Assessing the properties of patient-specific treatment effect estimates from causal forest algorithms under essential heterogeneity.

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.

Rationale, design, and protocol for a hybrid type 1 effectiveness-implementation trial of a proactive smoking cessation electronic visit for scalable delivery via primary care: the E-STOP trial.

BACKGROUND: Cigarette smoking remains the leading cause of preventable disease and death in the United States. Primary care offers an ideal setting to reach adults who smoke cigarettes and improve uptake of evidence-based cessation treatment. Although U.S. Preventive Services Task Force Guidelines recommend the 5As model (Ask, Advise, Assess, Assist, Arrange) in primary care, there are many barriers to its implementation. Automated, comprehensive, and proactive tools are needed to overcome barriers. Our team developed and preliminarily evaluated a proactive electronic visit (e-visit) delivered via the Electronic Health Record patient portal to facilitate evidence-based smoking cessation treatment uptake in primary care, with promising initial feasibility and efficacy. This paper describes the rationale, design, and protocol for an ongoing Hybrid Type I effectiveness-implementation trial that will simultaneously assess effectiveness of the e-visit intervention for smoking cessation as well as implementation potential across diverse primary care settings. METHODS: The primary aim of this remote five-year study is to examine the effectiveness of the e-visit intervention vs. treatment as usual (TAU) for smoking cessation via a clinic-randomized clinical trial. Adults who smoke cigarettes are recruited across 18 primary care clinics. Clinics are stratified based on their number of primary care providers and randomized 2:1 to either e-visit or TAU. An initial baseline e-visit gathers information about patient smoking history and motivation to quit, and a clinical decision support algorithm determines the best evidence-based cessation treatment to prescribe. E-visit recommendations are evaluated by a patient's own provider, and a one-month follow-up e-visit assesses cessation progress. Main outcomes include: (1) cessation treatment utilization (medication, psychosocial cessation counseling), (2) reduction in cigarettes per day, and (3) biochemically verified 7-day point prevalence abstinence (PPA) at six-months. We hypothesize that patients randomized to the e-visit condition will have better cessation outcomes (vs. TAU). A secondary aim evaluates e-visit implementation potential at patient, provider, and organizational levels using a mixed-methods approach. Implementation outcomes include acceptability, adoption, fidelity, implementation cost, penetration, and sustainability. DISCUSSION: This asynchronous, proactive e-visit intervention could provide substantial benefits for patients, providers, and primary care practices and has potential to widely improve reach of evidence-based cessation treatment. TRIAL REGISTRATION: NCT05493254.

"And then I found $5": Optimizing recruitment efficiency in remote clinical trials.

Introduction: 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. Methods: In the parent nationwide randomized clinical trial of adult smokers (N = 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. Results: Older age, less education, lower income, and female sex predicted enrolling via mail vs e-consent (p < .05's). In adjusted model, older age (AOR = 1.02, p = .016) and less education (AOR = 2.23, p < .001) remained predictive of mail enrollment. The $5 incentive (vs none) increased enrollment rate by 9% (AOR = 1.64, p = .007), with estimated cost of additional $59 per additional participant enrolled. Conclusions: 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.

Cost-effectiveness of peer-delivered physical activity promotion and maintenance programs for initially sedentary breast cancer survivors.

The evidence for the survival and health benefits of physical activity (PA) among cancer survivors is well documented. However, it has been challenging to maintain PA among cancer survivors. To evaluate the cost-effectiveness of peer support to encourage maintenance of moderate-to-vigorous physical activity (MVPA) among breast cancer survivors. Participants were randomized into Reach Plus Message (weekly text/email messages), Reach Plus Phone (monthly phone calls) or Reach Plus (a self-monitoring intervention) over 6 months after an initial adoption phase. We calculated the incremental cost-effectiveness ratios (ICER) in terms of quality-adjusted years life years (QALYs) and self-reported MVPA, from the payer's budgetary and societal perspectives over 1 year. Intervention costs were collected via time logs from the trainers and peer coaches, and participant costs from the participants via surveys. For our sensitivity analyses, we bootstrapped costs and effects to construct cost-effectiveness planes and acceptability curves. The intervention that provides weekly messages from peer coaches has an ICER of $14,446 per QALY gained and $0.95 per extra minute of MVPA per day over Reach Plus. Reach Plus Message has a 49.8% and 78.5% probability of cost-effectiveness respectively when decision makers are willing to pay approximately $25,000 per QALY and $10 per additional minute of MVPA. Reach Plus Phone, which requires tailored monthly telephone calls, costs more than Reach Plus Message but yields less QALY and self-reported MVPA at 1 year. Reach Plus Message may be a viable and cost-effective intervention strategy to maintain MVPA among breast cancer survivors.

Sustained physical activity (PA) among cancer survivors can increase survival and decrease the recurrence of cancer. However, it has been challenging to encourage cancer survivors to sustain exercise programs. In this study, we sought to understand whether two types of peer support interventions shown to sustain PA among cancer survivors can do so cost-effectively. Based on our previous study showing that weekly text messages or monthly personalized phone calls can help cancer survivors exercise more and for a longer period of time, we conducted this study to understand which intervention is more cost-effective to implement. We found that text messages are more cost-effective than personalized phone calls, costing $14,446 for every additional quality-adjusted life year gained and $0.95 for every additional minute of moderate-to-vigorous PA per week compared to the comparator group of cancer survivors who only received educational support at the beginning of the study.

Participation in the CenteringPregnancy Program and Pregnancy-Induced Hypertension.

INTRODUCTION: CenteringPregnancy emphasizes nutrition, learning, and peer support through a group meeting format in contrast to the standard of prenatal care that maximizes a pregnant patient's time with their provider. It was hypothesized that the program may yield a reduced risk of pregnancy-induced hypertension. In this observational study, authors examined the impacts of the CenteringPregnancy program versus those of standard of prenatal care on pregnancy-induced hypertension. METHODS: In 2021, birth certificate data were linked to hospital discharge records of women who delivered in obstetric clinics in the Midlands of South Carolina between 2015 and 2019. Logistic regression models were used to estimate the association between CenteringPregnancy participation (n=547) and any pregnancy-induced hypertension and specific pregnancy-induced hypertension diagnoses (gestational hypertension/unspecified hypertension, mild pre-eclampsia, and severe pre-eclampsia/eclampsia). Propensity score techniques (e.g., inverse probability of treatment weighting) were used to adjust for self-selection into the program versus into standard of prenatal care. RESULTS: CenteringPregnancy participants had higher odds of developing any pregnancy-induced hypertension under all specifications (OR=1.48, 95% CI=1.15, 1.92) and specifically gestational hypertension/unspecified hypertension (OR=1.76, 95% CI=1.28, 2.42) than those in standard of prenatal care. However, CenteringPregnancy participants did not experience significantly higher odds of mild pre-eclampsia (OR=1.06, 95% CI=0.65, 1.78) and severe pre-eclampsia/eclampsia (OR=1.21, 95% CI=0.78, 1.89) compared with standard of prenatal care participants. CONCLUSIONS: Participation in CenteringPregnancy was associated with higher odds of pregnancy-induced hypertension, particularly gestational hypertension, than participation in standard of prenatal care. Additional research is warranted to definitely rule out selection bias and identify contributing factor(s) that increased pregnancy-induced hypertension despite efforts to improve pregnancy-related health outcomes among CenteringPregnancy participants.

Differential patterns of opioid misuse between younger and older adults - a retrospective observational study using data from South Carolina's prescription drug monitoring program.

Background: Most research on opioid misuse focuses on younger adults, yet opioid-related mortality has risen fastest among older Americans over age 55.Objectives: To assess whether there are differential patterns of opioid misuse over time between younger and older adults and whether South Carolina's mandatory Prescription Drug Monitoring Program (PDMP) affected opioid misuse differentially between the two groups.Methods: We used South Carolina's Reporting and Identification Prescription Tracking System from 2010 to 2018 to calculate an opioid misuse score for 193,073 patients (sex unknown) using days' supply, morphine milligram equivalents (MME), and the numbers of unique prescribers and dispensaries. Multivariable regression was used to assess differential opioid misuse patterns by age group over time and in response to implementation of South Carolina's mandatory PDMP in 2017.Results: We found that between 2011 and 2018, older adults received 57% (p < .01) more in total MME and 25.4 days more (p < .01) in supply, but received prescriptions from fewer doctors (-0.063 doctors, p < 01) and pharmacies (-0.11 pharmacies, p < 01) per year versus younger adults. However, older adults had lower odds of receiving a high misuse score (OR 0.88, p < .01). After the 2017 legislation, misuse scores fell among younger adults (OR 0.79, p < .01) relative to 2011, but not among older adults.Conclusion: Older adults may misuse opioids differently compared to younger adults. Assessment of policies to reduce opioid misuse should take into account subgroup differences that may be masked at the population level.

Assessing the ability of an instrumental variable causal forest algorithm to personalize treatment evidence using observational data: the case of early surgery for shoulder fracture.

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.

Liability Waivers for COVID-19: Law, Policy, and Practice.

As businesses reopen, the practice of asking customers to sign COVID-19 liability waivers is increasing throughout the United States. Although the courts have not yet decided the enforceability of COVID-19-related liability waivers, existing case law, as well as new executive and legislative actions, suggests that such waivers may offer some protection to businesses from liability. Nevertheless, we believe that the legal and ethical rationales underlying liability waivers are not applicable to a pandemic. We further argue that the challenging nature of and the substantial unknowns about the novel coronavirus make waivers contrary to public policy. Fears over floods of litigation appear thus far unfounded, and businesses should not be relieved from their obligation of taking reasonable safety precautions. Waivers are not a panacea to reopen businesses in an ongoing pandemic, and the ultimate protection against liability is to operate in a manner that minimizes the spread of the virus consistent with evidence-based guidelines.

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.

Associations Between Physician Supply Levels and Amenable Mortality Rates: An Analysis of Taiwan Over Nearly 4 Decades.

Access to health care is an important determinant of health, but it remains unclear whether having more physicians reduces mortality. In this study, we used Taiwan's population-level National Death Certification Registry data to investigate whether a greater supply of physicians is associated with lower rates of amenable mortality, defined as deaths that can be delayed with appropriate and timely medical treatment. Our baseline regression analysis adjusting only for age and sex shows that an increase in the number of physicians per 1000 is associated with a reduction of 1.7 (P < .01) and 0.97 (P < .01) age-standardized deaths per 100 000 for men and women, respectively. However, in our full analyses that control for socioeconomic factors and Taiwan's health insurance expansion, we find that physician supply is no longer statistically associated with amenable mortality rates. Nevertheless, we found that greater physician supply levels are associated with a reduction in deaths from ischemic heart disease (-0.13 (P < .05) for men, and -0.066 (P < .05) for women). These findings suggest that overall, physician supply is not associated with amenable mortality rates after controlling for socioeconomic factors but may help reduce amenable mortality rates in specific causes of death.

Are quality-adjusted medical prices declining for chronic disease? Evidence from diabetes care in four health systems.

Improvements in medical treatment have contributed to rising health spending. Yet there is relatively little evidence on whether the spending increase is "worth it" in the sense of producing better health outcomes of commensurate value-a critical question for understanding productivity in the health sector and, as that sector grows, for deriving an accurate quality-adjusted price index for an entire economy. We analyze individual-level panel data on medical spending and health outcomes for 123,548 patients with type 2 diabetes in four health systems: Japan, The Netherlands, Hong Kong and Taiwan. Using a "cost-of-living" method that measures value based on improved survival, we find a positive net value of diabetes care: the value of improved survival outweighs the added costs of care in each of the four health systems. This finding is robust to accounting for selective survival, end-of-life spending, and a range of values for a life-year or fraction of benefits attributable to medical care. Since the estimates do not include the value from improved quality of life, they are conservative. We, therefore, conclude that the increase in medical spending for management of diabetes is offset by an increase in quality.

Early evidence from South Carolina's Medicare-Medicaid dual-eligible financial alignment initiative: an observational study to understand who enrolled, and whether the program improved health?

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.

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.

Avoidable Hospital Admissions From Diabetes Complications In Japan, Singapore, Hong Kong, And Communities Outside Beijing.

Improving the quality of primary care may reduce avoidable hospital admissions. Avoidable admissions for conditions such as diabetes are used as a quality metric in the Health Care Quality Indicators of the Organization for Economic Cooperation and Development (OECD). Using the OECD indicators, we compared avoidable admission rates and spending for diabetes-related complications in Japan, Singapore, Hong Kong, and rural and peri-urban Beijing, China, in the period 2008-14. We found that spending on diabetes-related avoidable hospital admissions was substantial and increased from 2006 to 2014. Annual medical expenditures for people with an avoidable admission were six to twenty times those for people without an avoidable admission. In all of our study sites, when we controlled for severity, we found that people with more outpatient visits in a given year were less likely to experience an avoidable admission in the following year, which implies that primary care management of diabetes has the potential to improve quality and achieve cost savings. Effective policies to reduce avoidable admissions merit investigation.

Patient Copayments, Provider Incentives and Income Effects: Theory and Evidence from the Essential Medications List under China's 2009 Healthcare Reform.

Expanding access through insurance expansion can increase healthcare utilization through moral hazard. Reforming provider incentives to introduce more supply-side cost sharing is increasingly viewed as crucial for affordable, sustainable access. Using both difference-in-differences and segmented regression analyses on a panel of 1,466 hypertensive and diabetic patients, we empirically examine Shandong province's initial implementation of China's 2009 Essential Medications List policy. The policy reduced drug sale markups to providers but also increased drug coverage benefits for patients. We find that providers appeared to compensate for lost drug revenues by increasing office visits, for which no fee reduction occurred. At the same time, physician agency (yielding to patient demand for pharmaceuticals) may have tempered provider incentives to reduce drug expenditures at the visit level. Taken together, the policy may have increased total spending or total out-of-pocket expenditures. Mandating payment reductions in a service that comprises a large portion of provider income may have unintended consequences.

Parity, Age at First Birth, and Risk of Death from Bladder Cancer: A Population-Based Cohort Study in Taiwan.

The evidence is limited on the relationship between reproductive factors and bladder cancer (BC). We studied 1,292,462 women who had a first and singleton delivery between 1 January 1978 and 31 December 1987. Each woman in the study cohort was tracked from their first childbirth to 31 December 2009. Vital status of the women was determined by crosswalking records with a computerized mortality database. We used Cox proportional hazard regression models to estimate the hazard ratios (HRs) of death from BC associated with maternal age at first birth and parity. The data showed 63 BC deaths during 34,980,246 person-years of follow-up. BC mortality rate was 0.90 cases for every 100,000 person-years. Compared with women who gave birth under the age of 23, the adjusted HR was 1.24 (95% confidence interval (CI) = 0.66-2.35) for women who gave birth between age 23 and 26 and 2.30 (95% CI = 1.21-4.39) for women who gave birth over the age of 26. Increasing age at first birth (p for trend = 0.01) is associated with a trend in increasing risk of BC mortality. Relative to women who had a single childbirth, the adjusted HRs were 1.17 (95% CI = 0.51-2.69) for women who gave birth to two children, and 1.31 (95% CI = 0.56-3.10) for women with three or more childbirths, respectively. These results were not statistically significant. Study results suggests that giving birth at an early age may confer a protective effect on the risk of death from BC.

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.

Petitioning the FDA to Improve Pharmaceutical, Device and Public Health Safety by Ordinary Citizens: A Descriptive Analysis.

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."

Statins are Associated With a Reduced Risk of Brain Cancer: A Population-Based Case-Control Study.

The aim of this study was to investigate whether statin utilization is associated with brain cancer risk.A population-based case-control study was conducted using nationally representative claims data from the National Health Insurance Bureau in Taiwan. Cases included all patients 50 years and older who received an index diagnosis of brain cancer between 2004 and 2011. Our controls were matched by age, sex, and index date. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using multiple logistic regression.We examined 213 brain cancer cases and 852 controls. The unadjusted ORs for any statin prescription was 0.77 (95% CI = 0.50-1.18) and the adjusted OR was 0.59 (95% CI = 0.37-0.96). Compared with no use of statins, the adjusted ORs were 0.68 (95% CI = 0.38-1.24) for the group having been prescribed with statins with cumulative defined daily dose (DDD) below 144.67 DDDs and 0.50 (95% CI = 0.28-0.97) for the group with the cumulative statin use of 144.67 DDDs or more.The results of this study suggest that statins may reduce the risk of brain cancer.