Helen Sammons

Substandard and counterfeit medicines: a systematic review of the literature

Objective To explore the evidence available of poor-quality (counterfeit and substandard) medicines in the literature. Design Systematic review. Data sources Databases used were EMBASE, MEDLINE, PubMed and the International Pharmaceutical Abstracts, including articles published till January 2013. Eligibility criteria Prevalence studies containing original data. WHO definitions (1992) used for counterfeit and substandard medicines. Study appraisal and synthesis Two reviewers independently scored study methodology against recommendations from the MEDQUARG Checklist. Studies were classified according to the World Bank classification of countries by income. Data extraction Data extracted: place of study; type of drugs sampled; sample size; percentage of substandard/counterfeit medicines; formulations included; origin of the drugs; chemical analysis and stated issues of counterfeit/substandard medicines. Results 44 prevalence studies were identified, 15 had good methodological quality. They were conducted in 25 different countries; the majority were in low-income countries (11) and/or lower middle-income countries (10). The median prevalence of substandard/counterfeit medicines was 28.5% (range 11–48%). Only two studies differentiated between substandard and counterfeit medicines. Prevalence data were limited to antimicrobial drugs (all 15 studies). 13 studies involved antimalarials, 6 antibiotics and 2 other medications. The majority of studies (93%) contained samples with inadequate amounts of active ingredients. The prevalence of substandard/counterfeit antimicrobials was significantly higher when purchased from unlicensed outlets (p<0.000; 95% CI 0.21 to 0.32). No individual data about the prevalence in upper middle-income countries and high-income countries were available. Limitations Studies with strong methodology were few. The majority did not differentiate between substandard and counterfeit medicines. Most studies assessed only a single therapeutic class of antimicrobials. Conclusions The prevalence of poor-quality antimicrobial medicines is widespread throughout Africa and Asia in lower income countries and lower middle-income countries . The main problem identified was inadequate amounts of the active ingredients.

Ciprofloxacin safety in paediatrics: a systematic review

Objective To determine the safety of ciprofloxacin in paediatric patients in relation to arthropathy, any other adverse events (AEs) and drug interactions. Methods A systematic search of MEDLINE, EMBASE, CINAHL, CENTRAL and bibliographies of relevant articles was carried out for all published articles, regardless of design, that involved the use of ciprofloxacin in any paediatric age group ≤17 years. Only articles that reported on safety were included. Results 105 articles met the inclusion criteria and involved 16 184 paediatric patients. There were 1065 reported AEs (risk 7%, 95% CI 3.2% to 14.0%). The most frequent AEs were musculoskeletal AEs, abnormal liver function tests, nausea, changes in white blood cell counts and vomiting. There were six drug interactions (with aminophylline (4) and methotrexate (2)). The only drug related death occurred in a neonate who had an anaphylactic reaction. 258 musculoskeletal events occurred in 232 paediatric patients (risk 1.6%, 95% CI 0.9% to 2.6%). Arthralgia accounted for 50% of these. The age of occurrence of arthropathy ranged from 7 months to 17 years (median 10 years). All cases of arthropathy resolved or improved with management. One prospective controlled study estimated the risk of arthropathy as 9.3 (OR 95% CI 1.2 to 195). Pooled safety data of controlled trials in this review estimated the risk of arthropathy as 1.57 (OR 95% CI 1.26 to 1.97). Conclusion Musculoskeletal AEs occur due to ciprofloxacin use. However, these musculoskeletal events are reversible with management. It is recommended that further prospective controlled studies should be carried out to evaluate the safety of ciprofloxacin, with particular focus on the risk of arthropathy.

What motivates British parents to consent for research? A questionnaire study

BackgroundInformed consent is the backbone of a clinical trial. In children this is given by their parents. There have been many studies in the neonatal population but little is known about the views of the parents of infants and young children from within the United Kingdom. The objectives of this study were to assess what motivates parents to consent to a randomised clinical trial (RCT), their feelings on consent and participation and the factors that would influence their decision to take part in a future study.MethodsThe setting was a multi-centre randomised but non-blinded equivalence trial of oral versus intravenous (IV) treatment for community acquired pneumonia in previously well children aged 6 months to 16 years in the UK (PIVOT Study). Parents were sent a postal questionnaire at the end of the study which included open and closed-ended questions. Fishers Exact Test was used to analyse associations in non parametric categorical data.Results243 children were recruited into the PIVOT study. Of a possible 235, 136 questionnaires were returned (response rate 59%). Of those questionnaires returned; 98% of parents remembered consenting, 95% felt they were given enough time to make their decision and 96% felt they received enough information. Major reasons for participation were benefit to other children in the future 31%, contribution to science 27%, benefit to their own child 18%. Most parents (85%) did not feel obliged to participate. 62% felt there was an advantage to taking part and 18% felt there was a disadvantage. 91% of parents said they would take part in a similar study in the future, stating influences on their decision being benefit to their own child (91%) and benefit to all children (89%).ConclusionThe major motivation in parents consenting for their previously well child to participate in an RCT of therapy for an acute medical illness was to increase medical knowledge in the future. Most saw an advantage in taking part in the trial and did not feel obliged to participate.

Educational interventions to reduce prescribing errors.

Objective: Little is known about teaching paediatricians to prescribe or about assessing their competency. This study aimed to identify educational interventions to reduce dose calculation errors. Design: Literature review, a questionnaire survey of paediatric healthcare professionals, observation and interviews were performed. Results: Literature review identified one paper describing an in-service test for medical trainees. 319/559 questionnaires were returned (57%). 34 mentioned educational interventions, 15 centres provided further information on teaching and assessment methods and 13 provided presentations, usually at doctors’ induction. Many interventions had a similar format, including describing differences from adult prescribing, common errors and how to calculate doses. Paediatric clinical pharmacists play a significant role in delivering training and competency assessment. Conclusion: Teaching of paediatric prescribing takes place mostly in the format of lectures during doctors’ induction. Few centres assess competency and no validated tool exists. There has been little evaluation of the impact of teaching on competency to prescribe.

Safety in paediatric clinical trials – a 7‐year review

Aim: The safety of clinical trials in children has not been previously studied. We aimed to identify how safety is monitored and the extent of adverse drug reactions (ADRs).

Ethical issues of clinical trials in children. A European perspective

Children should not be harmed by their participation in clinical trials, therefore should no clinical trials be performed? This is a view that needs to be balanced as clinical trials provide the evidence we need to allow children safe and effective prescribing of medicines. Therefore, is it unethical not to involve this population in research? This review looks at new ethical guidance released to support the recently introduced European legislation for the licensing of medicines.

A systematic review of pharmacokinetics studies in children with protein-energy malnutrition

ObjectiveProtein energy malnutrition (PEM) is a nutritional problem affecting many children world-wide. Its association with a wide spectrum of infections necessitates multiple drug therapies. A systematic review was performed to determine the effects of PEM on drug pharmacokinetics.MethodsLiterature searches in the MEDLINE and EMBASE databases (January 1960 to December 2009) were performed. Malnutrition, undernutrition, underweight, protein-energy malnutrition, protein-calorie malnutrition, marasmus, marasmic-kwashiorkor or kwashiorkor was the medical subject heading (MeSH) descriptor used. Inclusion criteria were abstracts that assessed or discussed absorption, distribution, metabolism, elimination, clearance, pharmacokinetics or pharmacodynamics of drugs, except micronutrients and appetite-stimulating drugs.ResultsAltogether, 41 publications were identified. A total of 34 drugs were studied. The absorption of 18 drugs was studied; the extent of absorption (AUC) was unaffected for 10 drugs. The plasma protein binding of 20 drugs was evaluated; it was significantly reduced for 12 drugs. The volume of distribution (Vd) of 13 drugs was evaluated; it was, however, unaffected for most of the drugs. The effect of PEM on total clearance and the half-life of drugs primarily metabolised by the liver was studied for 8 drugs. There was decreased total clearance and an associated increased half-life of 5 drugs. For 2 drugs (chloramphenicol and quinine), different degrees of PEM affected total clearance differently. The total clearance of six drugs primarily eliminated by the kidneys was studied; it was unaffected for four drugs, but significantly decreased for two drugs (cefoxitin and penicillin).ConclusionsConsidering the proportion of children affected with PEM world-wide, there have been relatively few pharmacokinetic studies of drugs frequently used for their treatment. More studies are therefore required to establish the appropriate dose and safety of these drugs for PEM children. The studies need to recognise that PEM is a disease spectrum and should further look at the differential effects of kwashiorkor and marasmus on drug pharmacokinetics in children.

Clinical trials of medication in children, 1996–2002

Randomised controlled trials (RCTs) are felt by the medical community to convey the best evidence. It has traditionally been said that these trials are difficult to conduct within the paediatric population. Some of the reasons cited are ethical concerns, recruitment problems and consent issues [1–4]. These issues, however, should be resolvable by good trial design. The number of RCTs involving children taking place around the world is unknown. In the United States in 1997, the Food and Drug Administration (FDA) passed the FDA Modernisation Act which provided financial incentives to pharmaceutical companies for performing paediatric trials [5]. The aim was to improve the availability of data within the paediatric population. There is currently no similar legislation within the European community, although it is planned. It is thought that legislation will have increased the number of paediatric trials within the North American setting. We undertook a review of therapeutic paediatric trials worldwide to determine (1) the number of clinical trials, (2) in which geographical areas these clinical trials were taking place, (3) trial design and (4) the number of children involved in these trials. Methods and results

Standard 1: Consent and Recruitment

A 4-year-old boy with a serious metabolic disorder is eligible for a trial of a new enzyme replacement, the first potential option to treat this disease. His parents have little understanding of the disease or trial, even with careful explanation, but eventually they consent to entry in the trial. The treating clinician doubts whether their consent is valid. This and similar dilemmas face pediatricians in research every day. Many of the therapeutic options for children have not been tested with the rigor applied to similar treatments in adults. This highlights the need for research to improve the evidence base of childrens medicine, for more pediatricians to undertake research, and for more children and families to participate.1 … Address correspondence to Martin Offringa, MD, PhD, Senior Scientist and Program Head, Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: martin.offringa{at}sickkids.ca

Safety of lamotrigine in paediatrics: a systematic review

Objectives To identify adverse drug reactions associated with lamotrigine in children and compare the safety profile with other antiepileptic drugs. Setting Databases EMBASE (1974–April 2015), MEDLINE (1946–April 2015), PubMed and the Cochrane library for randomised controlled trials were searched for studies on safety of lamotrigine. Participants All studies involving paediatric patients aged ≤18 years who have received at least a single dose of lamotrigine with safety as an outcome measure were included. Primary and secondary outcome measures The primary outcome measure was safety of lamotrigine. Drug interaction of lamotrigine was the secondary outcome. Results A total of 78 articles involving 3783 paediatric patients were identified. There were 2222 adverse events (AEs) reported. Rash was the most commonly reported AE, occurring in 7.3% of the patients. Stevens-Johnson syndrome was rarely reported, with a risk of 0.09 per 100 patients. Discontinuation due to an adverse drug reaction (ADR) was recorded in 72 children (1.9% of all treated patients). Fifty-eight per cent of treatment discontinuation was attributed to different forms of rash and 21% due to increased seizures. Children on lamotrigine monotherapy had lower incidences of AEs. Headache (p=0.02), somnolence (<0.001), nausea (p=0.01), vomiting (p<0.001), dizziness (p<0.001) and abdominal pain (p=0.01) were significantly lower among children on monotherapy. Conclusions Rash was the most common ADR of lamotrigine and the most common reason for treatment discontinuation. Children receiving polytherapy have a higher risk of AEs than monotherapy users. Trial registration number CRD42013006910.