Food And Drug Administration Drug Safety Communications Research Articles

A new analytic tool for assessing the impact of the US Food and Drug Administration regulatory actions.

Develop and test a flexible, scalable tool using interrupted time series (ITS) analysis to assess the impact of Food and Drug Administration (FDA) regulatory actions on drug use. We applied the tool in the Sentinel Distributed Database to assess the impact of FDA's 2010 drug safety communications (DSC) concerning the safety of long-acting beta2-agonists (LABA) in adult asthma patients. We evaluated changes in LABA use by measuring the initiation of LABA alone and concomitant use of LABA and asthma controller medications (ACM) after the DSCs. The tool generated ITS graphs and used segmented regression to estimate baseline slope, level change, slope change, and absolute and relative changes at up to two user-specified time point (s) after the intervention. We tested the tool and compared our results against prior analyses that used similar measures. Initiation of LABA alone declined among asthma patients aged 18-45 years before FDA DSCs (-0.10% per quarter; 95%CI: -0.11% to -0.09%) and the downward trend continued after. Concomitant use of LABA and ACM was stable before FDA DSCs. After FDA DSCs, there was a small trend decrease of 0.006% per quarter (95% CI, -0.008% to -0.003%). We found similar results among those aged 46-64 years and patients with poorly-controlled asthma. Our results were consistent with previous studies, confirming the performance of the new tool. We developed and tested a reusable ITS tool in real-world databases formatted to the Sentinel Common Data Model that can assess the impact of regulatory actions on drug use.

218 Online Social Listening Surveillance for Earlier Insights About Loperamide Abuse/Misuse, 2015-2021

Loperamide (LOP) is a safe, effective antidiarrheal medication available over-the-counter (OTC) for over 30 years with a maximum dose of 8 mg/day for adults. Intentional LOP abuse/misuse (ingesting 70-200 mg/day to self-treat opioid withdrawal symptoms or achieve euphoria) was first reported in online forums in 2005. Following a 2016 US Food and Drug Administration (FDA) Drug Safety Communication on the potential risk of cardiovascular adverse events with high doses of LOP, the OTC industry initiated a communications campaign (www.LoperamideSafety.org) to educate health professionals, including emergency medicine specialists, about LOP abuse/misuse awareness and prevention. Retrospective surveillance (eg, FDA Adverse Event Reporting System database and National Poison Data System) has traditionally been employed to track reports of drug abuse/misuse. We utilized modern online social listening technology to observe and analyze comments/conversations (posts) about LOP abuse/misuse on various websites and online social media platforms to gain earlier insight into potential LOP abuse/misuse. Utilizing the software tools Crimson Hexagon and Synthesio, we scanned thousands of publicly accessible user posts in online blogs, forums, and social networks – including major platforms such as Twitter, Facebook, YouTube, Reddit, and Forums – from January 2015 to March 2021 to observe posts about LOP abuse/misuse. Listening consisted of keyword-based scrapes of user-generated content using search terms including loperamide, Imodium, overdose, OD, get high, getting high, withdrawal, and related terms/phrases. Findings were analyzed and reported quarterly. From January 2015 to March 2021, there were 27,213 user posts regarding LOP abuse/misuse among all observed online platforms. Annual post volume peaked in 2016 before declining in 2019/2020, consistent with the pattern of annual intentional exposure cases reported by the American Association of Poison Control Centers. Over 2015-2021, there was an average of 390 posts per month. Since May 2018, Reddit contained the majority of posts (70%), followed by Twitter (18%), YouTube (6%), Forums (4%), Facebook (<1%), and other sites (<1%). Reddit and Forums accounted for an increasing percentage of posts over time with a decrease for all other platforms. Posts primarily addressed the use of high-dose LOP for easing withdrawal symptoms (73%) or seeking euphoria (17%). Posts about risks and dangers of misuse/abuse were 16% of Reddit posts from Q2 2020 to Q1 2021, with a peak of 22% in Q2 2020. Spikes in posts coincided with key events, including journal article publications regarding effects of high doses (2,499 posts in May 2016 and 830 posts in January 2017) and FDA Drug Safety Communications regarding abuse/misuse of LOP (650 posts in June 2016 and 1,400 posts in January 2018). Post volume also appeared to increase in relation to US COVID-19 infection rates in 2020/2021 slightly. Online chatter about LOP abuse/misuse rose from 2015 to a peak in 2016 before declining in 2019/2020, consistent with the pattern of reported annual intentional exposure cases. While not a substitute for epidemiological surveillance, online social media listening is a useful adjunct surveillance strategy for earlier insight into potential LOP abuse/misuse by observing and analyzing online comments/conversations, sentiments and contexts.

Fluoroquinolone Prescribing for Diabetic Foot Infections following an FDA Drug Safety Communication for Aortic Aneurysm Risk.

In 2018, the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication regarding fluoroquinolone-associated aortic aneurysm. This quasi-experimental study assessed antibiotic prescribing for 198 patients hospitalized with diabetic foot infection. Following the warning, median inpatient fluoroquinolone days of therapy (DOT) decreased from 3 to 0 days (P < 0.001), corresponding to increased beta-lactam DOT and outpatient parenteral antimicrobial therapy enrollment. FDA communications may influence antibiotic selection and transitions of care, representing opportunities for antimicrobial stewardship.

228. Fluoroquinolone Prescribing for Diabetic Foot Infections following an FDA Drug Safety Communication for Aortic Aneurysm Risk

BackgroundFluoroquinolones were commonly prescribed for hospitalized patients with diabetic foot infection (DFI) at our institution, included in 69% of empiric antibiotic regimens from 2011–2014. On December 20, 2018, the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication regarding the risk of aortic aneurysm with fluoroquinolones. The objective of this study was to assess the impact of the FDA Communication on antibiotic prescribing for DFI.MethodsThis was a single-center quasi-experimental study of hospitalized patients initiated on antibiotics for DFI before (February-December 2018) and after (February-December 2019) the 2018 FDA Communication. Patients with concomitant infections or documented beta-lactam or fluoroquinolone allergies were excluded. The primary outcome was inpatient days of fluoroquinolone therapy. Secondary outcomes included days of beta-lactam therapy and Outpatient Parenteral Antibiotic Therapy (OPAT) enrollment. Variables were compared using the Pearson’s chi square, Fisher’s exact, and Mann Whitney U tests, as appropriate. A logistic regression was performed to identify predictors for inpatient receipt of fluoroquinolones.ResultsA total of 198 patients were included. Baseline characteristics were similar between groups (Table 1). After the FDA Communication, the median duration of inpatient fluoroquinolones decreased from 3 [0–5.5] to 0 [0–1] days (p< 0.001). The duration of antipseudomonal beta-lactams increased from 0 [0–2] to 2 [0–6] days (p< 0.001). OPAT enrollment increased from 16.5% to 29.7% (p=0.028), with a corresponding increase in peripherally inserted central catheter placement (15.5% to 25.7%, p=0.074). There was no difference in outpatient fluoroquinolone prescribing over time. Incidence of re-infection, readmission for DFI, and antibiotic adverse events were similar between groups (Table 2).Table 1 Table 2 ConclusionInpatient fluoroquinolone prescribing for DFI decreased significantly following the 2018 FDA Communication, followed by an increase in antipseudomonal beta-lactam use and OPAT enrollment. FDA statements can influence institutional antibiotic prescribing and transitions of care decisions, representing an opportunity for education by Antimicrobial Stewardship programs.Disclosures All Authors: No reported disclosures

Pediatric anesthesiologists' attitudes about neurotoxicity and the FDA drug safety communication.

The 2016 Food and Drug Administration (FDA) Drug Safety Communication states that brain development in children under 3 years old may be affected by "repeated or lengthy use of general anesthetic and sedation drugs" and advises healthcare providers to "discuss with parents, caregivers, and pregnant women the benefits, risks, and appropriate timing of surgery or procedures requiring anesthetic and sedation drugs." This preliminary study's aims were to explore 1) pediatric anesthesiologists' attitudes regarding the FDA statement, 2) the statement's impact on informed consent practices, and 3) whether institutional policies pertaining to disclosure of neurotoxicity risk exist.

Association of eszopiclone, zaleplon, or zolpidem with complex sleep behaviors resulting in serious injuries, including death.

To identify and analyze postmarketing cases of complex sleep behaviors (CSBs) resulting in serious injuries, including death, associated with eszopiclone, zaleplon, or zolpidem (Z-drugs). Retrospective analysis of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 16 December 1992 through 27 February 2018 and medical literature using PubMed and EMBASE. We used random sampling and descriptive statistics. We identified 66 cases that met inclusion and exclusion criteria, four of which were identified in the medical literature. Twenty cases reported death and 46 cases reported serious injuries in association with CSBs occurring after the use of a Z-drug. Fatal cases described events, such as carbon monoxide poisoning, drowning, falls, hypothermia, motor vehicle collisions, and apparent completed suicide. Nonfatal cases resulting in serious injuries described events, such as accidental overdoses, falls, gunshot wounds, hypothermia, third-degree burns, and self-injuries or suicide attempts. Twenty-two cases reported a previous episode of a CSB while taking a Z-drug prior to the event reported in this case series. The FAERS and medical literature cases support the need for increased awareness of the consequences that may occur because of CSBs associated with the use of Z-drugs. Therefore, to protect public health, regulatory actions were taken, including adding a Boxed Warning, a Contraindication in patients who have experienced a prior episode of a CSB with a Z-drug, and updating the existing Warnings and Precautions. An FDA Drug Safety Communication was also disseminated to alert healthcare professionals and the public of this potential risk.

US Food and Drug Administration Safety Advisories and Reporting to theAdverse Event Reporting System (FAERS).

The US Food and Drug Administration (FDA) and other major regulators regularly issue safety advisories about licensed drugs with new adverse effects that have been documented through observational studies, clinical trials, and spontaneously reported adverse drug events. To assess the possible effects of a representative group of FDA Drug Safety Communications on the reporting of the specific adverse effect featured in the advisory on new cases reported to the FDA Adverse Event Reporting System (FAERS). We examined 16 FDA Drug Safety Communications issued from 2010 to 2015 that had not previously been the focus of advisories from regulators in the UK, Canada, or Australia. We compared the reports of the adverse effect in the 8 calendar quarters preceding the advisory and in the 4 quarters following. We measured change in reporting frequency by calculating the event reporting odds ratio (ROR) for the post-warning compared to the pre-warning periods. We defined a credible association of the advisory with increased reporting as a ROR ≥ 2.0 and p value of < 0.05 by Fisher's Exact Test. We found statistically significant increased reporting for 4/16 advisories with RORs that ranged from 3.9 to 40.6. Three advisories had smaller but still statistically significant increases that were less than the ROR ≥ 2.0 threshold. For 7 advisories, we found no statistically significant changes in reporting. No consistent pattern or effect was found on spontaneous reporting following these safety advisories. After results were available, we observed that some cases with the largest reporting increase also involved substantial numbers of legal claims. Changes in adverse event reporting following a warning need to be evaluated on a case-by-case basis.

Changes in emergency department visits for zolpidem‐attributed adverse drug reactions after FDA Drug Safety Communications

To identify possible changes in U.S. emergency department (ED) visits from zolpidem-attributed adverse drug reactions (ADRs) after 2013 Food and Drug Administration (FDA) Drug Safety Communications (DSCs), which notified the public about FDA's new dosing recommendations for zolpidem. We estimated the occurrence of ED visits from zolpidem-attributed ADRs using nationally representative, public health surveillance of medication harms (National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project, 2010-2017). We estimated the number of zolpidem prescriptions using IQVIA National Prescription Audit, 2010-2017. We calculated rates of ED visits for zolpidem-attributed ADRs per 10 000 dispensed zolpidem prescriptions and identified time trends and potential inflection points using joinpoint regression. For comparison, we repeated these analyses for sedating antidepressants commonly used to treat disordered sleep (trazodone, doxepin, and mirtazapine). The best-fit regression model for rates of ED visits for zolpidem-attributed ADRs by 6-month intervals identified a single inflection point in the second half of 2014 (P = .024) with a 6.7% biannual decrease from 2010 to 2014 ([-13.1%, 0.3%], P = .059) and a 13.9% biannual increase from the second half of 2014 through 2017 ([-1.1%, 31.3%], P = .068). No change or inflection points were identified for rates of ED visits for sedating antidepressant-attributed ADRs. While there was a nominal decline in the rate of ED visits for ADRs in the time period before and for 18 months after FDA's 2013 zolpidem DSCs, the decrease was not sustained, and thus questions remain concerning the long-term impact of the zolpidem DSCs on ADRs.

Varenicline and Nicotine Replacement Use Associated With US Food and Drug Administration Drug Safety Communications

Drug safety communications released by the US Food and Drug Administration (FDA) are often based on limited evidence on safety signals after approval. Varenicline may serve as a relevant case study because it was the target of several FDA communications in 2008 and 2009; ultimately, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) dismissed safety concerns on increased suicidal thoughts and aggressive and erratic behavior on December 16, 2016. To examine the association between FDA drug safety communications and the use of varenicline. Retrospective, longitudinal, cross-sectional study of Veterans Health Administration (VHA) outpatient data from October 1, 2001, through December 31, 2018, and Medicaid drug state use data from July 1, 2006, through September 30, 2018, on varenicline prescribing. Prescribing records for varenicline and nicotine replacement therapy (NRT) in the VHA were extracted, and the number of unique varenicline and NRT users in the VHA per quarter was measured. An interrupted time series analysis was performed to describe the association between FDA safety warnings and the use of varenicline and NRT. To test the generalizability of the findings, similar analyses were conducted using the number of prescriptions reimbursed for varenicline by Medicaid every quarter in 2006-2018. After its addition to the VHA national drug formulary in January 2007, varenicline use presented a steady increase, reaching a peak of 32 581 quarterly unique users in the first quarter of 2008. Within 12 months of the February 1, 2008, public health advisory, quarterly varenicline use in VHA patients decreased by 68.7% (from 32 581 to 10 182 patients; P < .001 for slope change), and NRT use increased by 32.1% (from 55 728 to 73 629 patients; P < .001 for slope change). In Medicaid prescriptions, varenicline use decreased by 38.0% (from 109 308 to 67 761 prescriptions; P < .001 for slope change) within 12 months of the 2008 public health advisory. Twelve months after the publication of the EAGLES trial, which showed no significant increase in psychiatric/behavioral effects with varenicline relative to NRT, use of varenicline increased by 42.7% in VHA patients (from 9251 to 13 199 patients; P = .01 for slope change) and by 26.0% in Medicaid prescriptions (112 063 to 141 122; P = .26 for slope change ). With use of varenicline as a case study, early communications from the FDA and VHA followed by a labeling change appeared to be associated with a considerable decrease in drug use, which may have been associated with negative public health consequences.

Multimodal Analysis of FDA Drug Safety Communications: Lessons from Zolpidem.

Because clinical trials conducted for US Food and Drug Administration (FDA) approval occur in carefully monitored settings and often have strict inclusion criteria for participation, new information about drug safety is commonly discovered once a medication is FDA approved and used by larger numbers of patients. The FDA issues Drug Safety Communications when new information arises about the safety of marketed drugs that may change decision making by healthcare providers and patients. Since their inception, over 250 Drug Safety Communications have been issued alerting consumers and prescribers in the USA about safety risks related to prescription and over-the-counter medications. Researchers at the Brigham and Women's Hospital in Boston in conjunction with officials from the FDA undertook a multi-modal study of the content, dissemination, and uptake of FDA messaging, focusing on two 2013 Drug Safety Communications related to zolpidem (Ambien; Sanofi, Paris, France). Traditional and social media analyses note incomplete dissemination of key DSC messages. Surveys of patients and interviews of physicians and patients suggest important limitations in patient-provider communication that have hindered sharing of safety information with patients. Finally, pharmacoepidemiologic analyses of zolpidem dispensing patterns after the Drug Safety Communications were released suggest possible opportunities for enhancing uptake of new safety knowledge that may lead to changes in clinical practice, where appropriate.

Annals for Educators - 5 February 2019.

Annals for Educators - 5 February 2019.

Anesthesia Exposure in Children: Practitioners Respond to the 2016 FDA Drug Safety Communication.

In December 2016, the US Food and Drug Administration (FDA) issued a drug safety warning stating that 11 commonly used anesthetic and sedative medications had potential neurotoxic effects when used in children under the age of 3 years and in pregnant women during the third trimester. A panel presentation at the sixth biennial Pediatric Anesthesia Neurodevelopmental Assessment (PANDA) symposium addressed the FDA announcement in a session entitled "Anesthesia Exposure in Children During Surgical and Non-Surgical Procedures: How Do We Respond to the 2016 FDA Drug Safety Communication?" Panelists included representatives from pediatric anesthesiology, obstetrics, pediatric surgery, and several pediatric surgical subspecialties. Each panelist was asked to address the following questions: How has the FDA labelling change affected your clinical practice including patient discussions, timing, and frequency of procedures? Has your professional society provided any guidelines for this discussion? Has there been any discussion of this topic at your national meetings? The panelists provided important perspectives specific to each specialty, which generated a lively discussion and a detailed response from the Deputy Director of the Division of Anesthesia and Addiction of the FDA describing the FDA procedures that led to this drug safety warning.

Accelerated approval of drugs: ethics versus efficacy.

To analyse the post-marketing status of molecules approved through the expedited review process in the last quintile. This observational study was carried out between January 2016 and June 2016. The details of the time taken to approve drugs were collected from the official website of United States Food and Drug Administration (FDA). The average time taken to review drugs and take a decision following the review were ascertained from the FDA's annual release of novel drugs from 2011 to 2015. Information on adverse drug reactions noted after approval was gathered from the FDA Drug Safety Communication and FDA Adverse Event Reporting System (FAERS). In the last five years, 166 products were approved by expedited review. Of these, 45 (27.1%) did not meet the stringent criteria framed for expedited review. Reports of serious adverse event alerts were submitted for 79 (47.5%) of the 166 molecules. Fourteen (8.4%) drugs were associated with inducing severe autoimmune disorders. It can be observed that a lower average time of review is positively correlated with a greater number of adverse events (p<0.05). Thirty-seven (45.7%) of the molecules failed to be of any benefit in the treatment scenario. Drug approval by accelerated review should be stringent. Beneficence and non-maleficence are applicable to the global population, and should apply equally to subjects involved in trials. Approving drugs on the basis of trivial evidence is non-scientific and absolutely unethical, since it can lead to clinical failure and produce serious adverse events.

Medication Safety

Medication Safety

Parkinson's Drug Doesn't Increase Cardiovascular Risk

* The Food and Drug Administration (FDA) has determined that drugs containing entacapone, used in the management of Parkinson's disease symptoms, does not increase the risk of cardiovascular events. * This announcement reverses an older FDA Drug Safety Communication in which the agency expressed concerns over possible cardiovascular events associated with use of the drug.

Consumer Understanding, Preferences, and Responses to Different Versions of Drug Safety Messages in the United States: A Randomized Controlled Trial.

IntroductionAs part of its mission, the US Food and Drug Administration (FDA) communicates with the public regularly about the benefits and risks of prescription and over-the-counter (OTC) drugs. Effectively communicating risk, however, is a significant public health challenge.ObjectiveTo better understand how different populations understand information communicated by the FDA about drug safety, we conducted a randomized experiment to examine comprehension and other measures of effectiveness of drug safety messages that occurred in a post-market surveillance phase.MethodsWe used an Internet panel survey of 1244 consumers, of whom 58 % used prescription drugs in the past year. Half of the sample panel was randomized to read a previous FDA Drug Safety Communication (DSC) with the drug name changed, and the other half was randomized to read a revised version of the same DSC. We examined how making certain modifications to the way drug risk information is communicated has an impact on comprehension and behavioral intentions, including the user’s likelihood of discontinuing the drug. We also studied how comprehension varied by respondent characteristics, health literacy skills, risk perceptions, and trust in the message.ResultsBased on a five-item comprehension index, the revised version of the message was associated with significantly greater comprehension of the information relative to the standard version (63 vs 52 % correct, p < 0.001). Significantly more respondents found the revised version to be clear (82 vs 73 %, p < 0.000), while fewer in that group reported learning something new (78 % vs 84 %, p = 0.015). No significant differences emerged between the two groups in terms of the message being informative, convincing, or helpful. We found no significant differences between the two groups in terms of behavioral intentions, risk perception, and trust.ConclusionsWe found that making plain language changes to the DSC significantly increased consumers’ level of comprehension of its content, providing support for ongoing use and further exploration of these strategies in pharmacovigilance communication research. The study findings have important implications for future drug safety and other communication messages related to prescription drugs.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-015-0358-9) contains supplementary material, which is available to authorized users.

NLA Task Force on Statin Safety--2014 update.

1933-2874/$ see front matter 2014 http://dx.doi.org/10.1016/j.jacl.2014.03 Statins are the most widely prescribed class of medications in the United States and their benefits for lowering lowdensity lipoprotein cholesterol (LDL-C) and reducing the risk for coronary heart disease (CHD) are well documented. Statins have been the cornerstone of pharmacotherapy for the management of high blood cholesterol levels virtually since their development. The American Heart Association /American College of Cardiology 2013 guidelines recently expanded the number of individuals eligible for statin therapy by recommending it for those with: (1) clinical atherosclerotic cardiovascular disease (ASCVD), (2) LDL-C $190 mg/dL, (3) type 2 diabetes and age between 40 and 75 years with LDL-C 70 to 189 mg/dL, and (4) an estimated 10-year risk of ASCVD $7.5% and age 40 to 75 years. Considering only those who qualify according to their estimated 10-year risk of ASCVD, it has been reported that of the 101 million people in the United States age 40 to 79 years who do not have cardiovascular disease, 33 million have an estimated 10-year risk of ASCVD $7.5%, and another 13 million have a risk between 5% and 7.4%. Using crude global estimates, 920 million people worldwide would be expected to be

Poster #T214 A SYSTEMATIC REVIEW OF FACTORS INFLUENCING ANTIPSYCHOTIC MEDICATION ADHERENCE IN SCHIZOPHRENIA

The US Food and Drug Administration (FDA) has new regulatory authorities intended to enhance drug safety monitoring in the postmarketing period. This has resulted in an increase in communication from the FDA in recent years about the safety profile of certain drugs. It is important to stay abreast of the current literature on drug risks to effectively communicate these risks to patients, other health care providers, and the general public.To summarize 4 new FDA drug safety communications by describing the evidence supporting the risks and the clinical implications for older adults.The FDA Web site was reviewed for new drug safety communications from May 2011 to April 2012 that would be relevant to older adults. Approved labeling for each drug or class was obtained from the manufacturer, and PubMed was searched for primary literature that supported the drug safety concern.FDA drug safety communications for 4 drugs were chosen because of the potential clinical importance in older adults. A warning for citalopram was made because of potential problems with QT prolongation in patients taking less than 40 mg per day. The evidence suggests minor changes in QT interval. Given the flat dose–response curve in treating depression with citalopram, the new 20-mg/d maximum dose in older adults is sensible. Another warning was made for proton pump inhibitors (PPIs) and an increased risk of Clostridium difficile infection. A dose–response relationship was found for this drug risk. With C. difficile infections on the rise in older adults, along with other safety risks of PPI therapy, PPIs should only be used in older adults indicated for therapy for the shortest duration possible. In addition, a warning about dabigatran was made. There is strong evidence from a large clinical trial, as well as case reports, of increased bleeding risk in older adults taking dabigatran, especially in older adults with decreased renal function. This medication should be used with caution in older adults. Finally, several warnings were made about statins. Routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury from statin use; thus, liver enzymes are no longer recommended to be routinely monitored. Statin-induced cognitive changes are rare, and insufficient evidence is currently available to establish causality. Statins appear to moderately increase the risk of developing diabetes (versus placebo), and regular screening for diabetes should be considered, especially for patients taking high-dose statins and patients with multiple risk factors for diabetes.FDA drug safety communications incorporate complex methodologies that investigate the risks (and relative benefits) of medication therapy. Clinicians caring for older adults need to be aware of the most current evidence behind these drug risks to effectively communicate with and care for their patients.

Novel Developments in the Pharmacological Management of Insomnia

Advances in the basic science of sleep/wake neurophysiology are driving the exploration of new pharmacologic approaches with continued improvement in efficacy and safety.

The Balance Between Effective Opioid-Based Pain Management and Patient Safety: Can It Be Achieved?

The Balance Between Effective Opioid-Based Pain Management and Patient Safety: Can It Be Achieved?