Drug shortages. Part 2: Trends, causes and solutions.

Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations. In the first part of this review we proposed an operational definition that incorporates the processes by which products are manufactured, the causes of shortages and stock-outs (local shortages), and the contributory factors. Here we discuss causes and possible solutions. Drug shortages have complex causes, and a single cause cannot always be identified. Reasons include lack or shortage of raw materials, manufacturing difficulties, regulatory and political actions, voluntary recalls, just-in-time inventory systems, halts in production for financial or other business reasons, low demand (eg, orphan products, reduced usage), mergers, market shifts (eg, diversion to home markets) and unexpected increases in demand (eg, improved diagnosis, new trial information, epidemics and pandemics, inappropriate use, off-label use). Potential solutions are as diverse as the potential causes. Prevention is hard, because shortages are not easily predicted. Everyone in the supply chain is involved in anticipating and managing shortages, with responsibilities for preventing them or at least trying to mitigate their effects. This includes manufacturers and suppliers, particularly of generic formulations, pharmacists, prescribers, patients and governments. Solutions can therefore be linked to the causes and classified according to where the responsibility for implementing them lies.

Medicines legislation and regulation in the United Kingdom 1500-2020.

The initial purposes of regulation of medicines in England, and latterly in the United Kingdom, were principally to raise government revenue, to discourage murder by poisoning and to regulate the activities of pharmacists. It was only much later that regulators sought to ensure that medicines were of good quality, reasonably safe, and at least somewhat effective, and to curtail misuse of drugs. Here we survey the history of the regulation of medicines and poisons in England from the perspective of clinicians with an interest in therapeutics.

Relation between opioid consumption and inclusion of opioids in 137 national essential medicines lists.

INTRODUCTION: Opioids are deemed essential medicines by the World Health Organization (WHO). However, many countries have inadequate access to them. Whether including opioids in national essential medicines lists (EMLs) influences national opioid consumption has not been evaluated. METHODS: We conducted a cross-sectional study to determine whether the listing of opioids in national EMLs was associated with consumption. We quantified the numbers and types of all opioids included in 137 national EMLs, for comparison with opioids in the WHO's Model List of Essential Medicines. Using the International Narcotics Control Board (INCB) consumption statistics for 2015-2017, we assessed the relation between annual mean opioid consumption (mg/person) and the numbers of opioids included in EMLs, controlling for region, population, healthcare expenditure, life expectancy, gross domestic product, human development and corruption. RESULTS: Five opioids were included in the 20th edition of the WHO's Model List of Essential Medicines: codeine, fentanyl, loperamide, methadone and morphine. On average, countries' lists included significantly (p<0.05) more opioids than the WHO's Model List. However, there were wide variations in the numbers (median 6 opioids; IQR: 5-9) and types (n=33) of opioids included in national EMLs. Morphine (95%), fentanyl (83%) and codeine (69%) were the most commonly included opioids. Most national EMLs were out of date (median publication date: 2011, IQR: 2009-2013). After adjusting for country characteristics, there was no relation between mean opioid consumption and the number of opioids in EMLs. CONCLUSIONS: Including opioids in national EMLs was not associated with consumption. National EMLs should be regularly updated to reflect the availability of opioids and the populations' needs for managing pain.

Effects of antihypertensives, lipid-modifying drugs, glycaemic control drugs and sodium bicarbonate on the progression of stages 3 and 4 chronic kidney disease in adults: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effects of drug interventions that may modify the progression of chronic kidney disease (CKD) in adults with CKD stages 3 and 4. DESIGN: Systematic review and meta-analysis. METHODS: Searching MEDLINE, EMBASE, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, International Clinical Trials Registry Platform, Health Technology Assessment, Science Citation Index, Social Sciences Citation Index, Conference Proceedings Citation Index and Clinical Trials Register, from March 1999 to July 2018, we identified randomised controlled trials (RCTs) of drugs for hypertension, lipid modification, glycaemic control and sodium bicarbonate, compared with placebo, no drug or a drug from another class, in ≥40 adults with CKD stages 3 and/or 4, with at least 2 years of follow-up and reporting renal function (primary outcome), proteinuria, adverse events, maintenance dialysis, transplantation, cardiovascular events, cardiovascular mortality or all-cause mortality. Two reviewers independently screened citations and extracted data. For continuous outcomes, we used the ratio of means (ROM) at the end of the trial in random-effects meta-analyses. We assessed methodological quality with the Cochrane Risk of Bias Tool and confidence in the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. RESULTS: We included 35 RCTs and over 51 000 patients. Data were limited, and heterogeneity varied. Final renal function (estimated glomerular filtration rate) was 6% higher in those taking glycaemic control drugs (ROM 1.06, 95% CI 1.02 to 1.10, I2=0%, low GRADE confidence) and 4% higher in those taking lipid-modifying drugs (ROM 1.04, 95% CI 1.00 to 1.08, I2=88%, very low GRADE confidence). For RCTs of antihypertensive drugs, there were no significant differences in renal function. Treatment with lipid-modifying drugs led to a 36% reduction in cardiovascular disease and 26% reduction in all-cause mortality. CONCLUSIONS: Glycaemic control and lipid-modifying drugs may slow the progression of CKD, but we found no pooled evidence of benefit nor harm from antihypertensive drugs. However, given the data limitations, further research is needed to confirm these findings. PROSPERO REGISTRATION NUMBER: CRD42015017501.

The British Pharmacological Society's WDM Paton Memorial Lecture 2019: How doctors were informed about pharmaceutical products through advertising in the British Medical Journal from 1955/6 to 1985/6.

We have reviewed pharmaceutical advertisements in every available issue of the British Medical Journal (BMJ) in 12-month periods during 1955/6, 1965/6, 1975/6, and 1985/6. We have determined the amount of advertising, the therapeutic areas covered, and whether adverts reflected the large number of New Chemical Entities (NCEs) launched during that time. For each product we recorded the therapeutic indications, the marketing company, and the number of adverts appearing. The total number of products advertised fell from 340 in 1955/6 to 260 in 1965/6, 70 in 1975/6, and 16 in 1985/6. Advertisement numbers and companies advertising also fell. Antimicrobial drugs and cardiovascular drugs were the top products advertised over the 30 years, with respiratory, analgesic, and gastrointestinal drugs also in the top five. The number of different drugs advertised by individual companies fell from around eight per company in 1955/6 to one or two in 1985/6. There was good concordance between the most advertised therapeutic areas and NCEs entering the market. From the 1950s to the 1980s prescribers were extensively informed about pharmacological advances in therapeutics through BMJ advertisements. Many novel drugs that were advertised proved to be of lasting value. The Medicines Act 1968 introduced product licensing, regulations requiring demonstration of quality, efficacy, and safety, and restrictions on advertising. Subsequently many companies reduced their advertising or stopped altogether. Since advertising influences prescribing, and since antimicrobial drugs were the most commonly advertised products during 1955-86, we speculate that advertising, resulting in excess use, may have, at least partly, driven bacterial drug resistance.

Comparison of essential medicines lists in 137 countries.

OBJECTIVE: To compare the medicines included in national essential medicines lists with the World Health Organization's (WHO's) Model list of essential medicines, and assess the extent to which countries' characteristics, such as WHO region, size and health care expenditure, account for the differences. METHODS: We searched the WHO's Essential Medicines and Health Products Information Portal for national essential medicines lists. We compared each national list of essential medicines with both the 2017 WHO model list and other national lists. We used linear regression to determine whether differences were dependent on WHO Region, population size, life expectancy, infant mortality, gross domestic product and health-care expenditure. FINDINGS: We identified 137 national lists of essential medicines that collectively included 2068 unique medicines. Each national list contained between 44 and 983 medicines (median 310: interquartile range, IQR: 269 to 422). The number of differences between each country's essential medicines list and WHO's model list ranged from 93 to 815 (median: 296; IQR: 265 to 381). Linear regression showed that only WHO region and health-care expenditure were significantly associated with the number of differences (adjusted R2 : 0.33; P < 0.05). Most medicines (1248; 60%) were listed by no more than 10% (14) of countries. CONCLUSION: The substantial differences between national lists of essential medicines are only partly explained by differences in country characteristics and thus may not be related to different priority needs. This information helps to identify opportunities to improve essential medicines lists.

Practice variation in the use of tests in UK primary care: a retrospective analysis of 16 million tests performed over 3.3 million patient years in 2015/16.

BACKGROUND: The UK's National Health Service (NHS) is currently subject to unprecedented financial strain. The identification of unnecessary healthcare resource use has been suggested to reduce spending. However, there is little very research quantifying wasteful test use, despite the £3 billion annual expenditure. Geographical variation has been suggested as one metric in which to quantify inappropriate use. We set out to identify tests ordered from UK primary care that are subject to the greatest between-practice variation in their use. METHODS: We used data from 444 general practices within the Clinical Practice Research Datalink to calculate a coefficient of variation (CoV) for the ordering of 44 specific tests from UK general practices. The coefficient of variation was calculated after adjusting for differences between practice populations. We also determined the tests that had both a higher-than-average CoV and a higher-than-average rate of use. RESULTS: In total, 16,496,218 tests were ordered for 4,078,091 patients over 3,311,050 person-years from April 1, 2015, to March 31, 2016. The tests subject to the greatest variation were drug monitoring 158% (95%CI 153 to 163%), urine microalbumin (52% (95%CI 49.9 to 53.2%)), pelvic CT (51% (95%CI 50 to 53%)) and Pap smear (49% (95%CI 48 to 51%). Seven tests were classified as high variability and high rate (clotting, vitamin D, urine albumin, prostate-specific antigen (PSA), bone profile, urine MCS and C-reactive protein (CRP)). CONCLUSIONS: There are wide variations in the use of common tests, which is unlikely to be explained by clinical indications. Since £3 billion annually are spent on tests, this represents considerable variation in the use of resources and inefficient management in the NHS. Our results can be of value to policy makers, researchers, patients and clinicians as the NHS strives towards identifying overuse and underuse of tests.

Marketing medicines: charting the rise of modern therapeutics through a systematic review of adverts in UK medical journals (1950-1980).

AIMS: To examine how pharmaceutical products that were first marketed between 1950 and 1980 were promoted to physicians through advertisements and briefly review advertising regulations and accuracy of the advertisements in the light of modern knowledge. METHODS: We systematically reviewed advertisements promoting drugs for specific therapeutic areas, namely central nervous system disorders (anxiety and sleep disorders, depression, psychoses, and Parkinson's disease), respiratory disorders, cardiovascular disorders, and gastrointestinal disorders. We examined about 800 issues of the British Medical Journal (1950-1980) and about 150 issues of World Medicine (1965-1984). RESULTS: Advertising material was minimally regulated until the mid-1970s. Many drugs were marketed with little preclinical or clinical knowledge and some with the expectation that prescribers would obtain further data. The peak of advertising occurred in parallel with the surge in the release of novel drugs during the 1960s, but declined markedly after the mid-1970s. Advertisements generally contained little useful prescribing information. The period we investigated saw the release of many novel pharmaceuticals in the therapeutic areas we examined, and many (or their class successors) still play important therapeutic roles, including benzodiazepines, tricyclic antidepressants, phenothiazines, levodopa, selective and non-selective ß-adrenoceptor antagonists, thiazide diuretics, ß-adrenoceptor agonists, and histamine H2 receptor antagonists. CONCLUSIONS: Advertising pharmaceuticals in the BMJ and World Medicine in 1950-1980 was poorly regulated and often lacked rigour. However, advertisements were gradually modified in the light of increasing clinical pharmacological knowledge, and they reflect an exciting period for the introduction of many drugs that continue to be of benefit today.

Drugs for rare disorders.

Estimates of the frequencies of rare disorders vary from country to country; the global average defined prevalence is 40 per 100 000 (0.04%). Some occur in only one or a few patients. However, collectively rare disorders are fairly common, affecting 6-8% of the US population, or about 30 million people, and a similar number in the European Union. Most of them affect children and most are genetically determined. Diagnosis can be difficult, partly because of variable presentations and partly because few clinicians have experience of individual rare disorders, although they may be assisted by searching databases. Relatively few rare disorders have specific pharmacological treatments (so-called orphan drugs), partly because of difficulties in designing trials large enough to determine benefits and harms alike. Incentives have been introduced to encourage the development of orphan drugs, including tax credits and research aids, simplification of marketing authorization procedures and exemption from fees, and extended market exclusivity. Consequently, the number of applications for orphan drugs has grown, as have the costs of using them, so much so that treatments may not be cost-effective. It has therefore been suggested that not-for-profit organizations that are socially motivated to reduce those costs should be tasked with producing them. A growing role for patient organizations, improved clinical and translational infrastructures, and developments in genetics have also contributed to successful drug development. The translational discipline of clinical pharmacology is an essential component in drug development, including orphan drugs. Clinical pharmacologists, skilled in basic pharmacology and its links to clinical medicine, can be involved at all stages. They can contribute to the delineation of genetic factors that determine clinical outcomes of pharmacological interventions, develop biomarkers, design and perform clinical trials, assist regulatory decision making, and conduct postmarketing surveillance and pharmacoepidemiological and pharmacoeconomic assessments.

Balanced prescribing - principles and challenges.

Balanced prescribing is a process that recommends a medicine appropriate to the patient's condition and, within the limits created by the uncertainty that attends therapeutic decisions, a dosage regimen that optimizes the balance of benefit to harm. The essential steps in achieving this are (a) careful attention to the history, examination, and investigation of the patient's condition and drug therapy, (b) accurate diagnosis, (c) detailed attention to prescribing the dosage regimen in the light of the therapeutic goal, (d) careful writing of the prescription and (e) regular monitoring of therapy, including attention to beneficial outcomes, adverse reactions, and patient adherence. The two major requirements in determining the dosage regimen are (1) understanding the pathophysiology of a health problem and matching it to the mechanisms of action of the relevant medicines and (2) assessing the benefit to harm balance of the therapy, although the difficulties in doing this in the individual are great. Major challenges in prescribing include provision of adequate education for all prescribers early in their undergraduate training and maintaining their expertise after graduation, obtaining evidence to inform appropriate monitoring of therapy, reducing the incidence of medication errors, and providing high quality information that will at the same time guide prescribing decisions and be sufficiently flexible to allow prescribers to tailor therapy to the needs of the individual patient. Careful attention to all facets of prescribing can improve the chances of benefit, reduce the risks of adverse reactions and interactions, and enhance adherence to therapy.

Evaluation and stages of surgical innovations.

Surgical innovation is an important part of surgical practice. Its assessment is complex because of idiosyncrasies related to surgical practice, but necessary so that introduction and adoption of surgical innovations can derive from evidence-based principles rather than trial and error. A regulatory framework is also desirable to protect patients against the potential harms of any novel procedure. In this first of three Series papers on surgical innovation and evaluation, we propose a five-stage paradigm to describe the development of innovative surgical procedures.

No surgical innovation without evaluation: the IDEAL recommendations.

Surgery and other invasive therapies are complex interventions, the assessment of which is challenged by factors that depend on operator, team, and setting, such as learning curves, quality variations, and perception of equipoise. We propose recommendations for the assessment of surgery based on a five-stage description of the surgical development process. We also encourage the widespread use of prospective databases and registries. Reports of new techniques should be registered as a professional duty, anonymously if necessary when outcomes are adverse. Case series studies should be replaced by prospective development studies for early technical modifications and by prospective research databases for later pre-trial evaluation. Protocols for these studies should be registered publicly. Statistical process control techniques can be useful in both early and late assessment. Randomised trials should be used whenever possible to investigate efficacy, but adequate pre-trial data are essential to allow power calculations, clarify the definition and indications of the intervention, and develop quality measures. Difficulties in doing randomised clinical trials should be addressed by measures to evaluate learning curves and alleviate equipoise problems. Alternative prospective designs, such as interrupted time series studies, should be used when randomised trials are not feasible. Established procedures should be monitored with prospective databases to analyse outcome variations and to identify late and rare events. Achievement of improved design, conduct, and reporting of surgical research will need concerted action by editors, funders of health care and research, regulatory bodies, and professional societies.

Challenges in evaluating surgical innovation.

Research on surgical interventions is associated with several methodological and practical challenges of which few, if any, apply only to surgery. However, surgical evaluation is especially demanding because many of these challenges coincide. In this report, the second of three on surgical innovation and evaluation, we discuss obstacles related to the study design of randomised controlled trials and non-randomised studies assessing surgical interventions. We also describe the issues related to the nature of surgical procedures-for example, their complexity, surgeon-related factors, and the range of outcomes. Although difficult, surgical evaluation is achievable and necessary. Solutions tailored to surgical research and a framework for generating evidence on which to base surgical practice are essential.

Medication errors: problems and recommendations from a consensus meeting.

Here we discuss 15 recommendations for reducing the risks of medication errors: 1. Provision of sufficient undergraduate learning opportunities to make medical students safe prescribers. 2. Provision of opportunities for students to practise skills that help to reduce errors. 3. Education of students about common types of medication errors and how to avoid them. 4. Education of prescribers in taking accurate drug histories. 5. Assessment in medical schools of prescribing knowledge and skills and demonstration that newly qualified doctors are safe prescribers. 6. European harmonization of prescribing and safety recommendations and regulatory measures, with regular feedback about rational drug use. 7. Comprehensive assessment of elderly patients for declining function. 8. Exploration of low-dose regimens for elderly patients and preparation of special formulations as required. 9. Training for all health-care professionals in drug use, adverse effects, and medication errors in elderly people. 10. More involvement of pharmacists in clinical practice. 11. Introduction of integrated prescription forms and national implementation in individual countries. 12. Development of better monitoring systems for detecting medication errors, based on classification and analysis of spontaneous reports of previous reactions, and for investigating the possible role of medication errors when patients die. 13. Use of IT systems, when available, to provide methods of avoiding medication errors; standardization, proper evaluation, and certification of clinical information systems. 14. Nonjudgmental communication with patients about their concerns and elicitation of symptoms that they perceive to be adverse drug reactions. 15. Avoidance of defensive reactions if patients mention symptoms resulting from medication errors.