The Regulatory Repercussions of Approving Muscular Dystrophy Medications on the Basis of Limited Evidence.

The U.S. Food and Drug Administration (FDA) approved eteplirsen (Exondys 51) for Duchenne muscular dystrophy in 2016 via its accelerated approval program on the basis of a study of 12 boys. After a contentious review process and a high-profile meeting of an external advisory committee, FDA leaders concluded that very small increases in treated patients' levels of dystrophin, a muscle protein, were reasonably likely to predict clinical benefit. The eteplirsen approval, which was followed by approvals of other drugs in the same class via the same pathway, has been controversial because of the questionable evidence underlying these decisions, delays in mandated postapproval testing, and high U.S. prices. Questions remain about the effectiveness and long-term safety of these products. Although the FDA initially set a November 2020 deadline for eteplirsen's manufacturer to complete a clinical trial determining whether the drug has clinical benefit, the company will not complete the trial until 2024 or later. The relationship between levels of truncated dystrophin, the muscle protein studied in eteplirsen's pivotal trial, and clinical outcomes remains uncertain. Despite recent legislative and regulatory changes to the FDA's accelerated approval pathway, the history of eteplirsen and similar drugs points to the need for additional reforms to better balance evidence generation with patient safety and access to promising medications. Lawmakers and regulators should take further action to limit excessive spending on unproven therapies and ensure that drug sponsors conduct robust and timely confirmatory trials after receiving accelerated approval.

Comparative effectiveness of hysteroscopic and laparoscopic sterilization for women: a retrospective cohort study.

OBJECTIVE: To compare real-world effectiveness of hysteroscopic to laparoscopic sterilization. DESIGN: Retrospective cohort of Medicaid claims for hysteroscopic or laparoscopic sterilization procedures performed in California, 2008-2014. After excluding postpartum procedures, we applied log-linear (Poisson) event-history regression models for clustered person-period data, weighted for propensity to receive either sterilization procedures, and adjusted for sociodemographic and clinical variables to examine the poststerilization pregnancy rates. SETTING: Clinics, hospitals. PATIENT(S): Women aged 18-50 years with Medicaid claims between January 1, 2008, and August 31, 2014. INTERVENTION(S): Hysteroscopic or laparoscopic sterilization procedure. MAIN OUTCOME MEASURE(S): Poststerilization pregnancy measured by pregnancy-related claims. RESULT(S): Among women with hysteroscopic (n = 5,906) or laparoscopic (n = 23,965) sterilization, poststerilization pregnancy claims were identified for 4.74% of women after hysteroscopic sterilization and 5.57% after laparoscopic sterilization. The pregnancy rates decreased over time after either procedure. Twelve months after the procedure, the crude incidence of pregnancy claims was higher for hysteroscopic sterilization than for laparoscopic sterilization (3.26 vs. 2.61 per 100 woman-years), but the propensity-weighted adjusted incidence rate ratio was 1.06 (95% confidence interval [CI], 0.85-1.26). Between 13 and 24 months after the procedure, there were fewer pregnancies for women after hysteroscopic sterilizations than for those after laparoscopic sterilizations (adjusted incidence rate ratio, 0.63 [95% CI, 0.45-0.88]), with no statistically significant differences in later years. The cumulative pregnancy rates 5 years after sterilization were lower with hysteroscopic sterilization than with laparoscopic sterilization (6.26 vs. 7.22 per 100 woman-years; propensity-weighted, adjusted risk ratio, 0.76 [95% CI, 0.62-0.90]). The poststerilization pregnancy rates varied by age and race/ethnicity. CONCLUSION(S): The pregnancy rates after female sterilization are higher than expected, whether performed hysteroscopically or laparoscopically. These findings are reassuring that the effectiveness of hysteroscopic sterilization was not inferior to laparoscopic sterilization. CLINICAL TRIAL REGISTRATION NUMBER: NCT03438682.

Comparative Effectiveness and Safety of Intrauterine Contraception and Tubal Ligation.

BACKGROUND: Tubal ligation remains common in the USA, especially among low-income patients. OBJECTIVE: To compare the effectiveness and safety of intrauterine contraceptives (IUC) to laparoscopic tubal ligation for Medicaid clients. DESIGN: We partnered with patient and clinician stakeholders to conduct a retrospective cohort study using California Medicaid claims for patients who had an IUC placed or laparoscopic tubal ligation performed in 2008-2014, excluding procedures performed within 42 days of a birth. We applied log-linear (Poisson) event-history regression models for clustered person-period data to adjust for sociodemographic variables and pre-procedure health status when examining associations between these contraceptive procedures and claims related to contraceptive failure, complications, and pain in the first year post-procedure. KEY RESULTS: We identified 35,705 patients who had a levonorgestrel IUC placed, 23,628 patients who had a copper IUC placed, and 23,965 patients who underwent laparoscopic tubal ligation. In unadjusted analyses, rates of pregnancy within 1 year were similar following levonorgestrel IUC (2.40%) or copper IUC placement (2.99%) or tubal ligation (2.64%). In adjusted analyses, compared to tubal ligation, pregnancy was less common following placement of a levonorgestrel IUC (adj IRR 0.72, 95% CI 0.64-0.82) and similar with placement of a copper IUC (adj IRR 0.92, 95% CI 0.82-1.05). Procedural complications such as infection (0.35% vs. 2.91%) were significantly less common with IUC placement than tubal ligation. Claims for pelvic and abdominal pain decreased in frequency with time since all procedures; 6 to 12 months post-procedure, pelvic pain claims were less common after levonorgestrel IUC (adj IRR 0.69, 95% CI 0.65-0.73) or copper IUC placement (adj IRR 0.70, 95% CI 0.66-0.75) than tubal ligation. CONCLUSIONS: IUC appears at least as effective as laparoscopic tubal ligation at 1-year post-procedure with lower rates of infection and pelvic pain 6 to 12 months post-procedure. CLINICAL TRIAL REGISTRATION: NCT03438682.

Patient-Centered Safety Outcomes After Hysteroscopic Compared With Laparoscopic Sterilization.

OBJECTIVE: To evaluate the real-world safety of hysteroscopic compared with laparoscopic surgical sterilization. METHODS: We conducted a retrospective cohort study of Medicaid claims for hysteroscopic or laparoscopic sterilization procedures performed in California, 2008-2014, among women aged 18-50 years. After excluding postpartum procedures, we applied log-linear (Poisson) event-history regression models for clustered person-period data, weighted for propensity to receive either sterilization procedures, and adjusted for sociodemographic and clinical characteristics that may affect outcomes of interest to patients and physicians. We assessed the following outcomes: procedural complications, additional surgical procedures (eg, hysterectomy), repeat sterilization procedures, pelvic pain, pelvic inflammatory disease (PID), abdominal pain, nonabdominal pain, and abnormal uterine bleeding. RESULTS: We identified 5,906 women who had undergone hysteroscopic and 23,965 who had undergone laparoscopic sterilization. After adjusting for sociodemographic and health history, women who had hysteroscopic sterilization were less likely to have claims for procedural complications (eg, transfusion, P<.001) on the day of surgical sterilization and additional surgical procedures (eg, hysterectomy, P=.002 at day 2-3 months postprocedure) than laparoscopic sterilization. Claims for a repeat attempt at sterilization were more common after hysteroscopic sterilization within 1 year (adjusted incident rate ratio 3.48, 95% CI 2.69-4.27) and within 5 years (adjusted incident rate ratio 2.32, 95% CI 1.84-2.79) than laparoscopic sterilization. Claims for pelvic pain (adjusted incident rate ratio 0.77, 95% CI 0.65-0.92 at 2 years), abdominal pain (adjusted incident rate ratio 0.80, 95% CI 0.68-0.93 at 7-12 months), and PID (adjusted incident rate ratio 0.55, 95% CI 0.33-0.93 at 2 years) were less common after hysteroscopic than laparoscopic sterilization. Although abnormal uterine bleeding claims were more common after hysteroscopic than laparoscopic sterilization up to 12 months postprocedure (adjusted incident rate ratio 1.37, 95% CI 1.06-1.77 at 7-12 months), there were no significant differences between methods 1 year after the procedure. CONCLUSION: Compared with laparoscopic sterilization, hysteroscopic sterilization was followed by more claims for repeat sterilization procedures and abnormal uterine bleeding, but fewer procedural complications and fewer claims for pelvic or abdominal pain. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03438682.

Using informatics to guide public health policy during the COVID-19 pandemic in the USA.

BACKGROUND: Current and future pandemics will require informatics solutions to assess the risks, resources and policies to guide better public health decision-making. METHODS: Cross-sectional study of all COVID-19 cases and deaths in the USA on a population- and resource-adjusted basis (as of 24 April 2020) by applying biomedical informatics and data visualization tools to several public and federal government datasets, including analysis of the impact of statewide stay-at-home orders. RESULTS: There were 2753.2 cases and 158.0 deaths per million residents, respectively, in the USA with variable distributions throughout divisions, regions and states. Forty-two states and Washington, DC, (84.3%) had statewide stay-at-home orders, with the remaining states having population-adjusted characteristics in the highest risk quartile. CONCLUSIONS: Effective national preparedness requires clearly understanding states' ability to predict, manage and balance public health needs through all stages of a pandemic. This will require leveraging data quickly, correctly and responsibly into sound public health policies.

Diversity in Medical Device Clinical Trials: Do We Know What Works for Which Patients?

Policy Points: A 1993 law required the National Institutes of Health to include women and racial and ethnic minorities in relevant research studies. Most federal health agencies adopted the same policy, but the US Food and Drug Administration (FDA) did not. A 2012 law encouraged the FDA to ensure that new medical products be analyzed for safety and effectiveness for key demographic patient groups. Our study of high-risk medical devices reviewed by the FDA in 2014-2017 found that due to lack of patient diversity and publicly available data, clinicians and patients often cannot determine which devices are safe and effective for specific demographic groups. CONTEXT: Demographic differences can influence the safety and effectiveness of medical devices; however, clinical trials of devices for adults have historically underrepresented women, people of color, and patients over age 65. The US Food and Drug Administration (FDA) Safety and Innovation Act became law in 2012, encouraging greater diversity and subgroup analyses. In 2013, the FDA reported that there was diversity in clinical trials considered "pivotal" for approval decisions and that subgroup analyses were conducted for most applications for the highest-risk medical devices. However, the FDA's report did not specify whether analyses included sufficient numbers to be meaningful, whether analyses were conducted for most major subgroups, or whether analyses included safety, effectiveness, or accuracy. METHODS: We examined publicly available documents for all 22 medical devices that the FDA designated "highest risk" or "novel," were reviewed through the premarket approval pathway, and were scrutinized at FDA public meetings from 2014 to 2017. We evaluated patient demographics and subgroup analyses for all pivotal trials. FINDINGS: Only 3 (14%) of the devices provided subgroup analyses for both effectiveness and safety or both sensitivity and selectivity for gender, race, and age. However, 55% of the devices reported both of those subgroup analyses for at least 1 of the 3 subgroups. Whether analyses were reported or not, the number of patients in most subgroups was too small to draw meaningful conclusions. Subgroup analyses were more likely to be reported to the FDA's Advisory Committees than in the FDA's public reviews or labeling. CONCLUSIONS: Despite a law encouraging more diversity and subgroup analyses in pivotal trials used as the basis for FDA approval, the results of our study indicate relatively few subgroup analyses are publicly available for the highest-risk and novel medical devices. The lack of subgroup analyses makes it impossible to inform patients or physicians as to whether many newly approved medical devices are safe and effective for specific demographic subgroups defined by gender, race, and age.

Software-Related Recalls of Health Information Technology and Other Medical Devices: Implications for FDA Regulation of Digital Health.

Policy Points: Medical software has become an increasingly critical component of health care, yet the regulation of these devices is inconsistent and controversial. No studies of medical devices and software assess the impact on patient safety of the FDA's current regulatory safeguards and new legislative changes to those standards. Our analysis quantifies the impact of software problems in regulated medical devices and indicates that current regulations are necessary but not sufficient for ensuring patient safety by identifying and eliminating dangerous defects in software currently on the market. New legislative changes will further deregulate health IT, reducing safeguards that facilitate the reporting and timely recall of flawed medical software that could harm patients. CONTEXT: Medical software has become an increasingly critical component of health care, yet the regulatory landscape for digital health is inconsistent and controversial. To understand which policies might best protect patients, we examined the impact of the US Food and Drug Administration's (FDA's) regulatory safeguards on software-related technologies in recent years and the implications for newly passed legislative changes in regulatory policy. METHODS: Using FDA databases, we identified all medical devices that were recalled from 2011 through 2015 primarily because of software defects. We counted all software-related recalls for each FDA risk category and evaluated each high-risk and moderate-risk recall of electronic medical records to determine the manufacturer, device classification, submission type, number of units, and product details. FINDINGS: A total of 627 software devices (1.4 million units) were subject to recalls, with 12 of these devices (190,596 units) subject to the highest-risk recalls. Eleven of the devices recalled as high risk had entered the market through the FDA review process that does not require evidence of safety or effectiveness, and one device was completely exempt from regulatory review. The largest high-risk recall categories were anesthesiology and general hospital, with one each in cardiovascular and neurology. Five electronic medical record systems (9,347 units) were recalled for software defects classified as posing a moderate risk to patient safety. CONCLUSIONS: Software problems in medical devices are not rare and have the potential to negatively influence medical care. Premarket regulation has not captured all the software issues that could harm patients, evidenced by the potentially large number of patients exposed to software products later subject to high-risk and moderate-risk recalls. Provisions of the 21st Century Cures Act that became law in late 2016 will reduce safeguards further. Absent stronger regulations and implementation to create robust risk assessment and adverse event reporting, physicians and their patients are likely to be at risk from medical errors caused by software-related problems in medical devices.

Bullying Harms Victims And Perpetrators of All Ages.

Bullying used to be considered an unfortunate, inevitable rite of childhood, but researchers now tell us that bullying often occurs in conjunction with more serious aggressive and antisocial behavior. They conclude that bullying, therefore, should not be considered a normal and accepted part of growing up.