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Background: To determine if marijuana legalization was associated with reduced opioid mortality., Study Design: The United States (US) opioid mortality trend during the 2010-2019 decade was compared in states and District of Columbia (jurisdictions) that had implemented marijuana legalization with states that had not. Acceleration of opioid mortality during 2020, the first year of the coronavirus disease 2019 (COVID-19) pandemic, was also compared in recreational and medicinal-only legalizing jurisdictions., Methods: Joinpoint methodology was applied to the Centers for Disease Control and Prevention WONDER data. Trends in legalizing jurisdictions were cumulative aggregates., Results: The overall opioid and fentanyl death rates and the percentage of opioid deaths due to fentanyl increased more during 2010-2019 in jurisdictions that legalized marijuana than in those that did not (pairwise comparison p = 0.007, 0.05, and 0.006, respectively). By 2019, the all-opioid and fentanyl death rates were 44 and 50 percent greater in the legalizing than in the nonlegalizing jurisdictions, respectively. When the COVID-19 pandemic hit in 2020, jurisdictions that implemented recreational marijuana legalization before 2019 had significantly greater increases in both overall opioid and fentanyl death rates than jurisdictions with medicinal-only legalization. For all-opioids, the mean (95 percent confidence interval) 2019-to-2020 increases were 46.5 percent (36.6, 56.3 percent) and 29.1 percent (20.2, 37.9 percent), respectively (p = 0.02). For fentanyl, they were 115.6 percent (80.2, 151.6 percent) and 55.4 percent (31.6, 79.2 percent), respectively (p = 0.01)., Conclusions: During the past decade, marijuana legalization in the US was associated at the jurisdiction level with a greater acceleration in opioid death rate. An even greater increase in opioid mortality occurred in recreational-legalizing jurisdictions with the onset of the COVID-19 pandemic. Marijuana legalization is correlated with worsening of the US opioid epidemic.

The legality of cannabis use has been changing in a number of jurisdictions around the world. In the U.S., it has been legalised for medicinal and/or recreational uses in 34 jurisdictions and counting. This study leverages the decades-long experience of legalisation in the U.S. to provide an overview of the associated changes in public attitudes, cannabis markets and adverse health effects. We found a broad-based warming of public attitudes toward legalisation, potentially influenced by the increasingly positive portrayal of cannabis in media and declines in cannabis risk perceptions. Potency of cannabis products increased significantly while prices fell sharply. Although adults were less responsive to price changes than adolescents, adults who use cannabis regularly were sensitive to prices, with an estimated 10% price reduction leading to about 2.5% increase in the rate of use. Overall, past-year cannabis use has increased in adults since 2002, and adults over 26 years old who resided in states with medicinal cannabis laws were more likely to have used cannabis in the past 30 days, to have used daily, and to have higher rates of cannabis use disorders than adults who resided in states without legalised medicinal cannabis. Traffic fatalities involving cannabis temporarily increased in some states post-legalisation, and there were more presentations to medical services related to chronic regular cannabis use. There is suggestive evidence that adverse health consequences have increased among people who use cannabis regularly since legalisation. More robust research is needed to determine whether these effects of legalisation are temporary or long-term., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To investigate characteristics and trends of methamphetamine exposures reported to United States (US) poison control centers., Methods: Data from the National Poison Data System were analyzed., Results: From January 1, 2000 through December 31, 2019, US poison control centers managed 54,199 cases involving methamphetamine as the first-ranked substance. Adults 20-39 years old accounted for more than half (56.3%) of cases. There were 1,291 deaths, of which 43.0% involved multiple-substance exposures. Among multiple-substance exposures in which methamphetamine was the first-ranked substance, stimulants and street drugs (excluding methamphetamine) were most commonly also present (22.7%), followed by opioids (19.0%). The substance class associated with the most fatalities was opioids ( n  = 243, 26.6%). The rate of methamphetamine exposures per 100,000 US population increased from 0.6 to 1.1 from 2000-2005, then decreased from 1.1 to 0.4 from 2005-2007, followed by an increase from 0.4 to 2.6 from 2007-2019. From 2007-2019, the rate significantly increased in all US regions, and among all age groups, except among 6-12-year-olds. Also, the rates of single-substance and multiple-substance exposures each increased significantly (both p  < 0.0001) from 2007-2019, as did the overall methamphetamine fatality rate per 100,000 US population (0.0036 to 0.022, p  < 0.0001). From 2000-2019, the proportions of cases resulting in admission to a health care facility and serious medical outcome increased from 30.2% to 47.8% ( p  < 0.0001) and from 37.6% to 54.0% ( p  < 0.0001), respectively., Conclusions: The rate of exposure to methamphetamine in the US declined initially following passage of the Combat Methamphetamine Epidemic Act of 2005. However, since 2007, the rate and severity of exposures to methamphetamine have increased, primarily driven by individuals 20 years or older. Increased prevention efforts are needed, including prevention of methamphetamine initiation among adolescents and young adults, improved access to effective treatment for co-occurring mental health and substance use disorders, and prevention of unintentional exposures among children.

This brief report covers recent advances in cannabis and cannabinoid regulation and drug approval. The popularity of cannabis and cannabinoid products continues to rise, and these products are available for the majority of the population in the United States to purchase as easily as alcohol. Although many states have approved programs and research licenses, these activities and products all remain federally illegal. The solution may be for the United States to offer multiple pathways for product approval that adapt to the diversity of the products and the needs of the consumer. Multiple pathways for market approval would protect public health, whether the public is using cannabis and cannabinoids as a medicine, a wellness product, or as a recreational substance.
., (© 2020, AICHServier GroupCopyright © 2020 AICH Servier Group. All rights reserved.)

Cannabidiol (CBD) is the second most abundant cannabinoid present in Cannabis sativa L. It is not associated with psychotropic activity and is capable to mitigate the psychotomimetic effects produced by tetrahydrocannabinol (THC). The latest cannabis decriminalization policies and the high applicability in therapeutic and technologic-industrial fields, have determined an exponential marketing growth of foods, cosmetics and in particularly medicinal products containing CBD, which are easily available for consumers. Most importantly, on 2018 United States Food and Drug Administration approved CBD oral solution with the trade name of Epidiolex® for the treatment of two rare and severe forms of epilepsy, "Lennox-Gastaut syndrome" and "Dravet syndrome", in pediatric patients. The aim of this review was to focus on pharmacology and on legal status of CBD, to highlight the lack of harmonization of international regulatory laws over the marketing authorization of CBD-based products.

Introduction: There is concern that recreational marijuana legalization (RML) may lead to increased cannabis use disorder (CUD) among youth due to increased marijuana use. This study investigates whether adolescent substance use disorder treatment admissions for marijuana use increased in Colorado and Washington following RML., Methods: Annual data on 2008-2017 treatment admissions for marijuana use from the SAMHSA TEDS-A dataset for adolescents age 12-17 were used to model state treatment admissions trends. Difference-in-differences models were used to investigate whether treatment admissions increased following RML in Colorado/Washington compared to non-RML states, after adjusting for socioeconomic characteristics and treatment availability., Results: Over all states in the analysis, the rate of adolescent treatment admissions for marijuana use declined significantly over the study period (β=-3.375, 95 % CI=-4.842, -1.907), with the mean rate falling nearly in half. The decline in admissions rate was greater in Colorado and Washington compared to non-RML states following RML, though this difference was not significant (β=-7.671, 95 % CI=-38.798, 23.456)., Conclusion: Adolescent treatment admissions for marijuana use did not increase in Colorado and Washington following RML. This may be because youth marijuana use did not increase, CUD did not increase (even if use did increase), or treatment seeking behaviors changed due to shifts in attitudes and perceptions of risk towards marijuana use., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The continued toll of opioid-related overdoses has motivated efforts to expand availability of naloxone to persons at high risk of overdose, with 2016 federal guidance encouraging clinicians to co-prescribe naloxone to patients with increased overdose risk. Some states have pursued analogous or stricter legal requirements that could more heavily influence prescriber behavior., Methods: We conducted a systematic legal review of state laws that mandate or recommend that healthcare providers prescribe naloxone to patients with indicators for opioid overdose risk. We coded relevant statutes and regulations for: applicable populations, patient criteria, educational requirements, and exemptions., Results: As of September 2019, 17 states had enacted naloxone co-prescribing laws, the earliest of which was implemented by Louisiana in January 2016. If patient overdose risk criteria are met, over half of these states mandate that providers prescribe naloxone (7 states, 41.1 %) or offer a naloxone prescription (2 states, 11.8 %); the remainder encourage prescribers to consider prescribing naloxone (8 states). Most states (58.8 %) define patient overdose risk based on opioid dosages prescribed, although the threshold varies substantially; other common overdose risk criteria include concomitant opioid and benzodiazepine prescriptions and patient history of substance use disorder or mental illness., Conclusions: A growing minority of states has adopted a naloxone prescribing law, although these policies remain less prevalent than other naloxone access laws. By targeting higher-risk patients during clinical encounters, naloxone prescribing requirements could increase naloxone prescribed, destigmatize naloxone use, and reduce overdose harms. Further investigation into policy effectiveness, unintended consequences, and appropriate parameters is warranted., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier B.V.)

Importance: US law requires testing of new drugs before approval to ensure that they provide a well-defined benefit that is commensurate with their risks. A major challenge for the US Food and Drug Administration (FDA) is to achieve an appropriate balance between rigorous testing and the need for timely approval of drugs that have benefits that outweigh their risks., Objective: To describe the evolution of laws and standards affecting drug testing, the use of new approval programs and standards, expansions of the role and authority of the FDA, and changes in the number of drugs approved from the 1980s to 2018., Evidence: Sources of evidence included principal federal laws and FDA regulations (1962-2018) and FDA databases of approved new drugs (1984-2018), generic drugs (1970-2018), biologics (1984-2018), and vaccines (1998-2018); special development and approval programs (Orphan drug [1984-2018], Fast-Track [1988-2018], Priority Review and its predecessors [1984-2018], Accelerated Approval [1992-2018], and Breakthrough Therapy [2012-2018]); expanded access (2010-2017) and Risk Evaluation and Mitigation Strategies (2008-2018); and user fees paid to the FDA by industry (1993-2018)., Findings: From 1983 to 2018, legislation and regulatory initiatives have substantially changed drug approval at the FDA. The mean annual number of new drug approvals, including biologics, was 34 from 1990-1999, 25 from 2000-2009, and 41 from 2010-2018. New biologic product approvals increased from a median of 2.5 from 1990-1999, to 5 from 2000-2013, to 12 from 2014-2018. The median annual number of generic drugs approved was 136 from 1970 to the enactment of the Hatch-Waxman Act in 1984; 284 from 1985 to the enactment of the Generic Drug User Fee Act in 2012; and 588 from 2013-2018. Prescription drug user fee funding expanded from new drugs and biologics in 1992 to generic and biosimilar drugs in 2012. The amount of Prescription Drug User Fee Act fees collected from industry increased from an annual mean of $66 million in 1993-1997 to $820 million in 2013-2017, and in 2018, user fees accounted for approximately 80% of the salaries of review personnel responsible for the approval of new drugs. The proportion of drugs approved with an Orphan Drug Act designation increased from 18% (55/304) in 1984-1995, to 22% (82/379) in 1996-2007, to 41% (154/380) in 2008-2018. Use of Accelerated Approval, Fast-Track, and Priority Review for new drugs has increased over time, with 81% (48/59) of new drugs benefiting from at least 1 such expedited program in 2018. The proportion of new approvals supported by at least 2 pivotal trials decreased from 80.6% in 1995-1997 to 52.8% in 2015-2017, based on 124 and 106 approvals, respectively, while the median number of patients studied did not change significantly (774 vs 816). FDA drug review times declined from more than 3 years in 1983 to less than 1 year in 2017, but total time from the authorization of clinical testing to approval has remained at approximately 8 years over that period., Conclusions and Relevance: Over the last 4 decades, the approval and regulation processes for pharmaceutical agents have evolved and increased in complexity as special programs have been added and as the use of surrogate measures has been encouraged. The FDA funding needed to implement and manage these programs has been addressed by expanding industry-paid user fees. The FDA has increasingly accepted less data and more surrogate measures, and has shortened its review times.

Objectives: There has been advocacy for legalization of abusable substances, but systematic data on societal beliefs regarding such legalization are limited. People who use substances may have unique beliefs about legalization, and this study assessed whether they would be in favor of drug legalization/decriminalization. It was hypothesized that those who use particular drugs (especially marijuana) would support its legalization/decriminalization, but that this would not be the case across all classes (especially opioids and stimulants)., Methods: A nationwide sample of 506 adults were surveyed online to assess demographic characteristics, substance misuse, and beliefs regarding drug legalization/decriminalization. Legalization/decriminalization beliefs for specific drugs were assessed on an 11-point scale (0, strongly disagree; 10, strongly agree)., Results: For persons with opioid misuse (15.4%), when asked about their agreement with: "heroin should be legalized," the mean score was 4.6 (SEE = 0.4; neutral). For persons with stimulant misuse (12.1%), when asked about their agreement with: "cocaine should be legalized," the score was 4.2 (0.5). However, for persons with marijuana misuse (34.0%), when asked about their agreement with: "medical marijuana should be legalized" the score was 8.2 (0.3; indicating agreement), and for "recreational marijuana" the score was also 8.2 (0.3)., Conclusions: These results suggest that persons who used marijuana strongly support the legalization of both recreational and medical marijuana, whereas persons who primarily have opioid or stimulant misuse have less strongly held beliefs about legalization of substances within those respective categories. By including those who misuse drugs, these data assist in framing discussions of drug legalization and have the potential to inform drug policy considerations.

We examine the association between opioid prescription patterns in privately insured adults and changes in state cannabis laws among five age groups (18-25, 26-35 36-45, 46-55 and 56-64 years). Using the 2016 Clinformatics Data Mart, a nationwide commercial health insurance database, we performed a cross-sectional analysis of two types of opioid prescribing (>30-day and >90-day prescriptions) among all adults aged 18-64 based on the stringency of cannabis laws. We found a significant interaction between age and cannabis law on opioid prescriptions. Age-stratified multilevel multivariable analyses showed lower opioid prescription rates in the four younger age groups only in states with medical cannabis laws, when considering both >30 day and >90 day opioid use [>30 day adjusted odds ratio (aOR) = 0.56, in 18-25, aOR = 0.67 in 26-35, aOR = 0.67 in 36-45, and aOR = 0.76 in 46-54 years; >90 day aOR = 0.56, in 18-25, aOR = 0.68 in 26-35, aOR = 0.69 in 36-45, and aOR = 0.77 in 46-54 years, P < 0.0001 for all]. This association was not significant in the oldest age group of 55-64 years. There was no significant association between opioid prescriptions and other categories of cannabis laws (recreational use and decriminalization) in any of the age groups studied., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The cost of prescription drugs in the United States continues to be a source of concern for patients, caregivers, and policymakers. Drug prices typically decline rapidly once generic drugs receive US Food and Drug Administration (FDA) approval and enter the market, but the past decade has witnessed rising costs and shortages of generic drugs. We describe the strategies used by brand-name manufacturers to undermine generic competition and the reasons underlying the price increases of off-patent drugs, some of which continue to lack any competition from generic versions, and others that have increased in price despite having generic versions. We discuss the FDA's role in addressing drug prices and promoting competition, including recent agency policies to modify its process of reviewing generic drug applications and to prioritize applications for off-patent drugs with few competitors. We also examine proposed policy solutions and research areas that could help address the price increases of off-patent drugs., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Objectives: Medical marijuana use may substitute prescription opioid use, whereas nonmedical marijuana use may be a risk factor of prescription opioid misuse. This study examined the associations between recreational marijuana legalization and prescription opioids received by Medicaid enrollees., Methods: State-level quarterly prescription drug utilization records for Medicaid enrollees during 2010-2017 were obtained from Medicaid State Drug Utilization Data. The primary outcome, opioid prescriptions received, was measured in three population-adjusted variables: number of opioid prescriptions, total doses of opioid prescriptions in morphine milligram equivalents, and related Medicaid spending, per quarter per 100 enrollees. Two difference-in-difference models were used to test the associations: eight states and DC that legalized recreational marijuana during the study period were first compared among themselves, then compared to six states with medical marijuana legalized before the study period. Schedule II and III opioids were analyzed separately., Results: In models comparing eight states and DC, legalization was not associated with Schedule II opioid outcomes; having recreational marijuana legalization effective in 2015 was associated with reductions in number of prescriptions, total doses, and spending of Schedule III opioids by 32% (95% CI: (-49%, -15%), p = 0.003), 30% ((-55%, -4.4%), p = 0.027), and 31% ((-59%, -3.6%), p = 0.031), respectively. In models comparing eight states and DC to six states with medical marijuana legalization, recreational marijuana legalization was not associated with any opioid outcome., Conclusions: No evidence suggested that recreational marijuana legalization increased prescription opioids received by Medicaid enrollees. There was some evidence in some states for reduced Schedule III opioids following the legalization., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: As of May 2017, the United States federal government renewed its prioritization for the enforcement of mandatory minimum sentences for illicit drug offenses. While the effect of such policies on racial disparities in incarceration is well-documented, less is known about the extent to which these laws are associated with decreased drug use. This study aims to identify changes in cocaine use associated with mandatory minimum sentencing policies by examining differential sentences for powder and crack cocaine set by the Anti-Drug Abuse Act (ADAA) (100:1) and the Fair Sentencing Act (FSA), which reduced the disparate sentencing to 18:1., Methods: Using data from National Survey on Drug Use and Health, we examined past-year cocaine use before and after implementation of the ADAA (1985-1990, N = 21,296) and FSA (2009-2013, N = 130,574). We used weighted logistic regressions and Z-tests across models to identify differential change in use between crack and powder cocaine. Prescription drug misuse, or use outside prescribed indication or dose, was modeled as a negative control to identify underlying drug trends not related to sentencing policies., Results: Despite harsher ADAA penalties for crack compared to powder cocaine, there was no decrease in crack use following implementation of sentencing policies (odds ratio (OR): 0.72, p = 0.13), although both powder cocaine use and misuse of prescription drugs (the negative control) decreased (OR: 0.59, p < 0.01; OR: 0.42, p < 0.01 respectively). Furthermore, there was no change in crack use following the FSA, but powder cocaine use decreased, despite no changes to powder cocaine sentences (OR: 0.81, p = 0.02), suggesting that drug use is driven by factors not associated with sentencing policy., Conclusions: Despite harsher penalties for crack versus powder cocaine, crack use declined less than powder cocaine and even less than drugs not included in sentencing policies. These findings suggest that mandatory minimum sentencing may not be an effective method of deterring cocaine use.

Background: Half of the US states have legalized medical cannabis (marijuana), some allow recreational use. The economic and public health effects of these policies are still being evaluated. We hypothesized that cannabis legalization was associated with an increase in the proportion of motor vehicle crash fatalities involving cannabis-positive drivers, and that cannabis use is associated with high-risk behavior and poor insurance status., Methods: Hawaii legalized cannabis in 2000. Fatality Analysis Reporting System data were analyzed before (1993-2000) and after (2001-2015) legalization. The presence of cannabis (THC), methamphetamine, and alcohol in fatally injured drivers was compared. Data from the state's highest level trauma center were reviewed for THC status from 1997 to 2013. State Trauma Registry data from 2011 to 2015 were reviewed to evaluate association between cannabis, helmet/seatbelt use, and payor mix., Results: THC positivity among driver fatalities increased since legalization, with a threefold increase from 1993-2000 to 2001-2015. Methamphetamine, which has remained illegal, and alcohol positivity were not significantly different before versus after 2000. THC-positive fatalities were younger, and more likely, single-vehicle accidents, nighttime crashes, and speeding. They were less likely to have used a seatbelt or helmet. THC positivity among all injured patients tested at our highest level trauma center increased from 11% before to 20% after legalization. From 2011 to 2015, THC-positive patients were significantly less likely to wear a seatbelt or helmet (33% vs 56%). They were twice as likely to have Medicaid insurance (28% vs 14%)., Conclusion: Since the legalization of cannabis, THC positivity among MVC fatalities has tripled statewide, and THC positivity among patients presenting to the highest level trauma center has doubled. THC-positive patients are less likely to use protective devices and more likely to rely on publically funded medical insurance. These findings have implications nationally and underscore the need for further research and policy development to address the public health effects and the costs of cannabis-related trauma., Level of Evidence: Prognostic, level III.

The legal landscape for addressing an injury related to the use of a pharmaceutical product varies from country to country. Approximately 10 countries have adopted some form of no-fault compensation, in which an individual must establish that they sustained an injury caused by the medicine, but need not demonstrate that the manufacturer acted negligently in order to recover. This commentary compares and contrasts the approach taken in Japan with that in the United States., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Background: Several countries and many U.S. states have allowed, for cannabis to be used as therapy to treat chronic conditions or pain., This has increased the use of cannabis, particularly among older people.Because cannabis has been linked to adverse cardiac events in the medical literature, there may be unintended consequences on increased use among older people., Methods: We analyze cardiac-related mortality data from the U.S. National Vital Statistics System for 1990-2014. We use difference-in-difference fixed-effects models to assess whether there are increased rates of cardiac-related mortality following passage of medical cannabis programs. We also analyze whether states with more liberal rules on dispensing cannabis show higher mortality rates., Results: For men, there is a statistically significant 2.3% increase in the rate of cardiac death following passage. For women, there is a 1.3% increase that is also statistically significant. he effects increase or both men and women with age. The effects are also stronger in states with more a lax approach to cannabis dispensing., Conclusion: Policymakers should be aware of a potential unintended consequence of allowing broader use of cannabis, specifically for those more at risk of cardiovascular events., (Copyright © 2017. Published by Elsevier B.V.)

Importance: Over the last 25 years, illicit cannabis use and cannabis use disorders have increased among US adults, and 28 states have passed medical marijuana laws (MML). Little is known about MML and adult illicit cannabis use or cannabis use disorders considered over time., Objective: To present national data on state MML and degree of change in the prevalence of cannabis use and disorders., Design, Participants, and Setting: Differences in the degree of change between those living in MML states and other states were examined using 3 cross-sectional US adult surveys: the National Longitudinal Alcohol Epidemiologic Survey (NLAES; 1991-1992), the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; 2001-2002), and the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III; 2012-2013). Early-MML states passed MML between NLAES and NESARC ("earlier period"). Late-MML states passed MML between NESARC and NESARC-III ("later period")., Main Outcomes and Measures: Past-year illicit cannabis use and DSM-IV cannabis use disorder., Results: Overall, from 1991-1992 to 2012-2013, illicit cannabis use increased significantly more in states that passed MML than in other states (1.4-percentage point more; SE, 0.5; P = .004), as did cannabis use disorders (0.7-percentage point more; SE, 0.3; P = .03). In the earlier period, illicit cannabis use and disorders decreased similarly in non-MML states and in California (where prevalence was much higher to start with). In contrast, in remaining early-MML states, the prevalence of use and disorders increased. Remaining early-MML and non-MML states differed significantly for use (by 2.5 percentage points; SE, 0.9; P = .004) and disorder (1.1 percentage points; SE, 0.5; P = .02). In the later period, illicit use increased by the following percentage points: never-MML states, 3.5 (SE, 0.5); California, 5.3 (SE, 1.0); Colorado, 7.0 (SE, 1.6); other early-MML states, 2.6 (SE, 0.9); and late-MML states, 5.1 (SE, 0.8). Compared with never-MML states, increases in use were significantly greater in late-MML states (1.6-percentage point more; SE, 0.6; P = .01), California (1.8-percentage point more; SE, 0.9; P = .04), and Colorado (3.5-percentage point more; SE, 1.5; P = .03). Increases in cannabis use disorder, which was less prevalent, were smaller but followed similar patterns descriptively, with change greater than never-MML states in California (1.0-percentage point more; SE, 0.5; P = .06) and Colorado (1.6-percentage point more; SE, 0.8; P = .04)., Conclusions and Relevance: Medical marijuana laws appear to have contributed to increased prevalence of illicit cannabis use and cannabis use disorders. State-specific policy changes may also have played a role. While medical marijuana may help some, cannabis-related health consequences associated with changes in state marijuana laws should receive consideration by health care professionals and the public.

Background: Historically, neonatal therapeutic interventions were derived from adult therapeutics, and tragedies resulting from this approach have demonstrated differences in the pathophysiologic and developmental processes between neonates and older patients. Over the past 3 decades, researchers and collaborative research networks have made progress in the systematic evaluation of neonatal therapies, yet most neonatal therapeutic products have been incompletely assessed for safety and efficacy, and remain unlabeled and unapproved., Approach: This work describes the legislative initiatives that have stimulated an increase in pediatric and neonatal studies. It highlights examples of successful neonatal drug studies that have resulted in informative neonatal labeling changes, as well as studies that have produced incomplete information. Strategies that support the design of successful studies, including targeting specific subpopulations, modeling and simulation to inform dose selection, innovative design strategies, biomarkers, and endpoints are discussed. Multi-stakeholder consortia such as the International Neonatal Consortium (INC), are working to improve the tools needed for the development of neonatal therapies. These research tools may be used by trial networks to inform consistent and efficient multicenter studies., Conclusion: More data are needed to support safe and effective use of drugs in neonates, and to obtain these data, a thorough understanding of pathophysiology, drug disposition, biomarkers, and clinically-meaningful endpoints is required. This information will be derived from clinical trials, registries, real-world evidence, and the medical literature. Collaboration of consortia and the development of research networks are essential to achieving these goals., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

This paper assesses the current regulatory environment, relevant regulations and guidelines, and their impact on continuous manufacturing. It summarizes current regulatory experience and learning from both review and inspection perspectives. It outlines key regulatory aspects, including continuous manufacturing process description and control strategy in regulatory files, process validation, and key Good Manufacturing Practice (GMP) requirements. In addition, the paper identifies regulatory gaps and challenges and proposes a way forward to facilitate implementation., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

In June, 2012 the United States Food and Drug Administration (FDA) developed a "blueprint" for prescriber education as a means of directing Certified Medical Education (CME) activities that included content which would meet the regulatory requirements of the class-wide, longacting/ extended-release (LA-ER) opioid Risk Evaluation Mitigation Strategies (REMS). Within the blueprint is the suggested adoption of Patient-Provider Agreements (PPAs) to be used in association with opioid prescribing, but, to our knowledge, there have been no reported evaluations of the role played by opioid-agent PPAs in clinical practice, or of the perceptions of this regulatory mandate by clinicians. Therefore, we conducted a survey regarding PPA perceptions by opioid prescribers that was posted for five weeks on a well-trafficked online CME service provider (Medscape). Of the 1,232 respondents (reflecting a 99.5% completion rate), 52.4% treat acute or chronic pain with opioids. The survey identified an improvement of opioid safe-use education (21% of respondents) as the most frequently selected beneficial element of PPAs. Conversely, the challenges to adoption included time constraints (21% of physicians) as well as lack of evidence that PPAs will reduce drug misuse, and the lack of a uniform, patient-friendly PPA. Based on our survey, clinicians consider the PPA of potential value, but data regarding the utility of such an instrument are lacking.

Importance: Opioid analgesic overdose mortality continues to rise in the United States, driven by increases in prescribing for chronic pain. Because chronic pain is a major indication for medical cannabis, laws that establish access to medical cannabis may change overdose mortality related to opioid analgesics in states that have enacted them., Objective: To determine the association between the presence of state medical cannabis laws and opioid analgesic overdose mortality., Design, Setting, and Participants: A time-series analysis was conducted of medical cannabis laws and state-level death certificate data in the United States from 1999 to 2010; all 50 states were included., Exposures: Presence of a law establishing a medical cannabis program in the state., Main Outcomes and Measures: Age-adjusted opioid analgesic overdose death rate per 100 000 population in each state. Regression models were developed including state and year fixed effects, the presence of 3 different policies regarding opioid analgesics, and the state-specific unemployment rate., Results: Three states (California, Oregon, and Washington) had medical cannabis laws effective prior to 1999. Ten states (Alaska, Colorado, Hawaii, Maine, Michigan, Montana, Nevada, New Mexico, Rhode Island, and Vermont) enacted medical cannabis laws between 1999 and 2010. States with medical cannabis laws had a 24.8% lower mean annual opioid overdose mortality rate (95% CI, -37.5% to -9.5%; P = .003) compared with states without medical cannabis laws. Examination of the association between medical cannabis laws and opioid analgesic overdose mortality in each year after implementation of the law showed that such laws were associated with a lower rate of overdose mortality that generally strengthened over time: year 1 (-19.9%; 95% CI, -30.6% to -7.7%; P = .002), year 2 (-25.2%; 95% CI, -40.6% to -5.9%; P = .01), year 3 (-23.6%; 95% CI, -41.1% to -1.0%; P = .04), year 4 (-20.2%; 95% CI, -33.6% to -4.0%; P = .02), year 5 (-33.7%; 95% CI, -50.9% to -10.4%; P = .008), and year 6 (-33.3%; 95% CI, -44.7% to -19.6%; P < .001). In secondary analyses, the findings remained similar., Conclusions and Relevance: Medical cannabis laws are associated with significantly lower state-level opioid overdose mortality rates. Further investigation is required to determine how medical cannabis laws may interact with policies aimed at preventing opioid analgesic overdose.

This article describes the shortage of generic injectable medications in Canada that affected hospitals in 2012. It traces the events leading up to the drug shortage, the causes of the shortage, and the responses by health administrators, pharmacists, and ethicists. The article argues that generic drug shortages are an ethical problem because health care organizations and governments have an obligation to avoid exposing patients to resource scarcity. The article also discusses some options governments could pursue in order to secure the drug supply and thereby fulfill their ethical obligations.

Application of personalized medicine in drug development and regulation has been limited by similar logistical, informatics, and cultural barriers that limit use of pharmacogenetics in the clinic. An additional challenge is coordinated codevelopment of new drugs and diagnostic tests. Nevertheless, the impact of personalized medicine strategies (e.g., pharmacogenomics) is being realized. We highlight some of our experiences to date and considerations for the development of the next generation of targeted therapies.

Many, if not most, commercially available diabetes treatment products are protected by some form of intellectual property. This article discusses the development and commercialization of products in view of the state of intellectual property for the diabetes treatment market, with respect to possible discouragement, for some, from seeking patent protection or commercializing a new product under the belief that patent protection is either unavailable or difficult to come by, or for fear of infringing existing patents. Upon closer investigation, the evolution of technology almost always creates opportunities for new improvements, which likely can be patent protected. Furthermore, while avoiding the claims of existing patents is sometimes challenging and opinion based, and thus not a guarantee of avoiding a patent litigation, patent litigation may be delayed and is often settled early on., (© 2013 Diabetes Technology Society.)

The medicinal and recreational use of cannabis has been controversial, especially in the United States. Marijuana for medicinal use is approved in 14 U.S. states and has recently been considered for legalization in several additional states. Given its demonstrated efficacy in symptom management, marijuana has a potential role in palliative care. This study utilized a 16-item questionnaire to assess the knowledge, experience, and views of hospice professionals regarding the use of marijuana in terminally ill patients. The study results revealed that, like the general public, hospice health care providers are generally in favor of legalization of marijuana and, if legalized, would support its use in symptom management for their terminally ill patients.

Ethnopharmacological Relevance: Herbal drugs are gaining worldwide prominence due to their distinct advantages. Developing countries have started exploring the ethnopharmacological approach of drug discovery and have begun to file patents on herbal drugs. The expansion of R&D in Indian herbal research organizations and presence of manufacturing units at non-Indian sites is an indication of the capability to develop new products and processes. The present study attempts to identify innovations in the Indian herbal drug sector by analyzing the patenting trends in India, US and EU., Methodology: Based on key word and IPC based search at the IPO, USPTO, Esp@cenet and WIPO databases, patent applications and grant in herbal drugs by Indian applicants/assignees was collected for the last ten years (from 1st January 2001 to 31st October 2010). From this collection patents related to human therapeutic use only were selected. Analysis was performed to identify filing trends, major applicants/assignees, disease area and major plant species used for various treatments., Result: There is a gradual increase in patent filing through the years. In India, individual inventors have maximum applications and grants. CSIR, among research organizations and Hindustan Unilever, Avesthagen, Piramal Life Science, Sahajanand Biotech and Indus Biotech among the companies have the maximum granted patents in India, US and EU respectively. Diabetes, cancer and inflammatory disorders are the major areas for patenting in India and abroad. Recent patents are on new herbal formulations for treatment of AIDS, hepatitis, skin disorders and gastrointestinal disorders., Conclusion: A majority of the herbal patents applications and grants in India are with individual inventors. Claim analysis indicates that these patents include novel multi-herb compositions with synergistic action. Indian research organizations are more active than companies in filing for patents. CSIR has maximum numbers of applications not only in India but also in the US and EU. Patents by research organizations and herbal companies are on development of new processes for active compound isolation and standardization of such components in addition to new compositions for therapeutic use. Pharmaceutical companies such as Ranbaxy, Lupin and Panacea Biotec are increasingly patenting on herbal drugs. There is increased patenting activity related to diabetes, cancer, cardiovascular diseases, asthma and arthritis in India and abroad., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Hormonal and antimicrobial therapies are essential to regulate and maintain healthy reproduction in domestic animals. The appropriate and legal use of these compounds is ultimately the responsibility of the veterinarian and other users, with a primary mission to directly protect and promote the health of animals, and indirectly the health of people. The appropriate use of these products is defined by the Federal Food, Drug, and Cosmetic Act, 21 United States of America § 301 et seq and implementing regulations in the Code of Federal Regulations. In the past, use of a drug in an animal for an unapproved use violated this Act. However, passage of the Animal Medicinal Drug Use Clarification Act 1994 legalized the extra-label use of certain animal and human drugs in veterinary practice for treating diseases. This manuscript reviews currently approved hormonal and antimicrobial drugs for use in theriogenology. Considering the ever increasing knowledge in the area of veterinary reproduction, particularly in the treatment and control of reproduction using antimicrobials and hormones, it would be beneficial to widen the therapeutic options in these categories. The potential for widening the therapeutic options is also discussed in this review, by providing a non-exhaustive but essential list of potential new drugs for use in clinical animal reproduction (theriogenology)., (Copyright © 2011 Elsevier Inc. All rights reserved.)