Use of Patient and Investigator Global Impression Scales: A Review of Food and Drug Administration-Approved Labeling, 2009 to 2019.

OBJECTIVE: Identify disease categories in which single-item global impression (GI) scales were included in product labeling of new drugs approved by the US Food and Drug Administration (FDA) in January 2009-December 2019 and review the characteristics of GIs included in product labeling of new FDA-approved drugs (January 2017-December 2019). METHODS: FDA Clinical Outcome Assessment (COA) Compendium was reviewed for drug labels that included GIs for drugs approved in 2009-2016. The indication, year of approval, ICD-10 code, and GI respondent were noted. A manual review of labels of FDA-approved drugs (2017-2019) was undertaken to identify GIs included in the labels. Corresponding drug approval packages were reviewed to identify details of any regulatory reviewer comments related to GIs. GI characteristics were noted from the drug label or the review documents, including the respondent, type of measure (static or dynamic), item wording, concept assessed, and response options. RESULTS: Product labeling containing GIs was most common in diseases related to the skin, nervous system, behavioral disorders, and the musculoskeletal system. GIs were included in 30/77 (39.0%) drug labels in the four disease categories. CONCLUSION: In the past 10 years, GIs have been included as endpoint measures in confirmatory clinical trials and have generated evidence of treatment benefit in diseases related to the skin, nervous system, behavioral disorders, and the musculoskeletal system. GIs frequently provide important insights into the patient experience. Before GIs are included in clinical trials to assess treatment benefit, it is important to ensure that they are valid, reliable, and responsive.

The Influence of the Food and Drug Administration Pregnancy and Lactation Labeling Rule on Drug Information Resources.

BACKGROUND: Drug information resources are commonly used by health-care providers answering pregnancy-related medication questions. In 2015, the United States Food and Drug Administration approved a new pregnancy and lactation medication labeling content and format, removing the pregnancy category, and using a narrative. Despite labeling requirements changing, it is unknown if drug information resources updated monographs to reflect these changes. OBJECTIVE: The primary objective was to evaluate if commonly used drug information resources provide pregnancy information listed similar to the requirements of the Pregnancy and Lactation Labeling Rule (PLLR). Secondary analyses included evaluating the references and inclusion of the pregnancy category rating. METHODS: Pregnancy recommendations for 23 medications were evaluated in 9 drug information resources (Clinical Pharmacology, Drugs in Pregnancy and Lactation, Epocrates®, First Databank, LexiComp® Online, LexiComp® Online Pregnancy & Lactation, In-Depth, Medi-Span®, Micromedex®, and Multum®). The number of references per drug monograph and most recent reference publication year was obtained. RESULTS: LexiComp® Online Pregnancy & Lactation, In-Depth mimics the new PLLR structure and consistently had the highest number of and most recent references when the medication was included. Drugs in Pregnancy and Lactation was the next most similar in content with the PLLR and second in most references per monograph; however, the most recent reference was the textbook publication year. CONCLUSION AND RELEVANCE: LexiComp® Online Pregnancy & Lactation, In-Depth and Drugs in Pregnancy and Lactation provided pregnancy information in a format most similar to the PLLR. However, several drug information resources contained pregnancy categories ratings that were to be removed from medication labeling per the PLLR.

The Importance of Clinical Research in Pregnant Women to Inform Prescription Drug Labeling.

Pregnant women have historically been an understudied population and have been excluded from clinical trials. Recent efforts by stakeholders have raised awareness of the importance of clinical research in pregnant women to inform prescribing decisions. The Food and Drug Administration continues working to improve the format and content of prescription drug labeling for pregnant and lactating women, as demonstrated with the Pregnancy and Lactation Labeling Rule (PLLR), effective in 2015. The pregnancy labeling subsection now includes a subheading dedicated to the inclusion of pharmacokinetic (PK) data that inform the need for dose adjustments during pregnancy and the postpartum period. In addition, the PLLR also requires prescription drug labeling to be updated when important pregnancy information becomes available. Although PLLR improved the presentation of pregnancy-related information in labeling, there is a need to increase the quality and quantity of human data on the use of prescription drugs during pregnancy. PK studies in pregnant women should be incorporated into drug development programs and prioritized to obtain important information about safe and appropriate doses of a drug when used during pregnancy. In addition, opportunistic PK studies, postapproval pregnancy safety studies, ex vivo studies, and in silico modeling can be leveraged to better inform the risks and benefits of using a drug during pregnancy to inform study design and to further understand various mechanisms impacting pharmacokinetic/pharmacodynamic of drugs during pregnancy. It is important to address the significant existing data gaps and better inform the safety and dosing of prescription drugs for pregnant women.

Implementation of pharmacogenomics in product information.

Aim: The aim of our study was to analyse the level of implementation of pharmacogenomics (PGx) in product information (PI) of medicinal products approved through national procedures in the EU. Materials & methods: In the analysis, we included nationally approved medicinal products in Croatia if guidelines for relevant substances were published. Results: Overall, 265 marketing authorizations were analyzed. The majority of data included in PI was only informative, while the most frequent PGx biomarkers were genes which code CYP P450. Analysis according to the Anatomical Therapeutic Chemical classification revealed that most substances belonged to the nervous system. Conclusion: Although hindrances in implementation are anticipated, PI should be more specific in terms of when the testing is indicated and should include actionable recommendations according to the results of PGx testing.

Impact of the EMA/FDA alerts on the use of effective contraceptive method in women of childbearing age undergoing valproic acid treatment in a long-stay psychiatric center.

OBJECTIVE: We aimed to evaluate the impact of the European Medicines Agency (EMA) and Food Drug and Administration (FDA) alerts on the use of effective contraceptive method in women of childbearing age undergoing valproic acid treatment in a long-stay psychiatric center. MATERIAL AND METHODS: An interrupted time-series analysis of women of childbearing age admitted in a long-stay psychiatric center (2013-2019), according to the EMA/FDA restrictions dates (October 2014 and February 2018). RESULTS: Of the 82 cases included, 50 (61.0%) had an 'off-label' prescription. The percentage of cases with a contraceptive method before October 2014 (31.6%) increased to 61.5% after October 2014, p = 0.004. Women with an 'off-label' prescription after 2018 were more likely to use a contraceptive method than those before 2014, and there were not statistically significant differences in women with an 'under indication' prescription. CONCLUSIONS: The recent regulatory restrictions on the use of a contraceptive method had a positive effect, mainly in women with an 'off-label' prescription. No effect was seen in women with epilepsy, probably because the intervention had started long before.

Pharmacogenomic biomarker information differences between drug labels in the United States and Hungary: implementation from medical practitioner view.

Pharmacogenomic biomarker availability of Hungarian Summaries of Product Characteristics (SmPC) was assembled and compared with the information in US Food and Drug Administration (FDA) drug labels of the same active substance (July 2019). The level of action of these biomarkers was assessed from The Pharmacogenomics Knowledgebase database. From the identified 264 FDA approved drugs with pharmacogenomic biomarkers in drug label, 195 are available in Hungary. From them, 165 drugs include pharmacogenomic data disposing 222 biomarkers. Most of them are metabolizing enzymes (46%) and pharmacological targets (41%). The most frequent therapeutic area is oncology (37%), followed by infectious diseases (12%) and psychiatry (9%) (p < 0.00001). Most common biomarkers in Hungarian SmPCs are CYP2D6, CYP2C19, estrogen and progesterone hormone receptor (ESR, PGS). Importantly, US labels present more specific pharmacogenomic subheadings, the level of action has a different prominence, and offer more applicable dose modifications than Hungarians (5% vs 3%). However, Hungarian SmPCs are at 9 oncology drugs stricter than FDA, testing is obligatory before treatment. Out of the biomarkers available in US drug labels, 62 are missing completely from Hungarian SmPCs (p < 0.00001). Most of these belong to oncology (42%) and in case of 11% of missing biomarkers testing is required before treatment. In conclusion, more factual, clear, clinically relevant pharmacogenomic information in Hungarian SmPCs would reinforce implementation of pharmacogenetics. Underpinning future perspective is to support regulatory stakeholders to enhance inclusion of pharmacogenomic biomarkers into Hungarian drug labels and consequently enhance personalized medicine in Hungary.

Trends in the off-label use of ß-blockers in pediatric patients.

The use of US Food and Drug Administration (FDA)-approved drugs for the treatment of an unapproved indication or in an unapproved age group, or at doses or route of administration not indicated on the label is known as off-label use. Off-label use may be beneficial in circumstances when the standard-of-care treatment has failed, and/or no other FDA-approved medications are available for a particular condition. In pediatric patients, off-label use may increase the risk of adverse events as pharmacokinetic and pharmacodynamic data are limited in children. Approximately 73% of off-label drugs currently prescribed for various conditions do not have sufficient scientific evidence for safety and efficacy. For example, ß-blockers are a class of drugs with FDA-approval for very few indications in pediatrics but are commonly used for various off-label indications. Interestingly, the proportion of off-label use of ß-blockers in adults is at about 52% (66.2 million) of the total number of ß-blockers prescribed. The frequency of off-label use of ß-blockers in children is also high with limited data on the indications as well as safety and efficacy. We present trends in off-label use of ß-blockers in children to discuss drug safety and efficacy and include recommendations for pediatric providers.

Future of the drug label: Perspectives from a multistakeholder dialogue.

Regulating drugs does not end when market access has been granted. Monitoring drugs over the life cycle has become state of the art, inherent to evolving legislation and societal need. Here, we explore how the drug label could move along in a changing playing-field and become a sustainable label for the future. A dialogue between academia, government, the pharmaceutical industry and patient/societal organizations was organized by the Regulatory Science Network Netherlands. This is their view.

Trends in the receipt of medicines information among Finnish adults in 1999-2014: a nationwide repeated cross-sectional survey.

OBJECTIVE: The aim of this study was to examine long-term trends in the receipt of medicines information (MI) among adult medicine users from 1999 to 2014. DESIGN: Repeated cross-sectional postal survey from the years 1999, 2002, 2005 and 2008-2014. SETTING: Each study year, a new nationally representative sample of 5000 Finns aged 15-64 years was drawn from the Population Register Centre of Finland. PARTICIPANTS: The range of annual respondents varied from 2545 to 3371 and response rates from 53% to 67%. Of the total responses (n=29 465), 64% were from medicine users (n=18 862, ranging by year from 58% to 68%). OUTCOME MEASURES: Receipt of information on medicines in use within 12 months prior to the survey from a given list of consumer MI sources available in Finland. RESULTS: Physicians, community pharmacists and package leaflets were the most common MI sources throughout the study period. Receipt of MI increased most from the Internet (from 1% in 1999 to 16% in 2014), while decreased most from physicians (62% to 47%) and package leaflets (44% to 34%), and remained stable from community pharmacists (46% to 45%) and nurses (14% to 14%). In 1999, of the medicine users 4% did not report receipt of MI from any of the sources listed in the survey, while this proportion had remarkably increased to 28% in 2014. CONCLUSIONS: Healthcare professionals and package leaflets had still a dominating importance in 2014 despite the growing number of MI sources over time, but still a minority of adult medicine users reported receiving MI via the Internet in 2014. Worrying is that the proportion of adult medicine users who did not receive MI from any of the sources became seven fold during the study period.

What Lies Beneath the Face Value of a BOX WARNING: A Deeper Look at Brodalumab.

Brodalumab, a fully human antibody of the interleukin-17 receptor, is highly effective in the treatment of moderate-to-severe plaque psoriasis. However, based on safety signals identified in clinical trials, brodalumab carries a boxed warning regarding possible risks of suicidal ideation and behavior (SIB). The validity of this link remains controversial, especially in the context of the psoriasis population as well as clinical trial data from other recently approved treatments. Herein, we critically examine the association between brodalumab and SIB. J Drugs Dermatol. 2018;17(8 Suppl):s29-34.

What do Australian consumers, pharmacists and prescribers think about documenting indications on prescriptions and dispensed medicines labels?: A qualitative study.

BACKGROUND: Documenting the indication on prescriptions and dispensed medicines labels is not standard practice in Australia. However, previous studies that have focused on the content and design of dispensed medicines labels, have suggested including the indication as a safety measure. The aim of this study was to investigate the perspectives of Australian consumers, pharmacists and prescribers on documenting the indication on prescriptions and dispensed medicines labels. METHODS: Semi-structured interviews were conducted and mock-up of dispensed medicines labels were designed for participants. Consumers (n = 19) and pharmacists (n = 7) were recruited by convenience sample at community pharmacies in Sydney (Australia) and prescribers (n = 8), including two medical students, were recruited through snowballing. RESULTS: Thirty-four participants were interviewed. Most participants agreed that documenting the indication would be beneficial especially for patients who are forgetful or take multiple medications. Participants also believed it would improve consumers' medication understanding and adherence. Prescribers and pharmacists believed it could help reduce prescribing and dispensing errors by matching the drug/dosage to the correct indication. Prescribers refrained from documenting the indication to protect patients' privacy; however, most patients did not consider documenting the indication as a breach of privacy. Prescribers raised concerns about the extra time to include indications on prescriptions and best language to document indications, using plain language as opposed to medical terminology. CONCLUSIONS: All interviewed stakeholders identified numerous benefits of documenting the indication on prescriptions and dispensed medicines labels. Whether these potential benefits can be realized remains unknown and addressing prescribers' concern regarding the time involved in documenting the indication on prescriptions remains a challenge for vendors of electronic medication management systems.

Impact of the black triangle label on prescribing of new drugs in the United Kingdom: lessons for the United States at a time of deregulation.

PURPOSE: Newly approved novel drugs in Europe receive a black triangle label to promote pharmacovigilance. With growing momentum for earlier drug approvals and reliance on real-world evidence, we studied if the black triangle label promotes more judicious prescribing. METHODS: We examined whether general practitioners prescribed escitalopram, tadalafil, and vardenafil with a black triangle more cautiously than the same or similar drugs without a black triangle in The Health Improvement Network (UK). We performed interrupted time-series analyses to estimate changes in new prescription rates and nested case-control studies to compare characteristics of new users before and after removal of a black triangle. RESULTS: Prescribing rates to the 33 441 new users of these new drugs were highest shortly after initial approval and declined subsequently; there were no increases in rates of new prescriptions after a black triangle's removal (new prescriptions/million/month postlabel: escitalopram -1.5 [95% CI, -1.9 to -1.2]; tadalafil and vardenafil: -0.1 [95% CI, -0.6 to 0.4]). Among drugs in the same class, loss of a patent had more impact on prescribing rates than loss of a black triangle. People who began taking black triangle drugs were less likely to be young or to have multiple comorbidities or recent hospitalization compared with those starting the same drugs after the label's removal. However, these differences generally reflected secular trends seen also in similar, unlabeled medicines. CONCLUSIONS: Accelerated drug approvals could cause more uncertainty about drug effectiveness and safety, but specific labeling of newly approved medicines is unlikely to promote more judicious prescribing.

A comprehensive review of the FDA-approved labels of diabetes drugs: Indications, safety, and emerging cardiovascular safety data.

AIMS: FDA-approved drug labels are an important source of information for clinicians who prescribe medications for treatment of diabetes. We reviewed drug labels to (1) understand the landscape of classes of medications approved for type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), (2) explore the indications and safety information and (3) examine their cardiovascular safety. METHODS: We searched four public references and reviewed all FDA-approved labels for "indication and usage," "adverse effects," "warnings and precautions," and "cardiovascular outcomes" from October 1982 to July 2016. We also reviewed FDA drug-safety communications from January 2015 to May 2017. RESULTS: The labels reveal 12 classes of medications approved for T2DM with only 2 classes approved for T1DM. There is emerging evidence about cardiovascular safety and risk reduction from diabetes medications which is now being incorporated in drug labels. CONCLUSIONS: All currently available diabetes medications are approved for adults with T2DM with a remarkably limited number for adults with T1DM and children with T1DM or T2DM. The incorporation of emerging data on cardiovascular outcomes in FDA drug labels is expected to influence the way physicians treat patients with diabetes.

Trends in utilization of smoking cessation agents before and after the passage of FDA boxed warning in the United States.

BACKGROUND: In 2009, the FDA required a black box warning (BBW) on bupropion and varenicline, the two commonly prescribed smoking cessation agents due to reports of adverse neuropsychiatric events. We investigated if there was a decline in use of bupropion and varenicline after the BBW by comparing the percent using these medications before and after BBW. METHODS: We conducted a retrospective observational study using data from the Medical Expenditure Panel Survey from 2007 to 2014. The study sample consisted of adult smokers, who were advised by their physicians to quit smoking. We divided the time period into "pre-warning", "post-warning: immediate", and "post-warning: late." Unadjusted analysis using chi-square tests and adjusted analyses using logistic regressions were conducted to evaluate the change in bupropion and varenicline use before and after the BBW. Secondary analyses using piecewise regression were also conducted. RESULTS: On an average, 49.04% of smokers were advised by their physicians to quit smoking. We observed a statistically significant decline in varenicline use from 22.1% in year 2007 to 9.23% in 2014 (p value<0.001). In the logistic (Adjusted Odds Ratio=0.36, 95% CI=0.22-0.58) and piecewise regressions (Odds Ratio=0.64, 95% CI=0.41-0.99) smokers who were advised to quit smoking by their physicians were less likely to use varenicline in the immediate post-BBW period as compared to pre-BBW period. While the use of varenicline continued to be significantly low in the late post-BBW period (AOR=0.45, 95% CI=0.31-0.64) as compared to the pre-BBW period, the trend in use as seen in piecewise regression remained stable (OR=0.90, 95% CI=0.75-1.06). We did not observe significant differences in bupropion use between the pre- and post-BBW periods. CONCLUSION: The passage of the FDA boxed warning was associated with a significant decline in the use of varenicline, but not in the use of bupropion.

Trends in antidepressant prescribing to children and adolescents in Canadian primary care: A time-series analysis.

PURPOSE: The purpose of this study was to describe the trends and patterns of antidepressant (AD) prescribing to children and adolescents in Canadian primary care before and after the black-box warning in 2004. METHODS: Prescription data from the Canadian Primary Care Sentinel Surveillance Network, a repository of primary care data on over 1 million patients, was used to analyze AD prescribing to children (8-11 y) and adolescents (12-18 y) between 2000 and 2014. Interrupted time series analyses were used to assess the impact of the 2004 black-box warning on the prescribing levels of ADs. RESULTS: The 2004 black-box warning had a significant and immediate effect on the prescribing of AD. However, this drop was not sustained, and 5 years after the advisory AD prescribing rates reversed direction and started to rise. Selective serotonin reuptake inhibitors dominated as the most common AD prescribed throughout the study period, increasing from 66% prior to the black-box warning to 83.12% after 2009. CONCLUSIONS: The black-box warning effectively reduced AD prescribing in primary care for approximately 5 years before a reversal back to a positive rate of prescribing. This rebounding could reflect an emerging consensus about the trade-off in risks and benefits.