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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.

Background Treatment variation from observational data has been used to estimate patient-specific treatment effects. Causal Forest Algorithms (CFAs) developed for this task have unknown properties when treatment effect heterogeneity from unmeasured patient factors influences treatment choice – essential heterogeneity . Methods We simulated eleven populations with identical treatment effect distributions based on patient factors. The populations varied in the extent that treatment effect heterogeneity influenced treatment choice. We used the generalized random forest application (CFA-GRF) to estimate patient-specific treatment effects for each population. Average differences between true and estimated effects for patient subsets were evaluated. Results CFA-GRF performed well across the population when treatment effect heterogeneity did not influence treatment choice. Under essential heterogeneity, however, CFA-GRF yielded treatment effect estimates that reflected true treatment effects only for treated patients and were on average greater than true treatment effects for untreated patients. Conclusions Patient-specific estimates produced by CFAs are sensitive to why patients in real-world practice make different treatment choices. Researchers using CFAs should develop conceptual frameworks of treatment choice prior to estimation to guide estimate interpretation ex post .

Background Comparative effectiveness research (CER) using observational databases has been suggested to obtain personalized evidence of treatment effectiveness. Inferential difficulties remain using traditional CER approaches especially related to designating patients to reference classes a priori. A novel Instrumental Variable Causal Forest Algorithm (IV-CFA) has the potential to provide personalized evidence using observational data without designating reference classes a priori, but the consistency of the evidence when varying key algorithm parameters remains unclear. We investigated the consistency of IV-CFA estimates through application to a database of Medicare beneficiaries with proximal humerus fractures (PHFs) that previously revealed heterogeneity in the effects of early surgery using instrumental variable estimators. Methods IV-CFA was used to estimate patient-specific early surgery effects on both beneficial and detrimental outcomes using different combinations of algorithm parameters and estimate variation was assessed for a population of 72,751 fee-for-service Medicare beneficiaries with PHFs in 2011. Classification and regression trees (CART) were applied to these estimates to create ex-post reference classes and the consistency of these classes were assessed. Two-stage least squares (2SLS) estimators were applied to representative ex-post reference classes to scrutinize the estimates relative to known 2SLS properties. Results IV-CFA uncovered substantial early surgery effect heterogeneity across PHF patients, but estimates for individual patients varied with algorithm parameters. CART applied to these estimates revealed ex-post reference classes consistent across algorithm parameters. 2SLS estimates showed that ex-post reference classes containing older, frailer patients with more comorbidities, and lower utilizers of healthcare were less likely to benefit and more likely to have detriments from higher rates of early surgery. Conclusions IV-CFA provides an illuminating method to uncover ex-post reference classes of patients based on treatment effects using observational data with a strong instrumental variable. Interpretation of treatment effect estimates within each ex-post reference class using traditional CER methods remains conditional on the extent of measured information in the data.

Background Individuals dually eligible for Medicare and Medicaid coverage are among the sickest patients in the United States. Prior literature has identified a lack of care coordination or even conflicts of interest between the two programs as barriers to more efficient care and better health outcomes among dual-eligibles. The purpose of this study is to assess characteristics of dual eligibles who participated in South Carolina’s 2015 voluntary Medicare-Medicaid financial alignment demonstration project, and to evaluate whether their participation led to better observable health outcomes. Methods We obtained all inpatient and emergency department visits, and all Medicaid outpatient visits of individuals identified as Medicare-Medicaid dual eligibles from 2011 to 2016 from South Carolina’s Revenue and Fiscal Affairs Office. We employed logistic regressions to assess the characteristics of participants and quitters in the Medicare-Medicaid financial alignment demonstration project. To evaluate the impact of participation on health outcomes, we used an event study analysis that examines trends in outcomes over time, with participation in the demonstration project as the triggering event, and a difference-in-differences methodology that compares changes in health outcomes before and after participation in the demonstration project compared with a control group. Results Urban patients, female patients, and patients with heart problems, social and mental disorders, and importantly, patients with multiple comorbidities (as indicated by a higher Charlson comorbidity index) are less likely to join South Carolina’s demonstration project. Once having joined, female patients and patients with a higher Charlson index appear to be more likely to quit. Those who joined did not appear to enjoy better health outcomes in the short time frame. Conclusions Policy makers should explore and address reasons why dual eligibles with complex health problems hesitate to join the alignment project, and continue to monitor whether such a program improves health given that a prolonged period of exposure to the program may be required to achieve better health among the nation’s most vulnerable patients.

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.

The United States Constitution protects the right of citizens to petition the government for \"a redress of grievances.\" This right has important implications for citizens desiring to advance the public health by petitioning administrative agencies, such as the Food and Drug Administration, to take safety actions. We examined a total of 1,915 petitions filed between 2001 and 2013 to investigate the outcomes of citizen petitions that address public health concerns. We found that most petitions were filed by manufacturers against other manufacturers. Only 346 (18%) of all petitions were submitted by individuals and non-profit organizations, and 178 (87.3%) of these petitions with a final response were denied. On average, these petitions required 2.85 years for a final agency decision, and many decisions remain pending 10-13 years after their initial submission. The great majority of the approved requests included some form of risk communication, such as labeling changes, boxed warnings or placement of a drug into a Risk Evaluation and Mitigation Strategy. As a policy instrument to improve the safety of medical and food products, the citizen petition process requires sophisticated legal and scientific expertise, and may not represent a viable route for ordinary citizens to petition the FDA to \"redress grievances.\"

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.

As clinical trials adopt remote methodologies, there is need to optimize efficiency of remote enrollment. Within a remote clinical trial, we aim to (1) assess if sociodemographic factors differ among those consenting via mail vs. technology-based procedures (e-consent), (2) determine if, among those consenting via mail, a small unconditional monetary reward ($5) increases likelihood of subsequent enrollment, (3) economically evaluate additional cost per additional participant enrolled with $5 reward. In the parent nationwide randomized clinical trial of adult smokers ( = 638), participants could enroll via mail or e-consent. Logistic regression models assessed relationships between sociodemographics and enrollment via mail (vs e-consent). Mailed consent packets were randomized (1:4) to include $5 unconditional reward or not, and logistic regression modeling examined impact of reward on subsequent enrollment, allowing for a randomized study within a study. Incremental cost-effectiveness ratio analysis estimated additional cost per additional participant enrolled with $5 incentive. Older age, less education, lower income, and female sex predicted enrolling via mail vs e-consent ( < .05's). In adjusted model, older age (AOR = 1.02, = .016) and less education (AOR = 2.23, < .001) remained predictive of mail enrollment. The $5 incentive (vs none) increased enrollment rate by 9% (AOR = 1.64, = .007), with estimated cost of additional $59 per additional participant enrolled. As e-consent methods become more common, they have potential to reach many individuals but with perhaps diminished inclusion across all sociodemographic groups. Provision of an unconditional monetary incentive is possibly a cost-effective mechanism to increase recruitment efficiency for studies employing mail-based consenting procedures.

Background: In this cohort study, we investigated whether a diagnosis of herpes zoster (HZ) was associated with a higher risk of subsequent cancer as compared with the Taiwanese general population. Methods: Data were obtained from the Taiwan National Health Insurance Research Database. In total, 38 743 patients who were aged 50 years or older and had received ambulatory care for HZ between 1997 and 2006 were identified as the study cohort; 116 229 age- and sex-matched patients without HZ were included as the comparison cohort. We used Cox proportional hazards regression models to estimate the hazard ratios (HRs) for subsequent cancer, after controlling for potential confounders. Results: The HR for subsequent cancer varied according to time since HZ diagnosis. The HR was 1.58 (95% CI, 1.38-1.80) within the first year, 1.30 (95% CI, 1.15-1.46) between 1 and 2 years, 1.10 (95% CI, 0.98-1.24) between 2 and 3 years, 1.02 (95% CI, 0.91-1.15) between 3 and 4 years, and 1.08 (95% CI, 0.96-1.21) between 4 and 5 years. The risk of subsequent cancer, particularly lung cancer, was significantly higher during the first 2 years after initial diagnosis of HZ. Conclusions: Our findings suggest that an HZ diagnosis is a marker of occult malignancy, particularly in lung cancer. The HRs for cancer decreased gradually over time and were no longer significant after 2 years of follow-up, which indicates that the association between HZ and cancer is likely due to detection bias.[PUBLICATION ABSTRACT]

[...]in the USA, 80% of reports on adverse event reported to the FDA's online database for the first three quarters of 2015 were for brand-name cancer medications, despite the high level of generic oncology pharmaceutical penetration.2 Nevertheless, quality concerns for generic oncology drugs (and more so for oncology biosimilars, which are not exact copies of the reference drug) exist in developing countries where oversight is less intensive.2,3 Measures to prevent counterfeit and substandard oncology generics in these countries should be rigorously monitored.