An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine.

Clinical annotations are one of the most popular resources available on the Pharmacogenomics Knowledgebase (PharmGKB). Each clinical annotation summarizes the association between variant-drug pairs, shows relevant findings from the curated literature, and is assigned a level of evidence (LOE) to indicate the strength of support for that association. Evidence from the pharmacogenomic literature is curated into PharmGKB as variant annotations, which can be used to create new clinical annotations or added to existing clinical annotations. This means that the same clinical annotation can be worked on by multiple curators over time. As more evidence is curated into PharmGKB, the task of maintaining consistency when assessing all the available evidence and assigning an LOE becomes increasingly difficult. To remedy this, a scoring system has been developed to automate LOE assignment to clinical annotations. Variant annotations are scored according to certain attributes, including study size, reported P value, and whether the variant annotation supports or fails to find an association. Clinical guidelines or US Food and Drug Administration (FDA)-approved drug labels which give variant-specific prescribing guidance are also scored. The scores of all annotations attached to a clinical annotation are summed together to give a total score for the clinical annotation, which is used to calculate an LOE. Overall, the system increases transparency, consistency, and reproducibility in LOE assignment to clinical annotations. In combination with increased standardization of how clinical annotations are written, use of this scoring system helps to ensure that PharmGKB clinical annotations continue to be a robust source of pharmacogenomic information.

Characteristics of Clinical Studies Used for US Food and Drug Administration Supplemental Indication Approvals of Drugs and Biologics, 2017 to 2019.

Importance: After US Food and Drug Administration (FDA) approval of a new drug, sponsors can submit additional clinical data to obtain supplemental approval for use for new indications. Objective: To characterize pivotal trials supporting recent supplemental new indication approvals of drugs and biologics by the FDA and to compare them with pivotal trials that supported these therapeutics' original indication approvals. Design, Setting, and Participants: This is a cross-sectional study characterizing pivotal trials supporting supplemental indication approvals by the FDA between 2017 and 2019 and pivotal trials that supported these therapeutics' original indication approvals. Data analysis was performed from August to October 2020. Main Outcomes and Measures: Number and design of pivotal trials supporting both supplemental and original indication approvals. Results: From 2017 to 2019, the FDA approved 146 supplemental indications for 107 therapeutics on the basis of 181 pivotal efficacy trials. The median (interquartile range) number of trials per supplemental indication was 1 (1-1). Most trials used either placebo (77 trials [42.5%; 95% CI, 35.6%-49.8%]) or active comparators (65 trials [35.9%; 95% CI, 29.3%-43.1%]), and most of these multigroup trials were randomized (141 trials [99.3%; 95% CI, 96.0%-100.0%]) and double-blinded (106 trials [74.5%; 95% CI, 66.6%-81.0%]); 80 trials (44.2%; 95 CI, 37.2%-51.5%) used clinical outcomes as the primary efficacy end point. There was no difference between oncology therapies and those approved for other therapeutic areas to have supplemental indication approvals be based on at least 2 pivotal trials (11.5% vs 20.6%; difference, 9.1%; 95% CI, 2.9%-21.0%; P = .10). Similarly, there was no difference in use of randomization (98.3% vs 100.0%; difference, 1.7%; 95% CI, 1.6%-5.0%; P = .43) among multigroup trials, although these trials were less likely to be double-blinded (50.8% vs 92.3%; difference, 41.5%; 95% CI, 27.4%-55.5%; P < .001); overall, these trials were less likely to use either placebo or active comparators (64.9% vs 86.7%; difference, 21.8% 95% CI, 9.8%-33.9%; P < .001) or to use clinical outcomes as their primary efficacy end point (27.5% vs 61.1%; difference, 33.6%; 95% CI, 14.1%-40.9%; P < .001) and were longer (median [interquartile range], 17 [6-48] weeks vs 95 [39-146] weeks). Original approvals were more likely than supplemental indication approvals to be based on at least 2 pivotal trials (44.0% [95% CI, 33.7%-42.6%] vs 15.8% [95% CI, 10.7%-22.5%]; difference, 28.2%; 95% CI, 17.6%-39.6%; P < .001) and less likely to be supported by at least 1 trial of 12 months' duration (27.6% [95% CI, 17.9%-35.0%] vs 54.8% [95% CI, 46.7%-62.6%]; difference, 27.2%; 95% CI, 14.5%-37.8%; P < .001). Pivotal trial designs were otherwise not significantly different. Conclusions and Relevance: These findings suggest that the number and design of the pivotal trials supporting supplemental indication approvals by the FDA varied across therapeutic areas, with the strength of evidence for cancer indications weaker than that for other indications. There was little difference in the design characteristics of the pivotal trials supporting supplemental indication and original approvals.

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.

Assessment of the Readability, Availability, and Quality of Online Patient Education Materials Regarding Uveitis Medications.

Purpose: To assess the availability, quality, and readability of online patient education materials regarding uveitis medications.Methods: The top 10 Google search results for 10 commonly prescribed uveitis medications (prednisone, azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, tacrolimus, chlorambucil, cyclophosphamide, adalimumab, and infliximab) were analyzed for readability and accountability. Readability was assessed with the Flesch reading ease score, Flesch-Kincaid grade level, Gunning Fog Index, Simple Measure of Gobbledygook Index, and Coleman Liau Index. JAMA benchmarks were used to assign websites accountability scores. Statistical analysis was performed with two-tailed t-tests.Results: Of 100 search results, none complied with the recommended sixth-grade reading level across all readability formulas. Only one website satisfied all 4 JAMA benchmarks, two websites were able to satisfy three benchmarks, and the remainder achieved two or less.Conclusions: Online information regarding uveitis medications lacks accountability and is not written at an appropriate level for the average patient.

Initiatives to reduce treatments in bronchiolitis in the emergency department and primary care.

We performed a quality improvement initiative to reduce unnecessary treatments for acute bronchiolitis (AB) in primary care (PC) and the referral paediatric emergency department (ED). The quality improvement initiative involved two seasons: 2016-2017 (preintervention) and 2017-2018 (postintervention). We distributed an evidence-based protocol, informative posters and badges with the slogan 'Bronchiolitis, less is more'. We also held interactive sessions, and paediatricians received weekly reports on bronchodilator prescription. The main outcome was the percentage of infants prescribed salbutamol. Secondary outcomes were epinephrine, antibiotic and corticosteroid prescription rates. Control measures were ED visit and hospitalisation rates, triage level, length of stay, intensive care admission and unscheduled returns with admission. We included 1878 ED and 1192 PC visits of which 855 (44.5%) and 534 (44.7%) occurred in the postintervention period, respectively. In the ED, salbutamol and epinephrine prescription rates fell from 13.8% (95% CI 11.8% to 16%) to 9.1% (95% CI 7.3% to 11.2%) (p<0.01) and 10.4% (95% CI 8.6% to 12.4%) to 9% (95% CI 7.2% to 11.1%) (n.s.), respectively. In PC, salbutamol, corticosteroid and antibiotic prescription rates fell from 38.3% (95% CI 34.6% to 42.0%) to 15.9% (95% CI 12.9% to 19.5%) (p<0.01), 12.9% (95% CI 10.5% to 15.7%) to 3.6% (95% CI 2.2% to 5.7%) (p<0.01) and 29.6% (95% CI 26.2% to 33.2%) to 9.5% (95% CI 7.2% to 12.5%) (p<0.01), respectively. No significant variations were noted in control measures. We safely decreased the use of unnecessary treatments for AB. Collaboration between PC and ED appears to be an important factor for success.

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.

Implementing parity for mental health and substance use treatment in Medicaid.

OBJECTIVE: To estimate the association between the implementation of parity in coverage for mental health and substance use disorder (MHSUD) services within the Medicaid program and MHSUD service use. DATA SOURCES/STUDY SETTING: Wisconsin Medicaid enrollment and claims data from 2013 to 2015. In April 2014, Wisconsin Medicaid transitioned childless adult beneficiaries from coverage with limited MHSUD services to parity-consistent coverage. Preparity, they only had Medicaid coverage for MHSUD visits to psychiatrists and the emergency department, while parent beneficiaries had parity-consistent coverage. STUDY DESIGN: The study uses a difference-in-differences design to compare outcome changes for childless adult and parent beneficiaries. DATA COLLECTION/EXTRACTION METHODS: We identified 76, 569 childless adult and parent beneficiaries aged 18-64 who were continuously enrolled for the 2-year study period. PRINCIPAL FINDINGS: Introducing parity-consistent coverage within Medicaid was associated with increased utilization of Medicaid-reimbursed MHSUD services: outpatient, prescription medication, ED, and inpatient. Increased MHSUD outpatient visits were driven by increased visits to nonpsychiatrists. CONCLUSIONS: Parity's effects on MHSUD service use have been studied in the context of private insurance, but its impact among Medicaid beneficiaries has not. Our findings suggest that parity implementation in Medicaid could increase access to effective MHSUD services in a high-need population.

Effectiveness of mandatory peer review to reduce antipsychotic prescriptions for Medicaid-insured children.

BACKGROUND: Prior authorization of prescription medications is a policy tool that can potentially impact care quality and patient safety. OBJECTIVE: To examine the effectiveness of a mandatory peer-review program in reducing antipsychotic prescriptions among Medicaid-insured children, accounting for secular trends that affected antipsychotic prescribing nationally. DATA SOURCE: Medicaid Analytical eXtracts (MAX) with administrative claims for health services provided between January 2006 and December 2011. STUDY DESIGN: This retrospective, observational study examined prescription claims records from Washington State (Washington) and compared them to a synthetic control drawing from 20 potential donor states that had not implemented any antipsychotic prior authorization program or mandatory peer review for Medicaid-insured children during the study period. This method provided a means to control for secular trends by simulating the antipsychotic use trajectory that the program state would have been expected to experience in the absence of the policy implementation. PRINCIPAL FINDINGS: Before the policy implementation, antipsychotic use prevalence closely tracked those of the synthetic control (6.17 per 1000 in Washington vs. 6.21 in the synthetic control group). Within two years after the policy was implemented, prevalence decreased to 4.04 in Washington and remained stable in the synthetic control group (6.47), corresponding to an approximately 38% decline. CONCLUSION: Prior authorization program designs and implementations vary widely. This mandatory peer-review program, with an authorization window and two-stage rollout, was effective in moving population level statistics toward safe and judicious use of antipsychotic medications in children.

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.

Differences in the Receipt of Low-Value Services Between Publicly and Privately Insured Children.

BACKGROUND: Children frequently receive low-value services that do not improve health, but it is unknown whether the receipt of these services differs between publicly and privately insured children. METHODS: We analyzed 2013-2014 Medicaid Analytic eXtract and IBM MarketScan Commercial Claims and Encounters databases. Using 20 measures of low-value care (6 diagnostic testing measures, 5 imaging measures, and 9 prescription drug measures), we compared the proportion of publicly and privately insured children in 12 states who received low-value services at least once or twice in 2014; the proportion of publicly and privately insured children who received low-value diagnostic tests, imaging tests, and prescription drugs at least once; and the proportion of publicly and privately insured children eligible for each measure who received the service at least once. RESULTS: Among 6 951 556 publicly insured children and 1 647 946 privately insured children, respectively, 11.0% and 8.9% received low-value services at least once, 3.9% and 2.8% received low-value services at least twice, 3.2% and 3.8% received low-value diagnostic tests at least once, 0.4% and 0.4% received low-value imaging tests at least once, and 8.4% and 5.5% received low-value prescription drug services at least once. Differences in the proportion of eligible children receiving each service were typically small (median difference among 20 measures, public minus private: +0.3 percentage points). CONCLUSIONS: In 2014, 1 in 9 publicly insured and 1 in 11 privately insured children received low-value services. Differences between populations were modest overall, suggesting that wasteful care is not highly associated with payer type. Efforts to reduce this care should target all populations regardless of payer mix.

Conformity in Prescription and Administration of Respiratory Distress Protocols in a Tertiary Care Hospital in the Province of Quebec: RELIEVE Study.

BACKGROUND: Respiratory distress protocols (RDPs) are protocolized prescriptions comprised of 3 medications (a benzodiazepine, an opioid, and an anticholinergic) administered simultaneously as an emergency treatment for respiratory distress in palliative care patients in the province of Quebec, Canada. However, data on appropriate use that justifies the combination of all 3 components is scarce and based on individual pharmacodynamic properties along with expert consensus. OBJECTIVES: Our study aimed to evaluate the conformity and the effectiveness of RDPs prescribed and administered to hospitalized adult patients. METHODS: This was a prospective and descriptive study conducted in a single center. Prescription and administration conformity were assessed based on predefined appropriateness criteria. RESULTS: A total of 467 adult patients were prescribed a RDP, 175 administrations were documented, and 78 patients received at least 1 RDP. Prescription conformity was assessed on 1473 separate occasions over the trial period. Overall prescription conformity was found to be 37% (95% confidence interval [CI]: 33.6-40.4), and administration conformity was 37.7% (95% CI: 26.2-50.7). Low administration conformity was primarily explained by incorrect indications for RDP use. Seemingly important determinants of higher conformity were prescriber's speciality in palliative care, use of preprinted orders, pharmacist involvement, and hospitalization in the palliative care unit. CONCLUSION: This study highlights important gaps in the use of RDPs in our institution. Health-care provider training appears necessary in order to ensure adequate conformity and allow for further evaluation of RDP effectiveness.

Campaign manufacturing of highly active or sensitizing drugs: a comparison between the GMPs of various Regulatory Agencies.

BACKGROUND: Cross-contamination and mix-ups are among the problems which could have a negative impact on the quality of the finished product during the production of highly active or sensitizing drugs with campaign manufacturing. Standardised, validated procedures ensure quality standards are maintained during production. In spite of this, the operating conditions and applicability of methods adopted by the various regulatory agencies manifest significant differences which could consequently compromise the safety of the finished product. This work has analysed and compared the GMP of various Regulatory Agencies to examine issues connected to campaign manufacturing highly active or sensitizing drugs. METHODS: The GMP of the following Regulatory Agencies have been studied: EMA, CFDA, COFEPRIS, FDA, Health Canada, ANVISA, CDSCO, PIC/S and WHO. The study was carried out for the purpose of understanding which agencies consent to the use of campaign manufacturing for the following categories of medicinal products: hormones, immunosuppressants, cytotoxic agents, highly active pharmaceutical ingredients (APIs), biological preparations, steroids, sensitizing pharmaceutical materials, antibiotics, cephalosporins, penicillins, carbapenems and beta-lactam derivatives. RESULTS: The GMP of Health Canada, EMA, PIC/S and FDA show a number of similarities, starting with the fact that they allow campaign manufacturing for similar categories of pharmaceutical products after an appropriate risk evaluation has been performed. CFDA, WHO, ANVISA authorise campaign manufacturing in "exceptional circumstances", though they do not always define what they mean by this. COFEPRIS authorises campaign manufacturing for certain classes of drugs, while there is no mention of campaign manufacturing in the CDSCO regulations. CONCLUSIONS: Quite a few significant differences have been found in the various regulations concerning the use of campaign manufacturing and the classes of drugs that can be produced with this method. In the light of this, it is obvious that efforts to harmonise legislation internationally have not yet been successful: currently, states can adopt different quality standards. The pharmaceutical industry could use this situation to its advantage by delocalising production on the basis of existing standards. The need to harmonise GMPs is a priority which must be achieved as soon as possible.

Patient-Centered Standards for Medically Integrated Dispensing: ASCO/NCODA Standards.

PURPOSE: To provide standards for medically integrated dispensing of oral anticancer drugs and supportive care medications. METHODS: An Expert Panel was formed, and a systematic review of the literature on patient-centered best practices for the delivery of oral anticancer and supportive care drugs was performed to April 2019 using PubMed and Google Scholar. Available patient-centered standards, including one previously developed by the National Community Oncology Dispensing Association (NCODA), were considered for endorsement. Public comments were solicited and considered in preparation of the final manuscript. RESULTS: A high-quality systematic review that was current to May 2016 was adopted into the evidence base. Five additional primary studies of multifaceted interventions met the inclusion criteria. These studies generally included a multicomponent intervention, often led by an oncology pharmacist, and also included patient education and regular follow-up and monitoring. These interventions resulted in significant improvements to patient quality and safety and demonstrated improvements in adherence and other patient outcomes. CONCLUSION: The findings of the systematic review were consistent with the NCODA patient-centered standards for patient relationships and education, adherence, safety, collection of data, documentation, and other areas. NCODA standards were adopted and used as basis for these American Society of Clinical Oncology/NCODA standards. Additional information is available at www.asco.org/mid-standards.

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.

The implementation of HTA in medicine pricing and reimbursement policies in Indonesia: Insights from multiple stakeholders.

OBJECTIVES: This study aimed to identify the barriers and facilitators to improve the use of health technology assessment (HTA) for the selection of medicines listed in the e-Catalogue and the national formulary in Indonesia. METHODS: Semi-structured interviews were conducted to collect qualitative data. Purposive sampling was used to recruit the stakeholders consisting of policymakers, a pharmaceutical industry representative, healthcare providers, and patients. The data were analyzed using directed content analysis and following the COnsolidated criteria for REporting Qualitative studies (COREQ). RESULTS: The twenty-five participants interviewed agreed with the use of HTA for supporting the e-Catalogue and the national formulary and perceived the advantages of HTA implementation outweighed the disadvantages. Barriers mentioned were a lack of capability of local human resources, financial incentives, a clear framework and insufficient data. Strategies suggested to overcome the barriers were establishing (inter)national networks to build up capacity, setting up departments of HTA in several universities in Indonesia, and introducing a clear HTA framework. Facilitators mentioned were the ambition to achieve universal health coverage, the presence of legal frameworks to implement HTA in the e-Catalogue and the national formulary, and the demands for appropriate medicine policies. CONCLUSIONS: Several barriers are currently hampering broad implementation of HTA in medicine pricing and reimbursement policy in Indonesia. Solutions to these issues appear feasible and important facilitators exist.