Analysis of US Food and Drug Administration new drug and biologic approvals, regulatory pathways, and review times, 1980-2022.

U.S. laws enacted since 1983 have aimed to enhance the development and marketing of new pharmaceutical products. We thoroughly characterized all new molecular entities, therapeutic biologics, and gene and cell therapies approved by the US Food and Drug Administration (FDA) during the period 1980-2022 in the context of these laws and regulations. Throughout the study period, the FDA approved 1355 new pharmaceutical products. The median FDA review time decreased from 26.6 months prior to the Prescription Drug User Fee Act (1992), which authorized the FDA to collect fees from drug companies to 9.9 months after the Food and Drug Administration Safety and Innovation Act (2012), which created new designations that eliminated the requirement for evidence of added therapeutic benefit for FDA expedited drug review. The greatest increase in approvals occurred in antineoplastic and immunomodulating drugs, biologics, and orphan drugs. More than half of new drug approvals benefited from regulatory designations and pathways that did not require addressing unmet medical needs or demonstrating therapeutic benefit over available alternatives. The legislative goal of bringing more drugs to the market faster has been achieved. Further studies are needed to determine the therapeutic value to patients of new drugs approved using expedited approval pathways.

A Comparative Assessment of Approvals and Discontinuations of Systemic Antibiotics and Other Therapeutic Areas.

Since 1980, the US Congress has passed legislation providing several incentives to encourage the development and regulatory approval of new drugs, particularly antibiotics. We assessed long-term trends and characteristics of approvals and discontinuations of all new molecular entities, new therapeutic biologics, and gene and cell therapies approved by the US Food and Drug Administration (FDA), as well as reasons for discontinuations by therapeutic class, in the context of laws and regulations implemented over the past four decades. In the period 1980-2021, the FDA approved 1310 new drugs, of which 210 (16.0%) had been discontinued as of 31 December 2021, including 38 (2.9%) withdrawn for safety reasons. The FDA approved 77 (5.9%) new systemic antibiotics, of which 32 (41.6%) had been discontinued at the end of the observation period, including 6 (7.8%) safety withdrawals. Since the enactment of the FDA Safety and Innovation Act in 2012, which created the Qualified Infectious Disease Product designation for antiinfectives to treat serious or life-threatening diseases due to resistant or potentially resistant bacteria, the FDA has approved 15 new systemic antibiotics, all using non-inferiority trials, for 22 indications and five different infections. Only one of the infections had labeled indications for patients with drug-resistant pathogens.

Analysis of the Gene Therapies Authorized by the United States Food and Drug Administration and the European Medicines Agency.

BACKGROUND: Gene therapy, altering the genes inside human cells, has recently emerged as an alternative for preventing and treating disease. Concerns have been expressed about the clinical value and the high cost of gene therapies. OBJECTIVE: This study assessed the characteristics of the clinical trials, authorizations, and prices of gene therapies in the United States and the European Union. RESEARCH DESIGN: We collected regulatory information from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and manufacturer-listed prices from the United States, UK, and Germany. Descriptive statistics and t tests were conducted in the study. RESULTS: As of January 1, 2022, the FDA and EMA authorized 8 and 10 gene therapies, respectively. The FDA and EMA granted orphan designation to all gene therapies except talimogene laherparepvec. Pivotal clinical trials were nonrandomized, open level, uncontrolled, phase I-III, and included a limited number of patients. Study primary outcomes were mainly surrogate endpoints without demonstration of direct patient benefit. The price of gene therapies at market entry ranged from $200,064 to $2,125,000 million. CONCLUSIONS: Gene therapy is used to treat incurable diseases that affect only a small number of patients (orphan diseases). Based on this, they are approved by the EMA and FDA with insufficient clinical evidence to ensure safety and efficacy, in addition to the high cost.

Safety implications of concomitant administration of antidepressants and opioid analgesics in surgical patients.

BACKGROUND: Commonly prescribed antidepressants (paroxetine, fluoxetine, duloxetine, bupropion) inhibit bioconversion of several prodrug opioid medications to their active metabolite, potentially decreasing analgesic effect. There is a paucity of studies assessing the risk-benefit of concomitant administration of antidepressants and opioids. RESEARCH DESIGN AND METHODS: Observational study of adult patients taking antidepressants prior to scheduled surgery using 2017-2019 electronic medical record data to assess perioperative use of opioids and to determine the incidence and risk factors for developing postoperative delirium. We conducted a generalized linear regression with the Gamma log-link to assess the association between use of antidepressants and opioids and a logistic regression to assess the association between antidepressants use and the likelihood of developing postoperative delirium. RESULTS: After controlling for patient demographic and clinical characteristics, and postoperative pain, use of inhibiting antidepressants was associated with 1.67 times greater use of opioids per hospitalization day (p = 0.00154), a two-fold increase in the risk for developing postoperative delirium (p = 0.0224), and an estimated average of four additional days of hospitalization (p < 0.00001) compared to use of non-inhibiting antidepressants. CONCLUSIONS: Careful consideration to drug-drug interactions and risk of related adverse events remains critical in the safe and optimal management of postoperative pain in patients taking concomitantly antidepressants.

Disentangling the Cost of Orphan Drugs Marketed in the United States.

The increasing number and high prices of orphan drugs have triggered concern among patients, payers, and policymakers about the affordability of new drugs approved using the incentives set by the Orphan Drug Act (ODA) of 1983. This study evaluated the factors associated to the differences in the treatment cost of new orphan and non-orphan drugs approved by the FDA from 2017 to 2021. A generalized linear model (GLM) with the Gamma log-link analysis was used to ascertain the association of drug characteristics with the treatment costs of orphan and non-orphan drugs. The results of the study showed that the median and interquartile range (IQR) drug cost was USD 218,872 (IQR = USD 23,105) for orphan drugs and USD 12,798 (IQR = USD 57,940) for non-orphan drugs (p < 0.001). Higher market entry prices were associated with biologics (108%; p < 0.001), orphan status (177%; p < 0.001), US sponsor companies (48%; p = 0.035), chronic use (1083%; p < 0.001), treatment intent (163%; p = 0.004), and indications for oncology (624%; p < 0.001) or genetic disorders (624%; p < 0.001). Higher market entry treatment cost for newly approved drugs were associated with biologics, orphan status, US sponsor companies, chronic use, therapeutic intent, and indications for oncology or genetic disorders.

Inpatient administration of opioids and risk for post-operative ileus in older adults.

OBJECTIVE: Post-operative ileus (POI) is a common and potentially serious complication after surgery. We assessed the incidence and identified predictors of POI in older surgical patients. DESIGN: A retrospective observational study. SETTING: University of California-San Francisco electronic medical record data. PARTICIPANTS: Opioid-naïve, noncancer patients, aged 65 and older, who underwent elective surgery in the period 2017-2019. EXPOSURE: Administration of opioid analgesics per day of hospitalization in opioid naïve patients. MAIN OUTCOMES MEASURE: Incidence of POI and likelihood of developing POI. RESULTS: In the study period, 3 percent of opioid naïve patients developed POI. Patients with POI used on average 197.1 oral morphine equivalents (OMEs) per day of hospitalization compared to 82.5 OME in patients without POI (p = 0.013). Yet, there were not statistically significant differences in post-operative pain scores between patients with and without POI. General surgery (p = 0.0031), length of surgery (p = 0.0031), and hospital length of stay (p < 0.0001) were significant predictors of the risk for developing POI. Adjusted inpatient administration of more than 90 OME per day of hospitalization was associated with a four times greater risk for developing POI (p = 0.016). Developing POI was associated with 6.5 (95 percent confidence interval: 5.2-7.8) additional days of hospitalization among patients who developed POI compared to patients who did not develop POI (p < 0.0001). CONCLUSIONS: Adjusted inpatient administration of more than 90 OME significantly increased the risk for developing POI in opioid-naïve older patients. Developing POI after surgery significantly increased the hospital length of stay. Optimizing inpatient administration of opioids may prevent opioid use-related POI and longer hospitalizations.

Opioid prescribing practices at hospital discharge for surgical patients before and after the Centers for Disease Control and Prevention's 2016 opioid prescribing guideline.

BACKGROUND: The Centers for Disease Control and Prevention's (CDC) March 2016 opioid prescribing guideline did not include prescribing recommendations for surgical pain. Although opioid over-prescription for surgical patients has been well-documented, the potential effects of the CDC guideline on providers' opioid prescribing practices for surgical patients in the United States remains unclear. METHODS: We conducted an interrupted time series analysis (ITSA) of 37,009 opioid-naïve adult patients undergoing inpatient surgery from 2013-2019 at an academic medical center. We assessed quarterly changes in the discharge opioid prescription days' supply, daily and total doses in oral morphine milligram equivalents (OME), and the proportion of patients requiring opioid refills within 30 days of discharge. RESULTS: The discharge opioid prescription declined by -0.021 (95% CI, -0.045 to 0.003) days per quarter pre-guideline versus -0.201 (95% CI, -0.223 to -0.179) days per quarter post-guideline (p < 0.0001). Likewise, the mean daily and total doses of the discharge opioid prescription declined by -0.387 (95% CI, -0.661 to -0.112) and -7.124 (95% CI, -9.287 to -4.962) OME per quarter pre-guideline versus -2.307 (95% CI, -2.560 to -2.055) and -20.68 (95% CI, -22.66 to -18.69) OME per quarter post-guideline, respectively (p < 0.0001). Opioid refill prescription rates remained unchanged from baseline. CONCLUSIONS: The release of the CDC opioid guideline was associated with a significant reduction in discharge opioid prescriptions without a concomitant increase in the proportion of surgical patients requiring refills within 30 days. The mean prescription for opioid-naïve surgical patients decreased to less than 3 days' supply and less than 50 OME per day by 2019.

The American Public Health Association Endorses Single-Payer Health System Reform.

Health care is a human right. Achieving universal health insurance coverage for all US residents requires significant system-wide reform. The most equitable and cost-effective health care system is a public, single-payer (SP) system. The rapid growth in national health expenditures can be addressed through a system that yields net savings over projected trends by eliminating profit and waste. With universal health insurance coverage through SP financing, providers can focus on optimizing delivery of services, rather than working within a system covered by payers who have incentives to limit costs regardless of benefit. Rather, with a SP, the people act as their own insurer through a partnership with provider organizations where tax dollars work for everyone. Consumer choice is then based on the best care to meet need with no out-of-pocket payments. SP financing is the best option to ensure equity, fairness, and public health priorities align with medical needs, providing incentives for wellness. Consumer choice will drive market forces, not provider network profits or insurer restrictions. This approach benefits public health, as everyone will have universal access to needed care, with treatment plans developed by providers based on what works best for the patient. In 2021, the American Public Health Association adopted a policy statement calling for comprehensive reforms to implement a SP system. The proposed action steps in this policy will help build a healthier nation, saving lives and reducing wasted health care expenditures while addressing inequities rooted in social, demographic, mental health, economic, and political determinants.

Postoperative Respiratory Events in Surgical Patients Exposed to Opioid Analgesic Shortages Compared to Fully Matched Patients Non-exposed to Shortages.

INTRODUCTION: Shortages of opioid analgesics critically disrupt clinical practice and are detrimental to patient safety. There is a dearth of studies assessing the safety implications of drug shortages. OBJECTIVE: We aimed to assess perioperative opioid analgesic use and related postoperative hypoxemia (oxygen saturation less than 90%) in surgical patients exposed to prescription opioid shortages compared to propensity score-matched patients non-exposed to opioid shortages. METHODS: We conducted a retrospective study including adult patients who underwent elective surgery at The University of California San Francisco in the period August 2018-December 2019. We conducted a Gamma log-link generalized linear model to assess the effect of shortages on perioperative use of opioids and a weighted logistic regression to assess the likelihood of experiencing postoperative hypoxemia. RESULTS: There were 1119 patients exposed to opioid shortages and 2787 matched non-exposed patients. After full matching, patients exposed to shortages used a greater mean of morphine milligram equivalents/day (146.94; 95% confidence interval 123.96-174.16) than non-exposed patients (117.92; 95% confidence interval 100.48-138.38; p = 0.0001). The estimated effect was a 1.25 (95% confidence interval 1.12-1.40; p = 0.0001) times greater use of opioids in patients exposed to opioid shortages than non-exposed patients. After full matching, a greater proportion of patients exposed to shortages (19.06%) experienced hypoxemia compared with non-exposed patients (16.91%). In addition, a greater proportion of patients exposed to opioid shortages (1.20%) experienced hypoxemia reversed by intravenous naloxone administration compared with non-exposed patients (0.44%). CONCLUSIONS: Given the shortage prevalence, reliance on opioid medications, and related risk of respiratory depression, harm prevention measures remain critical to prevent postoperative complications that may compromise patients' safety.

Hospital admission medication reconciliation in high-risk prescription opioid users.

BACKGROUND: No studies have assessed the clinical significance of medication reconciliation in surgical patients using high-risk extended-release/long-acting (ER/LA) opioid medications. OBJECTIVES: We assessed differences in the perioperative use of opioid analgesics in patients who underwent medication reconciliation upon hospital admission compared to patients who did not and identified predictors of perioperative use of opioids. METHODS: Retrospective observational quasi-experimental study including adult non-cancer patients who underwent elective surgery at UCSF Medical Center in the period January 2017 through December 2019 and received at least one opioid analgesic during surgical hospitalization. The primary study outcome was perioperative use of opioids measured in daily oral morphine equivalents (OME). Secondary outcomes were predictors of perioperative use of opioids after adjusting for baseline differences between groups. RESULTS: We identified 402 patients. Of them, 59.5% were female. The mean patient age was 58.5 years. Most patients underwent neurological or orthopedic surgery (each 40.8%). Over 94.3% of our patients underwent medication reconciliation upon hospital admission, with 78.4% completed by a pharmacy staff. Medication reconciliation evidenced that 5.5% patients were not taking the ER/LA opioids on their medication history list. Inactive ER/LA opioids were discontinued during hospitalization. None of the patients with inactive ER/LA opioids had those opioids restarted at hospital discharge. In addition, patients (26.9%) were successfully converted from ER/LA to SA opioids. After adjusting for patients' demographic and clinical characteristics, surgical procedure type and post-operative pain, opioid formulation conversion was the main predictor of perioperative use of opioids per hospitalization day. Switching patients from ER/LA to SA opioids reduced the mean daily use of OME by 66.03 units (p < 0.02) without adversely impacting postoperative pain. CONCLUSIONS: Medication reconciliation upon hospital admission reduced unnecessary exposure to opioids in hospitalized surgical patients.

The association of multimodal analgesia and high-risk opioid discharge prescriptions in opioid-naive surgical patients.

BACKGROUND: Opioids and multimodal analgesia are widely administered to manage postoperative pain. However, little is known on how improvements in inpatient pain control are correlated with high-risk (> 90 daily OME) discharge opioid prescriptions for opioid naïve surgical patients. METHODS: We conducted a retrospective observational study of adult opioid-naïve patients undergoing surgery from June 2012 through December 2018 at a large academic medical center. We used multivariate logistic regression to assess whether multimodal analgesic drugs consumed in the 24 h prior to discharge was associated with a reduction in high-risk opioid discharge prescriptions. We identified other risk factors for receiving a high-risk discharge opioid prescription. RESULTS: Among the 32,511 patients, 83% of patients were discharged with an opioid prescription. In 2013, 34.1% of patients with a discharge opioid prescription received a high-risk prescription and this declined to 17.7% by 2018. Use of multimodal analgesic agents during the final 24 h of hospitalization increased each year, with over 80% receiving at least one multimodal analgesic agent by 2018. The median OME consumed in the 24 h prior to discharge peaked in 2013 at 31 and steadily decreased to 19.8 by 2018. There was a significant association between the use of acetaminophen in the 24 h prior to discharge and a high-risk prescription at discharge (p < 0.01). OMEs consumed in the 24 h prior to discharge was a significant predictor of receiving a high-risk discharge prescription, even at low doses. Other factors associated with receipt of a high-risk discharge opioid prescription included male gender, race, history of anxiety disorder, and discharge service. DISCUSSION: Use of multimodal analgesia regimens in hospitalized surgical patients in the 24 h prior to hospital discharge increased between 2012 and 2018. Simultaneously, opioid use prior to hospital discharge decreased. Despite these gains, approximately one in five discharge prescriptions was high-risk (> 90 daily OME). In addition, we found that prescribing of discharge opioids above inpatient opioid requirements remains common in opioid naive surgical patients. CONCLUSION: Providers should account for pre-discharge opioid consumption and use of multimodal analgesia when considering the total and daily OME's that may be appropriate for an individual surgical patient on the discharge opioid prescription.

Substance use treatment services utilization and outcomes among probationers in drug courts compared to a matched cohort of probationers in traditional courts.

BACKGROUND AND OBJECTIVES: Drug courts provide an array of substance use treatments and community-based services for probationers struggling with substance use disorders. We assessed substance use treatment services utilization and related expenditures and relapse and recidivism outcomes and identified predictors of cost of provision of substance use treatment services in a matched cohort of Massachusetts probationers in drug courts and traditional courts. METHODS: This was an observational quasi-experimental study with 542 propensity-score-matched probationers initiating drug court between August 1, 2015 and February 28, 2018 and a minimum 6-month follow-up period. RESULTS: A significantly greater proportion of probationers in drug courts were female, self-reported opioids as their primary drug of choice, had a history of substance use treatment, and a high and very high risk of recidivism than their counterparts in traditional courts. We estimated that the provision of substance use treatment services was $1498 more expensive for probationers in drug courts than traditional courts (p = .054). There were no statistically significant differences in relapse or recidivism rates between court systems. DISCUSSION AND CONCLUSIONS: Probationer's age, gender, risk of recidivism at court intake, and enrollment length were strong predictors of expenditures on substance use treatment services. SCIENTIFIC SIGNIFICANCE: This was the first study to assess substance use treatment services utilization and outcomes among probationers in drug courts and traditional courts. Drug courts served the needs of probationers disproportionally impacted by nonserious drug-related offenses struggling with substance use disorders who were at a high and very high risk of recidivism at court intake.

Predictors of shortages of opioid analgesics in the US: Are the characteristics of the drug company the missing puzzle piece?

BACKGROUND: Shortages of opioid analgesics are increasingly common, interfere with patient care and increase healthcare cost. This study characterized the incidence of shortages of opioid analgesics in the period 2015-2019 and evaluated potential predictors to forecast the risk of shortages. METHODS: This was an observational retrospective study using the US Food and Drug Administration (FDA) drug shortages data. All FDA approved opioids were included in the study. Opioid analgesics were identified using the FDA National Drug Codes (NDC) and classified according to the Drug Enforcement Administration (DEA) schedule. We conducted Least Absolute Shrinkage and Selection Operator logistic regression analysis to assess direction of the association between risk of shortage and potential predictors. We used multivariable penalized logistic regression analysis to model predictors of shortages. We split the dataset into training and validation sets to evaluate the performance of the model. FINDINGS: The FDA approved 8,207 unique NDCs for opioid analgesics; 3,017 (36.8%) were in the market as of April 30, 2019 and 91(3.0%) of them were listed as in shortage by the FDA. All NDCs in shortage were schedule II opioids; 86 (94.5%) were injectable and 84 (92.3%) generics. There were 418 companies with at least one opioid NDC listed by the FDA. Three companies accounted for more than 4 in 5 of the schedule II active injectable opioids. For each unit increase in the number of prior instances of shortages of a company, the likelihood of an NDC shortage for that company increased by 3.4%. For each unit increase in number of NDCs marketed by a company, the odds of an NDC shortage for that company decreased by 1%. CONCLUSIONS: In the period 2015-2019, shortages of opioid analgesics disproportionally impacted schedule II and injectable opioids. The risk of shortage of opioid analgesics significantly increased with the incidence of previous instances of shortages of a manufacturing company and decreased with the number of NDCs marketed by a company. The characteristics of the manufacturing company, rather than the number of companies, might be the missing piece to the complex puzzle of drug shortages in the US.

Reductions in vancomycin and meropenem following the implementation of a febrile neutropenia management algorithm in hospitalized adults: An interrupted time series analysis.

OBJECTIVE: To evaluate broad-spectrum intravenous antibiotic use before and after the implementation of a revised febrile neutropenia management algorithm in a population of adults with hematologic malignancies. DESIGN: Quasi-experimental study. SETTING AND POPULATION: Patients admitted between 2014 and 2018 to the Adult Malignant Hematology service of an acute-care hospital in the United States. METHODS: Aggregate data for adult malignant hematology service were obtained for population-level antibiotic use: days of therapy (DOT), C. difficile infections, bacterial bloodstream infections, intensive care unit (ICU) length of stay, and in-hospital mortality. All rates are reported per 1,000 patient days before the implementation of an febrile neutropenia management algorithm (July 2014-May 2016) and after the intervention (June 2016-December 2018). These data were compared using interrupted time series analysis. RESULTS: In total, 2,014 patients comprised 6,788 encounters and 89,612 patient days during the study period. Broad-spectrum intravenous (IV) antibiotic use decreased by 5.7% with immediate reductions in meropenem and vancomycin use by 22 (P = .02) and 15 (P = .001) DOT per 1,000 patient days, respectively. Bacterial bloodstream infection rates significantly increased following algorithm implementation. No differences were observed in the use of other antibiotics or safety outcomes including C. difficile infection, ICU length of stay, and in-hospital mortality. CONCLUSIONS: Reductions in vancomycin and meropenem were observed following the implementation of a more stringent febrile neutropenia management algorithm, without evidence of adverse outcomes. Successful implementation occurred through a collaborative effort and continues to be a core reinforcement strategy at our institution. Future studies evaluating patient-level data may identify further stewardship opportunities in this population.

Liposomal Bupivacaine Decreases Postoperative Length of Stay and Opioid Use in Patients Undergoing Radical Cystectomy.

OBJECTIVE: To analyze differences in length of stay, opioid use, and other perioperative outcomes in patients undergoing radical cystectomy with urinary diversion who received either liposomal bupivacaine (LB) or epidural analgesia. METHODS: This was a single center, retrospective cohort study of patients undergoing open radical cystectomy with urinary diversion from 2015-2019 in the early recovery after surgery (ERAS) pathway. Patients received either LB or epidural catheter analgesia for post-operative pain control. LB was injected at the time of fascial closure to provide up to 72 hours of local analgesia. The primary outcome was post-operative length of stay. Secondary outcomes were post-operative opioid use, time to solid food, time to ambulation, and direct hospitalization costs. Multivariable Cox proportional hazards regression was used to determine associations between analgesia type and discharge. RESULTS: LB use was independently associated with shorter post-operative length of stay compared to epidural use (median (IQR) 4.9 days (3.9-5.8) vs 5.9 days (4.9-7.9), P<.001), less total opioid use (mean 188.3 vs 612.2 OME, P <.001), earlier diet advancement (mean 1.6 vs 2.4 days, P <.001), and decreased overall direct costs ($23,188 vs $29,628, P <.001). 45% of patients who received LB were opioid-free after surgery, none in the epidural group. On multivariable Cox proportional hazards regression modeling, LB use was independently associated with earlier discharge (HR 2.1, IQR 1.0-4.5). CONCLUSION: Use of LB in open radical cystectomy is associated with reduced LOS, less opioid exposure, and earlier diet advancement.

Perioperative Prescribing Practices of Extended-Release Opioids in Noncancer Surgical Patients, 2015-2018.

BACKGROUND: Extended-release (ER) opioids are indicated for the management of persistent moderate to severe pain in patients requiring around-the-clock opioid analgesics for an extended period of time. Concerns have been raised regarding safety of ER opioids due to its potential for abuse and dependence. However, little is known about perioperative prescribing practices of ER opioids. This study assessed perioperative prescribing practices of ER opioids in noncancer surgical patients stratified by type of opioid exposure prior to admission and examined predictors of postoperative opioid administration in oral morphine equivalents (OME). METHODS: This was a retrospective cohort study using the University of California San Francisco Medical Center electronic health record data. This study included 25,396 adult noncancer patients undergoing elective surgery under general anesthesia in the period 2015-2018. The primary study outcome was predictors of postoperative administration of opioids in hospitalized surgical patients. Secondary outcomes included patients discontinued and initiated on ER opioids during their hospital stay. RESULTS: substance use disorder diagnosis and use of opioids, surgery type, and postoperative administration of nonopioid analgesics were associated with postoperative administration of opioids (P < .0001). The estimated adjusted mean (95% confidence interval [CI]) of postoperative administration of OME prior to admission in ER opioid users (170.08 mg; 147.08-196.67) was twice the amount for opioid-naïve patients (81.36 mg; 70.7-93.63; P < .0001). One in 5 prior to admission ER opioid users were weaned off ER opioids while hospitalized without adversely affecting their postoperative pain or hospital length of stay (LOS). Four of 5 patients who used ER opioids prior to admission also received ER opioids after surgery, whereas, 1 in 100 opioid-naïve patients received ER opioids during their hospital stay. CONCLUSIONS: We found significant variability in the perioperative prescribing practices of ER opioids in hospitalized noncancer surgical patients by use of opioids prior to admission and surgery type. Pain medicine practitioners and surgeons may play a significant role tackling the surgery-related risk of exposure to ER opioids and decreasing opioid-related complications.

Long-Term Trends in Postoperative Opioid Prescribing, 1994 to 2014.

Opioids are routinely prescribed to manage acute postoperative pain, but changes in postoperative opioid prescribing associated with the marketing of long-acting opioids such as OxyContin have not been described in the surgical cohort. Methods: Using a large commercial claims data set, we studied postoperative opioid prescribing after selected common surgical procedures between 1994 and 2014. For each procedure and year, we calculated the mean postoperative morphine milligram equivalents (MME) filled on the index prescription and assessed the proportion of patients who filled a high-dose prescription (≥350 MME). We reported changes in postoperative opioid prescribing over time and identified predictors of filling a high-dose postoperative opioid prescription. Results: We identified 1,321,264 adult patients undergoing selected common surgical procedures between 1994 and 2014, of whom 80.3% filled a postoperative opioid prescription. One in five surgery patients filled a high-dose postoperative opioid prescription. Between 1994 and 2014, the mean MME filled increased by 145%, 84%, and 85% for lumbar laminectomy/laminotomy, total knee arthroplasty, and total hip arthroplasty, respectively. The procedures most likely to be associated with a high-dose opioid fill were all orthopaedic procedures (AOR 5.20 to 7.55, P < 0.001 for all). Patients whose postoperative opioid prescription included a long-acting formulation had the highest odds of filling a prescription that exceeded 350 MME (AOR 32.01, 95% CI, 30.23-33.90). Discussion: After the US introduction of long-acting opioids such as OxyContin, postoperative opioid prescribing in commercially insured patients increased in parallel with broader US opioid-prescribing trends, most notably among patients undergoing orthopaedic surgical procedures. The increase in the mean annual MME filled starting in the late 1990s was driven in part by the higher proportion of long-acting opioid formulations on the index postoperative opioid prescription filled by orthopaedic surgery patients.

Using a Machine Learning System to Identify and Prevent Medication Prescribing Errors: A Clinical and Cost Analysis Evaluation.

BACKGROUND: Clinical decision support (CDS) alerting tools can identify and reduce medication errors. However, they are typically rule-based and can identify only the errors previously programmed into their alerting logic. Machine learning holds promise for improving medication error detection and reducing costs associated with adverse events. This study evaluates the ability of a machine learning system (MedAware) to generate clinically valid alerts and estimates the cost savings associated with potentially prevented adverse events. METHODS: Alerts were generated retrospectively by the MedAware system on outpatient data from two academic medical centers between 2009 and 2013. MedAware alerts were compared to alerts in an existing CDS system. A random sample of 300 alerts was selected for medical record review. Frequency and severity of potential outcomes of alerted medication errors of medium and high clinical value were estimated, along with associated health care costs of these potentially prevented adverse events. RESULTS: A total of 10,668 alerts were generated. Overall, 68.2% of MedAware alerts would not have been generated by the existing CDS system. Ninety-two percent of a random sample of the chart-reviewed alerts were accurate based on structured data available in the record, and 79.7% were clinically valid. Estimated cost of adverse events potentially prevented in an outpatient setting was more than $60 per drug alert and $1.3 million when extrapolating study findings to the full patient population. CONCLUSION: A machine learning system identified clinically valid medication error alerts that might otherwise be missed with existing CDS systems. Estimates show potential for cost savings associated with potentially prevented adverse events.

The Landscape of Cellular and Gene Therapy Products: Authorization, Discontinuations, and Cost.

Background: Cell and gene therapy products belong to a diverse class of biopharmaceuticals known as advanced therapy medicinal products. Cell and gene therapy products are used for the treatment and prevention of diseases that until recently were only managed chronically. The objective of this study was to examine the characteristics of market authorizations, discontinuations, and prices of cellular and gene therapy products worldwide. Data and Methods: We conducted an electronic search of authorized cell, tissue-engineered, and gene therapy products from the databases of the main drug regulatory agencies. The analysis excluded hematopoietic progenitor cell cord blood products authorized by the U.S. Food and Drug Administration. Price information was derived from the Red Book (Truven Health Analytics) for the United States, health technology assessment agencies for Europe, and other public sector sources and company news for other countries. We also searched the scientific literature for authorizations, discontinuations, and price information using MEDLINE/PubMed, Cochrane Library, Google Scholar, and EMBASE databases. All cost data were converted to U.S. dollars. Descriptive analysis was conducted in this study. Results: There were 52 different cell, tissue engineering and gene therapy products with 69 market authorizations in the world as of December 31, 2018. The products included 18 (34%) cell therapies, 23 (43.4%) tissue engineered products, and 12 (22.6%) gene therapies. There were 21 (30.4% of all authorizations) cell therapy, 26 (37.7%) tissue-engineered, and 22 (31.9%) gene therapy market authorizations. The EMA withdrew the authorization for two tissue engineering products, one cell therapy and one gene therapy, and New Zealand lapsed approval of one cell therapy. Most products were first authorized after 2010, including 10 (83.3%) gene therapies, 13 (72.2%) cell therapies, and 13 (56.5%) tissue-engineered products. The treatment price for four allogenic cell therapies varied from $2,150 in India to $200,000 in Canada. The treatment price for three autologous cell therapies ranged from $61,500 in the United Kingdom to a listed price of $169,206 in the United States. Tissue-engineered treatment prices varied from $400 in South Korea to $123,154 in Japan. Gene therapy treatment prices ranged from $5,501 for tonogenchoncel-L in South Korea to $1,398,321 for alipogene tiparvovec in Germany. Conclusions: A significant number of new cell, tissue, and gene therapies have been approved in the past decade. Most products were conditionally authorized and targeted rare cancers, genetic diseases, and other debilitating diseases. However, there are also products approved for cosmetic reasons. Cell, tissue, and gene therapies are among the most expensive therapies available. Healthcare systems are not prepared to assume the cost of future therapies for a myriad of rare diseases and common diseases of epidemic proportions.