Paucity of intellectual property rights information in the US biologics system a decade after passage of the Biosimilars Act.

In this Policy Forum piece, Robin Feldman discusses how current legislation contributes to informational deficits around drug patents for biologic drugs in the United States.

Cerebral palsy pain instruments: Recommended tools for clinical research studies by the National Institute of Neurological Disorders and Stroke Cerebral Palsy Common Data Elements project.

AIM: This study describes the process of updating the cerebral palsy (CP) common data elements (CDEs), specifically identifying tools that capture the impact of chronic pain on children's functioning. METHOD: Through a partnership between the American Academy for Cerebral Palsy and Developmental Medicine and the National Institute of Neurological Disorders and Stroke (NINDS), the CP CDEs were developed as data standards for clinical research in neuroscience. Chronic pain was underrepresented in the NINDS CP CDEs version 1.0. A multi-step methodology was applied by an interdisciplinary professional team. Following an adapted CP chronic pain tools' rating system, and a review of psychometric properties, clinical utility, and compliance with inclusion/exclusion criteria, a set of recommended pain tools was posted online for external public comment in May 2022. RESULTS: Fifteen chronic pain tools met inclusion criteria, representing constructs across all components of the International Classification of Functioning, Disability and Health. INTERPRETATION: This paper describes the first condition-specific pain CDEs for a pediatric population. The proposed set of chronic pain tools complement and enhance the applicability of the existing pediatric CP CDEs. The novel CP CDE pain tools harmonize the assessment of chronic pain, addressing not only intensity of chronic pain, but also the functional impact of experiencing it in everyday activities.

Leading with the trailing edge: facilitating patient choice for insulin products.

Insulin prices have risen sharply, despite a century since its introduction. Against this backdrop, companies have discontinued dozens of insulin products. Discontinuation could relate to safety or effectiveness, or to the overwhelming benefits of newer products. On the other hand, discontinuation could suggest strategic behavior hampering competition and supporting prices. To test these theories, this project examined every insulin discontinuation, analyzing the role discontinuations play in insulin affordability. No evidence emerged of any discontinuation for safety or effectiveness. Rather, dozens of viable products were removed from the market, followed by more expensive versions, often with little or no clinical improvement. Insulin pens with a phone app may provide advantages, for example. However, for older patients, who may find the technology confusing, or for patients with budget constraints, the value proposition falters. Moreover, discontinuation blocks biosimilars from market entry because they cannot demonstrate biosimilarity without the drug. The problem exists for all biosimilars. If there are willing buyers and willing sellers of clinically effective products that are off-patent, entry should be facilitated. This article suggests a requirement that companies deposit samples at the time of FDA approval, laying the groundwork for later entry of trailing-edge products with clinically viable outcomes.

CalRx Biosimilar Insulin: California's Initiative to Enter the Insulin Market.

This viewpoint evaluates California's CalRx Biosimilar Insulin Initiative, which aims to address insulin affordability by offering less expensive alternatives to existing products, specifically targeting patients with insulin-dependent diabetes.

NIH Licensing Would Benefit from Free-Market Provisions.

Government encouragement of free markets is a highly effective means of fostering pharmaceutical innovation; the NIH, by including "free-market provisions" in its licensing agreements that discourage anti-competitive and research-impeding behavior, can do a great deal to support this goal even without legislative overhaul.

Challenges with Defining Pharmaceutical Markets and Potential Remedies to Screen for Industry Consolidation.

CONTEXT: Dramatic increases in pharmaceutical merger and acquisition (M&A) activity since 2010 suggest we are in the midst of a third wave of industry consolidation. METHODS: The authors reviewed 168 economic, legal, medical, industry, and government sources to examine the effects of consolidation on competition and innovation and to explore how industry attributes complicate M&A regulation in a pharmaceutical context. FINDINGS: The authors find that, in spite of certain metrics that might argue otherwise, consolidation consistently reduces innovation and harms the public good. They also find that several factors within the pharmaceutical industry impede proper evaluation of proposed mergers. Because consumer choice across substitutes is limited, pharmaceutical markets frustrate conventional methods of defining markets. Volume bargaining in the pharmaceutical supply chain and asset managers' common ownership of pharmaceutical firms further complicate the definitional process. Hence, the Herfindahl-Hirschman Index (HHI), one measure used by the Federal Trade Commission and the Department of Justice to screen for concerning M&A activity, sometimes depends on faulty market definitions and fails to capture the implications of consolidation for future market share. CONCLUSIONS: The authors describe ways to improve how pharmaceutical markets are defined, highlight quantitative alterations to HHI to account for common ownership, and propose areas requiring further research.

Understanding 'Evergreening': Making Minor Modifications Of Existing Medications To Extend Protections.

Recent studies have examined strategic behaviors in the pharmaceutical industry that extend patent and regulatory protection, known alternatively as "lifecycle management" or "evergreening." This literature highlights the extent to which the patent system is increasingly focused on granting new protections for minor modifications of existing innovations. The phenomenon raises questions regarding the value of the trend to society and its potential effects on innovation. Specifically, is there value in tinkering with existing medication, and does that value justify the extensive rewards available with a "golden" patent? Could aspects of the current system be distorting how companies choose to spend their precious innovation time and money? As a society, we may decide that certain parts of the system are valuable and that others require reform, but we cannot make any considered evaluation without understanding how the system works on the ground.

The devil in the tiers.

Prescription drug spending in the USA has soared, fueled by rising drug prices. A critical mechanism for restraining drug prices is the formulary tiering system. Although tiering should reflect the cost of a drug-and reward patients who choose less-expensive drugs-something is seriously amiss. Using Medicare claims data from roughly one million patients between 2010 and 2017, this article finds troubling amounts of distorted tiering and wasted cost. Increasingly, generics are shifted to more expensive-and therefore less accessible-tiers. The percentage of generics on the least-expensive tier drops from 73% to 28%; the percentage of drugs on inappropriate tiers rises from 47% to 74%. Considering only costs paid by patients and the federal Low-Income Subsidy Program, tier misplacement cumulatively costs society $13.25 billion over the time period. An unruly problem demands a disruptive solution. This article advances the counterintuitive regulatory reform that tiering should be based on a drug's list price. Yes, list price-that roundly dismissed figure-should become the touchstone. This would deter incentive-distorting rebate schemes while recognizing that many people already pay list price. It is a remarkably streamlined approach for cutting through a wide swath of perverse incentives and manipulations.

Physicians Treating Alzheimer's Disease Patients Should Be Aware that Televised Direct-to-Consumer Advertising Links More Strongly to Drug Utilization in Older Patients.

BACKGROUND: US direct-to-consumer advertising spending for medicine has soared in recent decades. Advertising has been shown to impact drug utilization. Most Alzheimer's disease patients are above age 65 and may take a range of prescription medications for various disease states. OBJECTIVE: To investigate how direct-to-consumer advertising is associated with the drug utilization of patients ≥65 years old. METHODS: Using advertising expenditure data and Medicare Part D drug purchase claims, we performed regression analyses for each of the highest-spending drugs and age group, with cumulative monthly spending as the predictor variable and drug utilization as the response variable. For each drug, we ran a second set of regression analyses to determine if the spending-utilization correlation showed a significant difference between the two patient age groups (older than 65, younger than 65). RESULTS: For all 14 drugs in our study, advertising spending is positively correlated with utilization (p < 0.01) in both age groups. For seven of the 14 drugs studied, the difference in the utilization of patients older than 65 and the utilization of patients younger than 65 is statistically significant at a p < 0.01 level. The 65-and-older age bracket exhibits significantly greater utilization for all seven of these drugs. CONCLUSION: We find televised advertising for certain drugs to be associated with significantly stronger drug utilization among seniors, as compared to younger patients. Alzheimer's disease physicians should be aware of this result, in light of the medications that patients may take for other disease states, particularly mood and mental health medications.

Development of Common Data Elements for Use in Chiari Malformation Type I Clinical Research: An NIH/NINDS Project.

The management of Chiari I malformation (CMI) is controversial because treatment methods vary and treatment decisions rest on incomplete understanding of its complex symptom patterns, etiologies, and natural history. Validity of studies that attempt to compare treatment of CMI has been limited because of variable terminology and methods used to describe study subjects. The goal of this project was to standardize terminology and methods by developing a comprehensive set of Common Data Elements (CDEs), data definitions, case report forms (CRFs), and outcome measure recommendations for use in CMI clinical research, as part of the CDE project at the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health. A working group, comprising over 30 experts, developed and identified CDEs, template CRFs, data dictionaries, and guidelines to aid investigators starting and conducting CMI clinical research studies. The recommendations were compiled, internally reviewed, and posted online for external public comment. In October 2016, version 1.0 of the CMI CDE recommendations became available on the NINDS CDE website. The recommendations span these domains: Core Demographics/Epidemiology; Presentation/Symptoms; Co-Morbidities/Genetics; Imaging; Treatment; and Outcome. Widespread use of CDEs could facilitate CMI clinical research trial design, data sharing, retrospective analyses, and consistent data sharing between CMI investigators around the world. Updating of CDEs will be necessary to keep them relevant and applicable to evolving research goals for understanding CMI and its treatment.

A common data language for clinical research studies: the National Institute of Neurological Disorders and Stroke and American Academy for Cerebral Palsy and Developmental Medicine Cerebral Palsy Common Data Elements Version 1.0 recommendations.

To increase the efficiency and effectiveness of clinical research studies, cerebral palsy (CP) specific Common Data Elements (CDEs) were developed through a partnership between the National Institute of Neurological Disorders and Stroke (NINDS) and the American Academy of Cerebral Palsy and Developmental Medicine (AACPDM). International experts reviewed existing NINDS CDEs and tools used in studies of children and young people with CP. CDEs were compiled, subjected to internal review, and posted online for external public comment in September 2016. Guided by the International Classification of Functioning, Disability and Health framework, CDEs were categorized into six domains: (1) participant characteristics; (2) health, growth, and genetics; (3) neuroimaging; (4) neuromotor skills and functional assessments; (5) neurocognitive, social, and emotional assessments; and (6) engagement and quality of life. Version 1.0 of the NINDS/AACPDM CDEs for CP is publicly available on the NINDS CDE and AACPDM websites. Global use of CDEs for CP will standardize data collection, improve data quality, and facilitate comparisons across studies. Ongoing collaboration with international colleagues, industry, and people with CP and their families will provide meaningful feedback and updates as additional evidence is obtained. These CDEs are recommended for NINDS-funded research for CP. WHAT THIS PAPER ADDS: This is the first comprehensive Common Data Elements (CDEs) for children and young people with CP for clinical research. The CDEs for children and young people with CP include common definitions, the standardization of case report forms, and measures. The CDE guides the standardization for data collection and outcome evaluation in all types of studies with children and young people with CP. The CDE ultimately improves data quality and data sharing.

NINDS Common Data Elements for Congenital Muscular Dystrophy Clinical Research: A National Institute for Neurological Disorders and Stroke Project.

BACKGROUND: A Congenital Muscular Dystrophy (CMD) Working Group (WG) consisting of international experts reviewed common data elements (CDEs) previously developed for other neuromuscular diseases (NMDs) and made recommendations for all types of studies on CMD. OBJECTIVES: To develop a comprehensive set of CDEs, data definitions, case report forms and guidelines for use in CMD clinical research to facilitate interoperability of data collection, as part of the CDE project at the National Institute of Neurological Disorders and Stroke (NINDS). METHODS: One working group composed of ten experts reviewed existing NINDS CDEs and outcome measures, evaluated the need for new elements, and provided recommendations for CMD clinical research. The recommendations were compiled, internally reviewed by the CMD working group, and posted online for external public comment. The CMD working group and the NIH CDE team reviewed the final version before release. RESULTS: The NINDS CMD CDEs and supporting documents are publicly available on the NINDS CDE website (https://www.commondataelements.ninds.nih.gov/CMD.aspx#tab=Data_Standards). Content areas include demographics, social status, health history, physical examination, diagnostic tests, and guidelines for a variety of specific outcomes and endpoints. The CMD CDE WG selected these documents from existing versions that were generated by other disease area working groups. Some documents were tailored to maximize their suitability for the CMD field. CONCLUSIONS: Widespread use of CDEs can facilitate CMD clinical research and trial design, data sharing and retrospective analyses. The CDEs that are most relevant to CMD research are like those generated for other NMDs, and CDE documents tailored to CMD are now available to the public. The existence of a single source for these documents facilitates their use in research studies and offers a clear mechanism for the discussion and update of the information as knowledge is gained.

May your drug price be evergreen.

Presenting the first comprehensive study of evergreening, this article examines the extent to which evergreening behavior-which can be defined as artificially extending the protection cliff-may contribute to the problem. The author analyses all drugs on the market between 2005 and 2015, combing through 60,000 data points to examine every instance in which a company added a new patent or exclusivity. The results show a startling departure from the classic conceptualization of intellectual property protection for pharmaceuticals. Rather than creating new medicines, pharmaceutical companies are largely recycling and repurposing old ones. Specifically, 78% of the drugs associated with new patents were not new drugs, but existing ones, and extending protection is particularly pronounced among blockbuster drugs. Once companies start down the road of extending protection, they show a tendency to return to the well, with the majority adding more than one extension and 50% becoming serial offenders. The problem is growing across time.

Toxicological evaluation of arachidonic acid (ARA)-rich oil and docosahexaenoic acid (DHA)-rich oil.

The safety of DHA-rich oil from Schizochytrium sp. and ARA-rich oil from Mortierella alpina was separately evaluated by testing for gene mutations, clastogenicity, and aneugenicity, and by conducting 28-day and 90-day dietary studies in Wistar rats. The results of all genotoxicity tests were negative. The 28-day and 90-day studies involved dietary exposure to 1000, 2500, and 5000 mg per kg bw of the DHA-rich and ARA-rich oils and two control diets: water and corn oil (vehicle control). There were no treatment-related effects of either the DHA-rich or ARA-rich oils on clinical observations, body weight, food consumption, behavior, hematology, clinical chemistry, coagulation, urinalysis parameters, or necropsy findings. Increases in cholesterol and triglyceride levels were considered related to a high oil diet and non-adverse. The no observable adverse effect level (NOAEL) for both the DHA-rich and ARA-rich oils was 5000 mg per kg bw, the highest dose tested. The results confirm that these oils possess toxicity profiles similar to those of other currently marketed oils and support the safety of DHA-rich oil from Schizochytrium sp. and ARA-rich oil from Mortierella alpina for their proposed uses in food.

Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials.

BACKGROUND: The effects of nuts on major cardiovascular disease (CVD) risk factors, including dose-responses and potential heterogeneity by nut type or phytosterol content, are not well established. OBJECTIVES: We examined the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts) on blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein, and triglycerides], lipoproteins [apolipoprotein A1, apolipoprotein B (ApoB), and apolipoprotein B100], blood pressure, and inflammation (C-reactive protein) in adults aged ≥18 y without prevalent CVD. DESIGN: We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two investigators screened 1301 potentially eligible PubMed articles in duplicate. We calculated mean differences between nut intervention and control arms, dose-standardized to one 1-oz (28.4 g) serving/d, by using inverse-variance fixed-effects meta-analysis. Dose-response for nut intake was examined by using linear regression and fractional polynomial modeling. Heterogeneity by age, sex, background diet, baseline risk factors, nut type, disease condition, duration, and quality score was assessed with meta-regression. Publication bias was evaluated by using funnel plots and Egger's and Begg's tests. RESULTS: Sixty-one trials met eligibility criteria (n = 2582). Interventions ranged from 3 to 26 wk. Nut intake (per serving/d) lowered total cholesterol (-4.7 mg/dL; 95% CI: -5.3, -4.0 mg/dL), LDL cholesterol (-4.8 mg/dL; 95% CI: -5.5, -4.2 mg/dL), ApoB (-3.7 mg/dL; 95% CI: -5.2, -2.3 mg/dL), and triglycerides (-2.2 mg/dL; 95% CI: -3.8, -0.5 mg/dL) with no statistically significant effects on other outcomes. The dose-response between nut intake and total cholesterol and LDL cholesterol was nonlinear (P-nonlinearity < 0.001 each); stronger effects were observed for ≥60 g nuts/d. Significant heterogeneity was not observed by nut type or other factors. For ApoB, stronger effects were observed in populations with type 2 diabetes (-11.5 mg/dL; 95% CI: -16.2, -6.8 mg/dL) than in healthy populations (-2.5 mg/dL; 95% CI: -4.7, -0.3 mg/dL) (P-heterogeneity = 0.015). Little evidence of publication bias was found. CONCLUSIONS: Tree nut intake lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. The major determinant of cholesterol lowering appears to be nut dose rather than nut type. Our findings also highlight the need for investigation of possible stronger effects at high nut doses and among diabetic populations.