetin and darbepoetin for chemotherapy-induced anemia (CIA). Approved epoetin and darbepoetin dosing schedules were three times per week and weekly, respectively, although off-label, less frequent scheduling was common. In 2004, 2007, and 2008, a US Food and Drug Administration Advisory Committees warned of risks associated with erythropoiesis-stimulating agents. During this period, lawsuits alleging illegal darbepoetin marketing practices have concluded, resulting in $1.1 billion in fines and settlements and one criminal conviction. No prior study, to our knowledge, has reported on the use of darbepoetin versus epoetin for CIA. METHODS: We evaluated the dosing, utilization, and costs of erythropoiesis-stimulating agents among 3,761 South Carolina Medicaid patients with CIA. RESULTS: Epoetin and darbepoetin utilization rates were 22% and 28% in 2003, 10% and 33% in 2007, and 3% and 7% in 2010, respectively. Mean per-patient per-administration epoetin and darbepoetin doses were 40,983 IU and 191 µg, respectively, in 2003 and 47,753 IU and 369 µg, respectively, in 2010. Mean monthly patient costs for epoetin and darbepoetin were $1,030 and $981, respectively, in 2003 and $932 and $1,352, respectively, in 2010. Epoetin use decreased steadily between 2002 and 2010; darbepoetin use increased steadily between 2003 and 2007 and then decreased steadily thereafter. Per-patient dosing of darbepoetin, but not epoetin, increased steadily between 2003 and 2010, and monthly per-patient epoetin costs decreased 3% while the per-patients costs of darbepoetin increased 30% between 2003 and 2010. CONCLUSION: To our knowledge, our findings are the first data reporting on epoetin versus darbepoetin use for CIA and support recently concluded lawsuits involving allegations of illegal marketing practices of the manufacturer of darbepoetin.

Effects of the US Food and Drug Administration Boxed Warning of Erythropoietin-Stimulating Agents on Utilization and Adverse Outcome.

Purpose In March 2007, a US Food and Drug Administration boxed warning was issued for erythropoietin-stimulating agents (ESAs) regarding serious adverse events, such as venous thromboembolism (VTE). We evaluated the US Food and Drug Administration's boxed warning of ESAs used to treat chemotherapy-induced anemia because evidence on the effectiveness of boxed warnings remains inconclusive. Patients and Methods Using 2004 to 2009 SEER-Medicare data, we exploited a natural experiment to examine the effects of ESA boxed warnings on utilization and risk of VTE. The intervention group included Medicare fee-for-services patients diagnosed with colorectal, breast, or lung cancers targeted by this warning and undergoing chemotherapy; the control group included patients with myelodysplastic syndromes not targeted by this warning. The period from January 2004 to September 2006 was used as the prewarning period; the period from April 2007 to September 2009 was used as the postwarning period. The two binary dependent variables included ESA use and hospitalized VTE. Linear probability models with a difference-in-differences specification were used for estimation. Results Our sample consisted of 45,319 unique patients between 2004 and 2009. The trends in ESA use remained similar between the intervention and control groups before the warning, but started declining sharply in the intervention group only after the warning. The trends in hospitalized VTE were relatively stable. Regressions showed that the ESA boxed warning was associated with a 20.2-percentage-point reduction ( P < .001) in the likelihood of ESAs being used to treat cancers targeted by the warning, but not significantly associated with the likelihood of hospitalized VTE. Conclusion Our study showed that the warning was effective in reducing ESA utilization. Future studies should examine other regulatory drug safety actions, such as the Risk Evaluation and Mitigation Strategy initiative, whose effectiveness remains unknown.

Types of oral contraceptives and breast cancer survival among women enrolled in Medicaid: A competing-risk model.

INTRODUCTION: Oral contraceptive pills have been implicated in the pathophysiology of breast cancer. Although many studies have examined the relationship between combined oral contraceptives (COCs) and breast cancer, there is a paucity of literature that discusses progestin-only oral contraceptives (POCs) and breast cancer. The purpose of this investigation is to examine potential associations between different types of oral contraceptives and breast cancer mortality in the South Carolina Medicaid population among different racial/ethnic groups. METHODS: Subjects included 4816 women diagnosed with breast cancer between 2000 and 2013. Kaplan-Meier curves were calculated to determine time-to-mortality rates among users of oral contraceptives. Competing-risks models and Cox multivariate survival models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer and other-cause mortality, as well as all-cause mortality. RESULTS: POCs were associated with a significantly decreased risk of breast cancer mortality (HR: 0.07; 95% CI: 0.01, 0.52) and a non-significant increased risk of all-cause mortality (HR: 1.04; 95% CI: 0.52, 2.07). COCs increased the risk of breast cancer mortality (HR: 1.61; 95% CI: 1.14, 2.28) and all-cause mortality (HR: 1.83; 95% CI: 1.30, 2.57). CONCLUSION: Use of POCs may be associated with a decreased risk of breast cancer mortality. Due to the small sample size of POC users in the current study, additional research is needed to confirm these findings.

Generic oncology drugs: are they all safe?

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.