What should patients do if they miss a dose? A systematic review of patient information leaflets and summaries of product characteristics.

PURPOSE: Medicines regulatory authorities advise that patient information leaflets (PILs) should provide specific advice on what actions to take if one or more doses are missed. We aimed to assess the content in this regard, of PILs and Summaries of Product Characteristics (SmPCs) of prescription only medicines (POMs) marketed in the UK. METHODS: PILs and SmPCs were accessed via the electronic Medicines Compendium. The following terms were used in the advanced search facility: miss(ed), omit(ted), adhere(d), delay(ed), forgot, forget, lapse. Identified documents were screened for instructions on missed doses which were categorised according to level of specificity, and cross-referenced to the National Patient Safety Agency (NPSA) grading of risk of harm from omitted and delayed medicines. Any supporting clinical or pharmacological evidence was identified from SmPCs. RESULTS: Two thousand two hundred eighty-four documents were identified from 7248 PILs and SmPCs relating to 1501 POMs. Seven hundred eighty-three (52%) POMs had SmPCs or PILs with no instructions on missed doses; 487 POMs (32%) included non-specific advice (e.g. "take as soon as possible"); 138 (9%) provided specific instructions; and 93 (6%) referred patients to seek medical advice. SmPCs for only 13/138 (9%) of those which included specific instructions provided any supporting clinical or pharmacological evidence. Instructions were absent for several medicines where the NPSA assessed that dose omissions may result in significant risk of harm. CONCLUSIONS: Advice on missed doses is generally inadequate. Pharmaceutical companies and regulatory authorities should produce clear and concise instructions on what patients should do if they miss doses, with supporting evidence where necessary.

Quality, efficacy, safety-it is not enough!

There is a need of comparative studies to understand the differences in term of efficacy and safety of drugs with different mechanisms of action but similar therapeutic indications. This requires changes in the European Legislation of criteria for drug approval.

Consumer understanding of the scope of FDA's prescription drug regulatory oversight: A nationally representative survey.

PURPOSE: Misperceptions of how the US Food and Drug Administration (FDA) regulates prescription drugs may affect how consumers assess the safety and efficacy of prescription drugs. The study objective was to survey the public on their knowledge of FDA oversight regarding prescription drug approval and advertising. METHODS: In 2017, we conducted a nationally representative mail-push-to-web survey with 1,744 US adults. RESULTS: Although most respondents (86%) knew that FDA approves prescription drugs, we found misperceptions about what that approval means. In addition, few respondents understood FDA oversight of prescription drug advertising, with approximately half of respondents reporting that they did not know whether FDA approved these ads or components of the ads, and several mis-reporting that FDA approves these ads (31%) or components of the ads (22%-41%). CONCLUSIONS: Enhanced collaboration and communication with the public by key stakeholders in this space could increase public understanding of the roles and responsibilities of FDA.

Preventing Lethal Prostate Cancer with Diet, Supplements, and Rx: Heart Healthy Continues to Be Prostate Healthy and "First Do No Harm" Part II.

PURPOSE OF REVIEW: To discuss the overall and latest observations of the effect of diet, lifestyle, supplements, and some prescription heart healthy medications for prostate cancer prevention. RECENT FINDINGS: The concept of maximizing heart health to prevent aggressive prostate cancer continues to be solidified with the addition of more prospective observational and randomized controlled trial data. Heart healthy is prostate healthy, and heart unhealthy is prostate unhealthy. The primary goal of reducing the risk of all-cause and cardiovascular disease (CVD) morbidity and mortality also coincides with maximizing prostate cancer prevention. The obesity epidemic in children and adults along with recent diverse research has only strengthened the nexus between heart and prostate health. Greater dietary adherence toward a variety of healthy foods is associated with a graded improved probability of CVD and potentially aggressive cancer risk reduction. Preventing prostate cancer via dietary supplements should encourage a "first do no harm," or less is more approach until future evidence can reverse the concerning trend that more supplementation has resulted in either no impact or an increased risk of prostate cancer. Supplements to reduce side effects of some cancer treatments appear to have more encouraging data. A discussion of quality (QC) before utilizing any pill also requires attention. Medications or interventions that potentially improve heart health including statins, aspirin, and metformin (S.A.M.), specific beta-blocker medications, and even preventive vaccines are in general generic, low-cost, "natural," and should continue to garner research interest. A watershed moment in medical education has arrived where the past perception of a diverse number of trees seemingly separated by vast distances, in reality, now appear to exist within the same forest.

Application of Prescription Drug Monitoring Program to detect underreported controlled substance use in patients evaluated for liver transplant.

Presurgical controlled substance use predicts postoperative complications, increased readmissions, and mortality. We aimed to examine if a Prescription Drug Monitoring Program (PDMP) would detect underreported controlled substance use in patients undergoing liver transplant evaluation. We performed a retrospective cohort study at a tertiary referral center of patients undergoing liver transplant evaluation in 2017. PDMP reviews were performed on all 360 patients and urine drug screen (UDS) results were reviewed when available to evaluate dispensed controlled substances. These results were compared to the patient's self-reported medication list at evaluation to identify any underreporting. The primary outcome was the number of self-reported controlled substance discrepancies on the medication list identified by PDMP and UDS at the time of evaluation. Among the 360 patients, 87 (24%) had a discrepancy where PDMP revealed a controlled substance prescription that the patient did not report on their medication list. Seventy-seven (67/87) of these discrepancies involved opiates. Of the 360 patients, 219 (61%) had a negative UDS, but 70 (32%) of these patients had at least one controlled substance listed on PDMP. PDMP is a promising screening tool when used in conjunction with the UDS for detecting underreported controlled substance use in liver transplant candidates.

Patient-provider communications about pharmacogenomic results increase patient recall of medication changes.

Effective doctor-patient communication is critical for disease management, especially when considering genetic information. We studied patient-provider communications after implementing a point-of-care pharmacogenomic results delivery system to understand whether pharmacogenomic results are discussed and whether medication recall is impacted. Outpatients undergoing preemptive pharmacogenomic testing (cases), non-genotyped controls, and study providers were surveyed from October 2012-May 2017. Patient responses were compared between visits where pharmacogenomic results guided prescribing versus visits where pharmacogenomics did not guide prescribing. Provider knowledge of pharmacogenomics, before and during study participation, was also analyzed. Both providers and case patients frequently reported discussions of genetic results after visits where pharmacogenomic information guided prescribing. Importantly, medication changes from visits where pharmacogenomics influenced prescribing were more often recalled than non-pharmacogenomic guided medication changes (OR = 3.3 [1.6-6.7], p = 0.001). Case patients who had separate visits where pharmacogenomics did and did not, respectively, influence prescribing more often remembered medication changes from visits where genomic-based guidance was used (OR = 3.4 [1.2-9.3], p = 0.02). Providers also displayed dramatic increases in personal genomic understanding through program participation (94% felt at least somewhat informed about pharmacogenomics post-participation, compared to 61% at baseline, p = 0.04). Using genomic information during prescribing increases patient-provider communications, patient medication recall, and provider understanding of genomics, important ancillary benefits to clinical use of pharmacogenomics.

Antimicrobial stewardship program (ASP): an effective implementing technique for the therapy efficiency of meropenem and vancomycin antibiotics in Iranian pediatric patients.

BACKGROUND: Antimicrobial stewardship program (ASP) is a distinguished method to improve the prescription and efficacy of antibiotics. AIM: The efficacy of ASP and conventional methods was compared to measure the effectiveness of meropenem (MPM) and vancomycin (VMN) antibiotics in pediatric patients. DESIGN: In an interventional quasi-experimental study, 135 children admitted in Children's Hospital affiliated to University of Medical Sciences in time periods of 2014-2015 and 2015-2016 were assessed. METHODS: The conventional and ASP methods in 2014-2015 and 2015-2016 were respectively utilized to provide the best antimicrobial therapy of MPM and VMN antibiotics in patient children. The data of mortality rate (MR), antibiotic prescription (AP), antibiotic dose (ADe), antibiotic duration (ADn), length of hospital stay (LOHS), and blood cultures (BCs) were compared across the years using the Chi square, independent t test, and Fisher's exact test. RESULTS: The levels of MR, AP, ADe, ADn, LOHS, and positive BCs using the ASP method in 2015-2016 were significantly lower those of in 2014-2015 using the conventional one (p < 0.05). CONCLUSIONS: The ASP method versus conventional one with a better efficacy can be employed as an antibiotic administration guide for MPM and VMN in the therapy of patients in community-based hospitals.

Implementation fidelity of patient-centered prescription label to promote opioid safe use.

PURPOSE: Patient-centered labels may improve safe medication use, but implementation challenges limit use. We assessed implementation of a patient-centered "PRN" (as needed) label entitled "Take-Wait-Stop" (TWS) with three deconstructed steps replacing traditional wording. METHODS: As part of a larger investigation, patients received TWS prescriptions (eg, Take: 1 pill if you have pain; Wait: at least 4 h before taking again; Stop: do not take more than 6 pills in 24 h). Prescriptions labels recorded at follow-up were classified into three categories: (1) one-step wording (Take 1 pill every 4 h [without daily limits]), (2) two-step wording (Take 1 pill every 4 h; do not exceed 6 pills/day), and (3) three-step wording. There were three subtypes of three-step wording: (3a) three-step, not TWS (three deconstructed steps, not necessarily TWS wording), (3b) TWS format, employing three steps with leading verbs, but "with additions or replacements" (eg, replaced "do not take" with "do not exceed"), and (3c) verbatim TWS. RESULTS: Two hundred eleven participants completed follow-up. Mean age was 44.3 years (SD 14.3); 44% were male. One-step bottles represented 12% (n = 25) of the sample, whereas 26% (n = 55) had two-step wording. The majority (44%, n = 93) had three-deconstructed steps, not TWS (3a); 16% (n = 34) retained TWS structure, but not verbatim (3b). Only 2% (n = 4) displayed verbatim TWS wording (3c). All category three labels (utilizing deconstructed instructions) were considered adequate implementation (62%). CONCLUSIONS: Exact intervention adherence was not achieved in the majority of cases, limiting impact. Nonetheless, community pharmacies were responsive to new instructions, but higher implementation reliability requires additional supports.

Development and content validation of an instrument to document the dispensing of prescribed medicines.

WHAT IS KNOWN AND OBJECTIVE: Qualified dispensing is fundamental for the promotion of the rational use of medicines. Documentation is an indicator of quality and one of the essential steps in the care process. However, in Brazil, there are no models of clinical documentation applicable to dispensing practices. Thus, the objective of this study was to develop and validate an instrument to document the dispensing process of prescribed medicines. METHODS: A methodological development study was carried out from February 2017 to October 2017 in two stages, which were (i) the development of the instrument and (ii) content validation of the proposed instrument. The development phase comprised three stages, which were (i) the elaboration of the prototype based on a previously performed systematic review, (ii) academic brainstorming and (iii) a pre-Delphi consensus. The content validation process was performed using the Delphi technique. The instrument was sent to 40 experts with experience in dispensing, and the consensus among them was calculated using the content validity index (CVI). The study was approved by the Ethics Committee, and all participants signed an informed consent document detailing the terms of the study. RESULTS: In the development stage, three versions of the instrument were generated, which were the prototype, version 1 (changed after academic brainstorming) and version 2 (changed after the pre-Delphi). In the content validation process of version 2 of the instrument, 23 experts returned their evaluation in the first round of the Delphi process and 17 in the second. All the items obtained a CVI >0.83, which resulted in the validation of the instrument. The final instrument comprised the following sections: general information, the identification of technical and legal problems of prescriptions, the conduct for the resolution of the technical and legal problems of prescriptions, medication dispensed, suspected drug-related problems, verbal guidance, written guidance, referral and the referral result. WHAT IS NEW AND CONCLUSION: The developed and validated instrument presents the main variables that should be documented during the dispensing process.

Current Status of Expiry of Homeopathic Medicines in Brazil, Germany, India and the United States: A Critical Review.

BACKGROUND: Assignment of expiry date to homeopathic medicines is a subject of important concern to its pharmacists and practitioners. This study compares the regulatory framework for the expiry of homeopathic medicines in four countries: Brazil, Germany, India and the United States. FINDINGS: Different or no expiry periods are variously followed. Whereas Germany, with some exceptions, employs a maximum expiry of 5 years for both potencies and finished products, Brazil adopts a 5-year expiry for finished products only, potencies used in manufacture being exempted from an assigned expiry date. In India, all homeopathic medicines except dilutions and back potencies have a maximum of 5 years' shelf-life, including those supplied to consumers. In the United States, homeopathic medicines are exempted from expiry dates. COMMENTS: There is neither a rational basis nor scientific evidence for assigning a short (3-5 years) expiry period for homeopathic medicines as followed in some of the countries, particularly in light of the fact that some studies have shown homeopathic medications to be effective even after 25 years. Homeopathic ultra-dilutions seem to contain non-material activity that is maintained over time and, since these exhibit different chemical properties compared to the original starting material, it is quite possible they possess properties of longer activity than conventional medicines. Regulators should acknowledge this feature and differentiate expiry of homeopathic medicinal products from that of conventional drugs.

Baclofen in gamma-hydroxybutyrate withdrawal: patterns of use and online availability.

PURPOSE: Gamma-hydroxybutyrate (GHB) withdrawal is a life-threatening condition that does not always respond to standard treatment with benzodiazepines. Baclofen has potential utility as a pharmacological adjunct and anecdotal reports suggest that it is being used by drug users to self-manage GHB withdrawal symptoms. Here, we investigate current patterns of use and the online availably of baclofen. METHODS: Data triangulation techniques were applied to published scientific literature and publicly accessible Internet resources (grey literature) to assess the use of baclofen in GHB withdrawal. An Internet snapshot survey was performed to identify the availability of baclofen for online purchase and the compliance of retailers with the UK regulations. Data were collected according to pre-defined criteria. RESULTS: A total of 37 cases of baclofen use in GHB withdrawal were identified in the scientific literature, as well as 51 relevant discussion threads across eight Internet forums in the grey literature. Baclofen was available to purchase from 38 online pharmacies, of which only one conformed to the UK regulations. CONCLUSIONS: There is limited published evidence on the use of baclofen in GHB withdrawal, but both scientific and grey literature suggests clinical utility. Online pharmacies are readily offering prescription-only-medication without prescription and due to inadequate regulation, pose a danger to the public.

Unsolicited Reporting to Prescribers of Opioid Analgesics by a State Prescription Drug Monitoring Program: An Observational Study with Matched Comparison Group.

Objective: State prescription drug monitoring programs (PDMPs) can help detect individuals with multiple provider episodes (MPEs; also referred to as doctor/pharmacy shopping), an indicator of prescription drug abuse and/or diversion. Although unsolicited reporting by PDMPs to prescribers of opioid analgesics is thought to be an important practice in reducing MPEs and the potential harm associated with them, evidence of its effectiveness is mixed. This exploratory research evaluates the impact of unsolicited reports sent by Massachusetts' PDMP to the prescribers of persons with MPEs. Methods: Individuals with MPEs were identified from PDMP records between January 2010 and July 2011 as individuals having Schedule II prescriptions (at least one prescription being an opioid) from four or more distinct prescribers and four or more distinct pharmacies within six months. Based on available MA-PDMP resources, an unsolicited report containing the patient's 12-month prescription history was sent to prescribers of a subset of patients who met the MPE threshold; a comparison group closely matched on demographics and baseline prescription history, whose prescribers were not sent a report, was generated using propensity score matching. The prescription history of each group was examined for 12 months before and after the intervention. Results: There were eighty-four patients (intervention group) whose prescribers received an unsolicited report and 504 matched patients (comparison group) whose prescribers were not sent a report. Regression analyses indicated significantly greater decreases in the number of Schedule II opioid prescriptions (P < 0.01), number of prescribers visited (P < 0.01), number of pharmacies used (P < 0.01), dosage units (P < 0.01), total days' supply (P < 0.01), total morphine milligram equivalents (MME; P < 0.01), and average daily MME (P < 0.05) for the intervention group relative to the comparison group. A post hoc analysis suggested that the observed intervention effects were greater for individuals with an average daily dose of less than 100 MMEs. Conclusions: This study suggests that PDMP unsolicited reporting to prescribers can help reduce risk measures in patients' prescription histories, which may improve health outcomes for patients receiving opioid analgesics from multiple providers.

A DECADE OF HEALTH TECHNOLOGY ASSESSMENT IN POLAND.

OBJECTIVES: The objective of this study is to illustrate and provide a better understanding of the role of health technology assessment (HTA) processes in decision making for drug reimbursement in Poland and how this approach could be considered by other countries of limited resources. METHODS: We analyzed the evolution of the HTA system and processes in Poland over the past decade and current developments based on publicly available information. RESULTS: The role of HTA in drug-reimbursement process in Poland has increased substantially over the recent decade, starting in 2005 with the formation the Agency for Health Technology Assessment and Tariff System (AOTMiT). The key success factors in this development were effective capacity building based on the use of international expertise, the implementation of transparent criteria into the drug reimbursement processes, and the selective approach to the adoption of innovative medicines based on the cost-effectiveness threshold among other criteria. CONCLUSIONS: While Poland is regarded as a leader in Central and Eastern Europe, there is room for improvement, especially with regard to the quality of HTA processes and the consistency of HTA guidelines with reimbursement law. In the "pragmatic" HTA model use by AOTMiT, the pharmaceutical company is responsible for the preparation of a reimbursement dossier of good quality in line with HTA guidelines while the assessment team in AOTMiT is responsible for critical review of that dossier. Adoption of this model may be considered by other countries with limited resources to balance differing priorities and ensure transparent and objective access to medicines for patients who need them.

INTRODUCTION OF HEALTH TECHNOLOGY ASSESSMENT FOR MEDICINES IN SLOVAKIA.

OBJECTIVES: The aim of our study was to describe approaches to health technology assessment (HTA) for medicines in the Slovak healthcare system and the related decision-making processes concerning reimbursement for medicines. METHODS: Analysis of the Slovak legislative framework related to HTA and the reimbursement process for medicines was performed. Additionally, current practices of the Working Group for Pharmacoeconomics, Clinical Outcomes and Health Technology Assessment of the Slovak Ministry of Health were evaluated. RESULTS: In Slovakia, there is always at least one treatment available in each determined therapeutic class with no co-payment. HTA is becoming an established method for the evaluation of cost-effectiveness of medicines in Slovak healthcare policy. The majority of decision makers within Slovakia support the idea of increased use of and the quality and efficiency of HTA methods. However, it is crucial to overcome several practical barriers to facilitate progress in the field of HTA in the Slovak Republic. CONCLUSIONS: It can be seen that participation within the European Network for Health Technology Assessment (EUnetHTA JA 2 and EUnetHTA JA 3 projects) has significantly improved the quality of the process of HTA in Slovakia. Further legislative activities in this field are required due to the approved strategy for European Union cooperation on HTA.

HEALTH TECHNOLOGY ASSESSMENT IN EVALUATION OF PHARMACEUTICALS IN THE CZECH REPUBLIC.

OBJECTIVES: In the Czech Republic, the health technology assessment (HTA) approaches have been implemented in evaluation of medicinal products since 2008. The aim of this study was to provide an overview of the implementation of HTA and different levels thereof in the evaluation process conducted by the State Institute for Drug Control (SUKL) and to describe the impact of HTA on the entrance of new medicinal entities into out-patient healthcare system including highly innovative and orphan drugs. METHODS: Materials supporting this overview were collected using the records in the database of administrative proceedings of SUKL, in-house standard operating procedures, and the legislation in force. Based on these sources as well as the hands-on knowledge of the current practice, a brief description of the general rules of administrative proceedings involving HTA of varying complexity was elaborated. Characteristic features of the individual types of proceedings, basic differences in the complexity of HTA employed, and its most important challenges were summarized. RESULTS: In Czech Republic, HTA in the formal administrative proceedings ensures a transparent process of introduction of new medicinal products into clinical practice and leaves space for restriction of reimbursement conditions to minimize budget impact. CONCLUSIONS: As a robust as well as pragmatic HTA methodology has been implemented by SUKL, relevant stakeholders (marketing authorization holders, Health Care Funds, clinical expert groups) are now able to influence reimbursement of new technologies.

Encouraging pharmacist intervention and standardization of labeling and dispensing of oral liquid medications.

OBJECTIVES: To initiate a call to action for community pharmacists and key-pharmacy stakeholders in the standardization of oral-liquid dosage forms. DATA SOURCES: Not applicable. SUMMARY: Unintentional overdose of medication due to administration error results in thousands of pediatric hospitalizations yearly. A lack of prescription and dosage device standardization pertaining to oral-liquid medications continue to be a public health hazard. Multiple professional organizations have publicly endorsed the standardization of oral liquid dosage forms. Universal adoption will not be achieved until key-pharmacy stakeholders encourage their pharmacists to use best practices when verifying and preparing prescription medication. Specifically, these practices should include immediate conversion of prescriptions containing non-metric volumes into metric volumes, providing appropriate sized oral dosing syringes for all oral liquid prescriptions, writing dosing directions in the safest format, and counseling patients and caretakers of proper medication administration. CONCLUSION: Community pharmacists are uniquely positioned to lead the universal adoption of these best practices to ensure proper oral-liquid dosing administration for all patients.

Do Residents Need All Their Medications? A Cross-Sectional Survey of RNs' Views on Deprescribing and the Role of Clinical Pharmacists.

A cross-sectional survey was mailed to 307 RNs of a nationally representative sample of residential aged care facilities to investigate their views and perceptions on medication use and deprescribing in older adults. Questions were grouped according to each stage of the medication use process, and a dedicated section to explore nurses' views on deprescribing was included. Ninety-one questionnaires were received, yielding a 29.6% response rate. Respondents highlighted several challenges including achieving medication reconciliation for new residents, access to physicians to admit patients in a timely fashion, and issues pertaining to lack of clear medical information transcribing when transferring patients between health care settings. More than one half (67.4%) of nurses agreed or strongly agreed that deprescribing implemented with the help of a clinical pharmacist would be beneficial to residents and could improve medication adherence (44%), benefit residents' quality of life (50.5%), and reduce the length of time spent by nurses on medication administration (35.2%). Increased awareness regarding polypharmacy and potential deprescribing benefits is necessary to improve appropriate prescribing and medication use. [Journal of Gerontological Nursing, 43(10), 13-20.].

Pharmaceutical Industry Off-label Promotion and Self-regulation: A Document Analysis of Off-label Promotion Rulings by the United Kingdom Prescription Medicines Code of Practice Authority 2003-2012.

BACKGROUND: European Union law prohibits companies from marketing drugs off-label. In the United Kingdom--as in some other European countries, but unlike the United States--industry self-regulatory bodies are tasked with supervising compliance with marketing rules. The objectives of this study were to (1) characterize off-label promotion rulings in the UK compared to the whistleblower-initiated cases in the US and (2) shed light on the UK self-regulatory mechanism for detecting, deterring, and sanctioning off-label promotion. METHODS AND FINDINGS: We conducted structured reviews of rulings by the UK self-regulatory authority, the Prescription Medicines Code of Practice Authority (PMCPA), between 2003 and 2012. There were 74 off-label promotion rulings involving 43 companies and 65 drugs. Nineteen companies were ruled in breach more than once, and ten companies were ruled in breach three or more times over the 10-y period. Drawing on a typology previously developed to analyse US whistleblower complaints, we coded and analysed the apparent strategic goals of each off-label marketing scheme and the practices consistent with those alleged goals. 50% of rulings cited efforts to expand drug use to unapproved indications, and 39% and 38% cited efforts to expand beyond approved disease entities and dosing strategies, respectively. The most frequently described promotional tactic was attempts to influence prescribers (n = 72, 97%), using print material (70/72, 97%), for example, advertisements (21/70, 30%). Although rulings cited prescribers as the prime target of off-label promotion, competing companies lodged the majority of complaints (prescriber: n = 16, 22%, versus companies: n = 42, 57%). Unlike US whistleblower complaints, few UK rulings described practices targeting consumers (n = 3, 4%), payers (n = 2, 3%), or company staff (n = 2, 3%). Eight UK rulings (11%) pertaining to six drugs described promotion of the same drug for the same off-label use as was alleged by whistleblowers in the US. However, while the UK cases typically related to only one or a few claims made in printed material, several complaints in the US alleged multifaceted and covert marketing activities. Because this study is limited to PMCPA rulings and whistleblower-initiated federal cases, it may offer a partial view of exposed off-label marketing. CONCLUSION: The UK self-regulatory system for exposing marketing violations relies largely on complaints from company outsiders, which may explain why most off-label promotion rulings relate to plainly visible promotional activities such as advertising. This contrasts with the US, where Department of Justice investigations and whistleblower testimony have alleged complex off-label marketing campaigns that remain concealed to company outsiders. UK authorities should consider introducing increased incentives and protections for whistleblowers combined with US-style governmental investigations and meaningful sanctions. UK prescribers should be attentive to, and increasingly report, off-label promotion.

A Patient-Centered Prescription Drug Label to Promote Appropriate Medication Use and Adherence.

BACKGROUND: Patient misunderstanding of prescription drug label instructions is a common cause of unintentional misuse of medication and adverse health outcomes. Those with limited literacy and English proficiency are at greater risk. OBJECTIVE: To test the effectiveness of a patient-centered drug label strategy, including a Universal Medication Schedule (UMS), to improve proper regimen use and adherence compared to a current standard. DESIGN: Two-arm, multi-site patient-randomized pragmatic trial. PARTICIPANTS: English- and Spanish-speaking patients from eight community health centers in northern Virginia who received prescriptions from a central-fill pharmacy and who were 1) ≥30 years of age, 2) diagnosed with type 2 diabetes and/or hypertension, and 3) taking ≥2 oral medications. INTERVENTION: A patient-centered label (PCL) strategy that incorporated evidence-based practices for format and content, including prioritized information, larger font size, and increased white space. Most notably, instructions were conveyed with the UMS, which uses standard intervals for expressing when to take medicine (morning, noon, evening, bedtime). MAIN MEASURES: Demonstrated proper use of a multi-drug regimen; medication adherence measured by self-report and pill count at 3 and 9 months. KEY RESULTS: A total of 845 patients participated in the study (85.6 % cooperation rate). Patients receiving the PCL demonstrated slightly better proper use of their drug regimens at first exposure (76.9 % vs. 70.1 %, p = 0.06) and at 9 months (85.9 % vs. 77.4 %, p = 0.03). The effect of the PCL was significant for English-speaking patients (OR 2.21, 95 % CI 1.13-4.31) but not for Spanish speakers (OR 1.19, 95 % CI 0.63-2.24). Overall, the intervention did not improve medication adherence. However, significant benefits from the PCL were found among patients with limited literacy (OR 5.08, 95 % CI 1.15-22.37) and for those with medications to be taken ≥2 times a day (OR 2.77, 95 % CI 1.17-6.53). CONCLUSIONS: A simple modification to pharmacy-generated labeling, with minimal investment required, can offer modest improvements to regimen use and adherence, mostly among patients with limited literacy and more complex regimens. Trial Registration (ClinicalTrials.gov): NCT00973180, NCT01200849.

Statistical issues in the design, conduct and analysis of two large safety studies.

BACKGROUND/AIMS: The emergence, post approval, of serious medical events, which may be associated with the use of a particular drug or class of drugs, is an important public health and regulatory issue. The best method to address this issue is through a large, rigorously designed safety study. Therefore, it is important to elucidate the statistical issues involved in these large safety studies. METHODS: Two such studies are PRECISION and EAGLES. PRECISION is the primary focus of this article. PRECISION is a non-inferiority design with a clinically relevant non-inferiority margin. Statistical issues in the design, conduct and analysis of PRECISION are discussed. RESULTS: Quantitative and clinical aspects of the selection of the composite primary endpoint, the determination and role of the non-inferiority margin in a large safety study and the intent-to-treat and modified intent-to-treat analyses in a non-inferiority safety study are shown. Protocol changes that were necessary during the conduct of PRECISION are discussed from a statistical perspective. Issues regarding the complex analysis and interpretation of the results of PRECISION are outlined. EAGLES is presented as a large, rigorously designed safety study when a non-inferiority margin was not able to be determined by a strong clinical/scientific method. In general, when a non-inferiority margin is not able to be determined, the width of the 95% confidence interval is a way to size the study and to assess the cost-benefit of relative trial size. CONCLUSION: A non-inferiority margin, when able to be determined by a strong scientific method, should be included in a large safety study. Although these studies could not be called "pragmatic," they are examples of best real-world designs to address safety and regulatory concerns.