Fetal alcohol spectrum disorder and attention deficit hyperactivity disorder stimulant trial in children: an N-of-1 pilot trial to compare stimulant to placebo (FASST): protocol.

INTRODUCTION: Fetal alcohol spectrum disorder (FASD) is a neurodevelopmental disorder caused by alcohol exposure during pregnancy. FASD is associated with neurodevelopmental deviations, and 50%-94% of children with FASD meet the Diagnostic and Statistical Manual of Mental Disorders-fifth edition diagnostic criteria for attention deficit hyperactivity disorder (ADHD). There is a paucity of evidence around medication efficacy for ADHD symptoms in children with FASD. This series of N-of-1 trials aims to provide pilot data on the feasibility of conducting N-of-1 trials in children with FASD and ADHD. METHODS AND ANALYSIS: A pilot N-of-1 randomised trial design with 20 cycles of stimulant and placebo (four cycles of 2-week duration) for each child will be conducted (n=20) in Melbourne, Australia.Feasibility and tolerability will be assessed using recruitment and retention rates, protocol adherence, adverse events and parent ratings of side effects. Each child's treatment effect will be determined by analysing teacher ADHD ratings across stimulant and placebo conditions (Wilcoxon rank). N-of-1 data will be aggregated to provide an estimate of the cohort treatment effect as well as individual-level treatment effects. We will assess the sample size and number of cycles required for a future trial. Potential mediating factors will be explored to identify variables that might be associated with treatment response variability. ETHICS AND DISSEMINATION: The study was approved by the Hospital and Health Service Human Research Ethics Committee (HREC/74678/MonH-2021-269029), Monash (protocol V6, 25 June 2023).Individual outcome data will be summarised and provided to participating carers and practitioners to enhance care. Group-level findings will be presented at a local workshop to engage stakeholders. Findings will be presented at national and international conferences and published in peer-reviewed journals. All results will be reported so that they can be used to inform prior information for future trials. TRIAL REGISTRATION NUMBER: NCT04968522.

The potential of repetitive transcranial magnetic stimulation for addressing sleep difficulties in children with autism - A brief communication.

Sleep difficulties can co-occur with autistic traits and have been frequently reported in children diagnosed with autism. Thus, sleep difficulties may impact neural development, cognition, and behavioural functioning in children with autism. Interventions, such as repetitive transcranial magnetic stimulation (rTMS), that target aberrant neural structures underpinning autistic traits and sleep difficulties in children could have beneficial effects. The rTMS effects on the pathophysiological pathways hypothesised to underpin autism and sleep difficulties are well-established in the literature; however, clinical evidence of its potential to improve sleep difficulties in children with autism is limited. While the preliminary data is promising, further robust rTMS studies are warranted to encourage its use in clinical practices.

The effectiveness of aerobic versus strengthening exercise therapy in individuals with chronic whiplash-associated disorder: a randomised single case experimental design study.

PURPOSE: Recent RCTs and meta-analyses compare the effectiveness of different types of exercise for chronic whiplash associated disorder (WAD). This study aimed to verify whether the results of these studies translate to statistically significant and clinically meaningful effects in individual participants. MATERIALS AND METHODS: A series of replicated randomised single case experimental design studies (SCEDs) with A-B design (A: baseline, B: intervention). Eight participants with chronic WAD (8 female, mean [SD] age 47 [10] years) were randomised into one of four baseline durations (5, 8, 11, and 14 days) and to one of two eight-week exercise interventions (aerobic or strengthening). Daily measures of pain intensity, bothersomeness, and interference were collected during the baseline phase and the intervention phase. RESULTS: Visual analyses indicated that three participants in the aerobic exercise group meaningfully improved. No improvements were found in the strengthening group. Effect sizes favoured the aerobic exercise group, yet randomisation tests of pooled effects did not show a difference in between-intervention effectiveness. CONCLUSION: Contrary to our expectations, three out of four participants were nearly pain-free at the end of the aerobic exercise intervention, whereas none of the participants in the strengthening group improved meaningfully. This suggests that aerobic exercise may be favourable for WAD.Implications for RehabilitationOur results suggest that aerobic exercises are favourable over strengthening exercises and may be the preferred option for patients with chronic WAD.We found substantial variability in self-reported outcomes within participants, clinicians should be aware of this in the judgement of treatment effectiveness.

Pregabalin vs placebo to prevent chronic pain after whiplash injury in at-risk individuals: results of a feasibility study for a large randomised controlled trial.

ABSTRACT: There are few effective treatments for acute whiplash-associated disorders (WADs). Early features of central sensitisation predict poor recovery. The effect of pregabalin on central sensitisation might prevent chronic pain after acute whiplash injury. This double blind, placebo-controlled randomised controlled trial examined feasibility and potential effectiveness of pregabalin compared with placebo for people with acute WAD. Twenty-four participants with acute WAD (<48 hours) and at risk of poor recovery (pain ≥5/10) were recruited from hospital emergency departments in Queensland, Australia, and randomly assigned by concealed allocation to either pregabalin (n = 10) or placebo (n = 14). Pregabalin was commenced at 75 mg bd, titrated to 300 mg bd for 4 weeks, and then weaned over 1 week. Participants were assessed at 5 weeks and 3, 6, and 12 months. Feasibility issues included recruitment difficulties and greater attrition in the placebo group. For the primary clinical outcome of neck pain intensity, attrition at 5 weeks was pregabalin: 10% and placebo: 36% and at 12 months was pregabalin: 10% and placebo: 43%. Pregabalin may be more effective than placebo for the primary clinical outcome of neck pain intensity at 3 months (mean difference: -4.0 [95% confidence interval -6.2 to -1.7]) on an 11-point Numerical Rating Scale. Effects were maintained at 6 months but not 12 months. There were no serious adverse events. Minor adverse events were more common in the pregabalin group. A definitive large randomised controlled trial of pregabalin for acute whiplash injury is warranted. Feasibility issues would need to be addressed with modifications to the protocol.

Exploring Symptom Fluctuations and Triggers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Novel Patient-Centred N-of-1 Observational Designs: A Protocol for a Feasibility and Acceptability Study.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic condition of unknown aetiology associated with a range of disabling symptoms, including post-exertional malaise, chronic fatigue, musculoskeletal pain, orthostatic intolerance, unrefreshing sleep, and cognitive dysfunction. ME/CFS is a heterogeneous disorder, with significant variation in symptom type and severity between individuals, as well as within individuals over time. The diversity of ME/CFS symptom presentation makes management challenging; treatments supported by data from randomised controlled trials may not work for all individuals due to the variability in experienced symptoms. Studies using quantitative N-of-1 observational designs involve repeated outcome measurements in an individual over time and can generate rigorous individual-specific conclusions about symptom patterns and triggers in individuals with ME/CFS. This study aims to explore the feasibility and acceptability of using novel patient-centred N-of-1 observational designs to explore symptom fluctuations and triggers in ME/CFS at the individual level. METHODS AND ANALYSIS: Individuals with a medical diagnosis of ME/CFS will be recruited through ME/CFS patient organisations to participate in a series of patient-centred N-of-1 observational studies. Using a wrist-worn electronic diary, participants will complete ecological momentary assessments of fatigue, stress, mood, and cognitive demand, three times per day for a period of 6-12 weeks. Personally relevant symptoms and triggers will also be incorporated into the questionnaire design. Physical activity will be objectively measured via an integrated accelerometer. Feasibility and acceptability outcomes will be assessed including the percentage of diary entries completed, as well as recruitment and retention rate, feasibility of analysing and interpreting the data collected, and participant views about participation elicited via a post-study semi-structured interview. DISCUSSION: This study will assess the feasibility and acceptability of patient-centred N-of-1 observational studies to assess diseases with complex presentations such as ME/CFS, as well as provide individual-level evidence about fluctuations and triggers of ME/CFS symptoms that may aid self-management. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12618001898246. Registered on 22 November 2018.

Evaluation of a physical activity promotion intervention for adults with whiplash associated disorders: a single-case experimental design study.

PURPOSE: There is considerable variation in the physical and psychological presentations of people with whiplash-associated disorder (WAD). Optimal treatment continues to be a challenge. This research evaluated the efficacy of a community-located, theory-based intervention designed to promote physically active behaviour in people with persistent WAD, and thereby improve perceptions of pain interference and confidence completing activities in the presence of neck pain. MATERIALS AND METHODS: A multiple-baseline, single-case experimental design was used to evaluate the 16-week intervention across six participants. RESULTS: Weighted Tau-U showed significantly increased accelerometer-measured physical activity in three participants with large effect sizes (>0.5), with increased confidence in one participant (ES > 0.5), and reduced pain interference in another participant (ES > 0.7). Changes in other behaviours included clinically important improvements in quality of life for five participants and, in those participants with baseline symptom levels outside threshold levels, improvements in pain catastrophizing and pain self-efficacy. CONCLUSIONS: Participation in a theory-based intervention resulted in significant improvements in physical and psychological health for five of six participants. Providing this type of community-located physical activity promotion strategy, to individuals with persistent WAD, may help address physical impairments and psychological distress commonly experienced in WAD. Trial registration: The trial was registered with the Australia and New Zealand Clinical Trials Registry (ACTRN: ACTRN12617001261303p) and ClinicalTrials.gov (Protocol Number: 2018000349/2017/743).Implications for rehabilitationRehabilitation professionals should consider recommending theory-based physical activity promotion strategies to reduce physical impairments and psychological distress in individuals with persistent WAD.Individually tailored physical activity promotion strategies may help individuals with persistent WAD become more physically active thereby reducing their risk of diseases associated with inactivity which may compound the effects of WADImprovements in physical and psychological health may occur independently of increasing habitual physical activity.Rehabilitation professionals may find that other community-located strategies which aim to promote physically active behaviour confer similar benefits for individuals with persistent WAD.

N-of-1 Trials in Neurology: A Systematic Review.

BACKGROUND AND OBJECTIVES: To perform a systematic review of published N-of-1 trials (e.g., single patient crossover trials) in neurologic disorders, including an assessment of methodologic quality and reporting. METHODS: We searched PubMed, MEDLINE, and Embase from inception date to the December 1, 2019, for reports on N-of-1 trials in neurologic disorders. Basic trial information on design, disease, intervention, analysis, and treatment success was extracted. Strengths and weaknesses of the N-of-1 trials were assessed with the Consolidated Standards of Reporting Trials extension for N-of-1 trials (CENT) 2015 criteria checklist and the Jadad score as measures of quality and reporting. RESULTS: We retrieved 40 reports of N-of-1 trials in neurologic disorders (19 individual N-of-1 trials, 21 series of N-of-1 trials). Most N-of-1 trials were performed in neuromuscular and neurodegenerative/movement disorders. Unlike the majority of trials that studied the main symptom(s) of a chronic stable condition, 9 N-of-1 trials studied a stable chronic symptom of a progressive or acute neurologic disorder. Besides pharmacologic interventions, electric stimulation protocols and nutritional products were studied. A mean total CENT score of 20.88 (SD 9.10, range 0-43) and mean total Jadad score of 2.90 (SD 2.15, range 0-5) were found as methodologic measures of quality and reporting across all N-of-1 trials. DISCUSSION: N-of-1 trials have been reported in numerous neurologic disorders, not only in chronic stable disorders, but also in progressive or acute disorders with a stable symptom. This indicates the emerging therapeutic area of N-of-1 trials in neurology. Methodologic quality and reporting of N-of-1 trials were found to be suboptimal and can easily be improved in future trials by appropriately describing the methods of blinding and randomization and following CENT guidelines. Because most N-of-1 trials remain unreported in medical literature, this systematic review probably represents only the tip of the iceberg of conducted N-of-1 trials in neurologic disorders. In addition to conventional trial designs, N-of-1 trials can help to bridge the gap between research and clinical care by providing an alternative, personalized level 1 evidence base for suitable treatments.

Comparing pregabalin and gabapentin for persistent neuropathic pain: A protocol for a pilot N-of-1 trial series.

BACKGROUND: Evidence-based management of neuropathic pain is commonly ineffective due to the large variability in response between cases. Patients often have to trial several drugs before finding one that provides adequate relief, leading to increased costs and worsened outcomes. There is thus a need for tools to guide and streamline prescribing decisions in neuropathic pain. N-of-1 trials provide a potentially precise and economical method of selecting between multiple interventions in an individual patient, and merit a feasibility assessment for use in clinical pain practice. AIMS: We aim to evaluate the feasibility of N-of-1 trials to compare pregabalin and gabapentin for individual presentations of neuropathic pain. METHODS: This is a double-blinded multiple crossover study, with recruitment from existing patients at an outpatient pain clinic in New South Wales, Australia. Participants will undergo three 4-week treatment pairs, comprising 2 weeks of pregabalin (150-600 mg/day) and 2 weeks of gabapentin (900-3600 mg/day), in an individually randomised order. Intervention doses will be derived from participants' existing treatment dose. Medications will be taken orally three times daily. The primary outcome will be pain intensity; measures will be self-reported daily in patient diaries. After completing all three cycles, participants and their physicians will be presented with the results of the trial to form an informed decision about their treatment. DISCUSSION: As a stable yet debilitating condition, neuropathic pain is especially amenable to an N-of-1 study design. A successful trial would represent a significant quality of life improvement for the patient, possibly extending over the course of their lifetime.

Establishment of an International Collaborative Network for N-of-1 Trials and Single-Case Designs.

In this article we briefly examine the unique features of Single-Case Designs (SCDs) (studies in a single participant), their history and current trends, and real-world clinical applications. The International Collaborative Network for N-of-1 Trials and Single-Case Designs (ICN) is a formal collaborative network for individuals with an interest in SCDs. The ICN was established in 2017 to support the SCD scientific community and provide opportunities for collaboration, a global communication channel, resource sharing and knowledge exchange. In May 2021, there were more than 420 members in 31 countries. A member survey was undertaken in 2019 to identify priorities for the ICN for the following few years. This article outlines the key priorities identified and the ICN's progress to date in these key areas including network activities (developing a communications strategy to increase awareness, collecting/sharing a comprehensive set of resources, guidelines and tips, and incorporating the consumer perspective) and scientific activities (writing position papers and guest editing special journal issues, exploring key stakeholder perspectives about SCDs, and working to streamline ethical approval processes for SCDs). The ICN provides a practical means to engage with this methodology through membership. We encourage clinicians, researchers, industry, and healthcare consumers to learn more about and conduct SCDs, and to join us in our mission of using SCDs to improve health outcomes for individuals and populations.

N-of-1 Trials in Healthcare.

Interest in N-of-1 trials and single-case designs is increasing worldwide, particularly due to the movement towards personalised medicine and patient-centred healthcare [...].

A systematic review of the effectiveness of sleep hygiene in children with ADHD.

Attention deficit/hyperactivity disorder (ADHD) is often accompanied by sleep problems in children. Sleep hygiene is defined as a set of behavioural, environmental, or cognitive modifications to improve sleep, and is routinely clinically utilised as first-line treatment for insomnia in ADHD. The objective of this systematic review of the literature is to evaluate the effectiveness of sleep hygiene interventions for sleep difficulties in children with ADHD. Sixteen relevant articles met the inclusion criteria, involving 1,469 participants, with a mean age of 9.6 years, across 6 countries. Fifteen studies found that sleep hygiene interventions were effective in improving sleep, while one did not show any significant improvement. Definite conclusions on the effectiveness of the interventions are difficult to draw due to the limited number of studies and a high risk of bias. There is growing evidence to support the use of sleep hygiene interventions to improve sleep quality in children with ADHD and sleep disturbance. However, well-conducted clinical trials are required to strengthen the evidence.

Protocol for a longitudinal study of melatonin therapy and cost effectiveness analysis in stimulant-treated children with ADHD and insomnia: An N-of-1 trial.

BACKGROUND: Children with ADHD and sleep problems have more caregiver deficits and decreased school attendance than children with ADHD but without a sleep problem. We conducted an N-of-1 trial of melatonin for children with ADHD on stimulants. As a follow-up study, we aim to conduct a cost effectiveness analysis (CEA) of melatonin therapy by comparing costs of this condition (of using melatonin) to costs of the baseline condition (usual care with no N-of-1 trial). METHODS: The CEA will compare participants who remained on melatonin vs those who chose to cease melatonin. Costs will be determined by medication cost to the caregiver(s), school/work absences, other sleep remedy costs, and health service utilization costs, including incidentals like parking. These costs will be determined at baseline, end of 6-week trial, and 6 months post-trial. We will also calculate Quality-Adjusted Life-Years (QALY) based on responses to PedsQL or SF-12v2 for patients and caregiver(s) and assess differences between remaining on melatonin or not; and assess the intermediate-term effectiveness and adverse effects of melatonin at 6 months. DISCUSSION: We hypothesize that shorter sleep-onset-latency will be associated with improved QALYs for patients and caregivers. We also expect that targeting melatonin to positive responders will be cost effective both for individuals and society. Cost per QALY for positive responders to melatonin is useful for doctors when creating treatment plans since melatonin is not an over-the-counter pharmaceutical in Australia. TRIAL REGISTRATION NUMBER: ACTRN12614000542695.

Comparison of Aggregated N-of-1 Trials with Parallel and Crossover Randomized Controlled Trials Using Simulation Studies.

Background: N-of-1 trials offer an innovative approach to delivering personalized clinical care together with population-level research. While increasingly used, these methods have raised some statistical concerns in the healthcare community. Methods: We discuss concerns of selection bias, carryover effects from treatment, and trial data analysis conceptually, then rigorously evaluate concerns of effect sizes, power, and sample size through simulation study. Four variance structures for patient heterogeneity and model error are considered in a series of 5000 simulated trials with three cycles, which compare N-of-1 trials to parallel randomized controlled trials (RCTs) and crossover trials. Results: N-of-1 trials outperformed both traditional parallel RCTs and crossover designs when trial designs were simulated in terms of power and required sample size to obtain a given power. N-of-1 designs resulted in a higher type-I error probability than parallel RCT and cross over designs when moderate-to-strong carryover or washout effects were not considered or in the presence of modeled selection bias. However, N-of-1 designs allowed better estimation of patient-level random effects. These results reinforce the need to account for these factors when planning N-of-1 trials. Conclusion: N-of-1 trial designs offer a rigorous method for advancing personalized medicine and healthcare with the potential to minimize costs and resources. Interventions can be tested with adequate power with far fewer patients than traditional RCT and crossover designs. Operating characteristics compare favorably to both traditional RCT and crossover designs.

Acceptability and barriers to implementation of N-of-1 tests in Ethiopia - a qualitative study.

BACKGROUND: Locally produced generic drugs offer a cost-effective alternative to imported drugs to treat patients in Ethiopia. However, due to a lack of bioequivalence testing, additional assurance tests are needed to build trust in cheaper, locally made drugs. By testing bioequivalence of local drugs to gold standard, N-of-1 tests have the potential to promote patient centred quality use of medicines. METHOD: We sought to assess the acceptability of, and explore barriers to, conducting N-of-1 tests to evaluate local medicines in a resource limited clinical setting. We conducted a descriptive qualitative study, analysing four focus group discussions and five key informant interviews. Participants were senior drug regulatory authority members, institutional review board members, physicians and patients. All interviews were audio taped and transcribed verbatim. Patient interviews were conducted in Amharic and translated to English prior to analysis. Data analysis used an inductive, thematic process. RESULTS: Five major themes were identified; (1) Appropriateness of N-of-1 tests to determine the therapeutic equivalence of local drugs, (2) N-of-1 therapeutic equivalence tests: clinical care or research? (3) Ethical and regulatory requirements (IRB), (4) Potential barriers to implementing N-of-1 tests and (5) Possible solutions to identified challenges. The study demonstrated considerable support for using N-of-1 tests for clinical equivalence studies between local and imported medicines, but important impediments were very likely to impact the feasibility of conducting N-of-1 tests in Ethiopia. Key informants from the regulatory authority did not support additional tests of local drugs. There were also mixed opinions regarding ethical requirements for conducting N-of-1 tests. The Institutional Review Board (IRB) members believed that IRB approval was sufficient to conduct N-of-1 tests, however, the regulatory authority members considered that N-of-1 tests constituted a clinical trial, and required approval at the regulatory level. CONCLUSION: This study showed that there were key uncertainties that could impact the feasiblity of using N-of-1 testing local drugs in Ethiopia. Therefore, a number of protocol amendments to address contextual threats and regulatory challenges, would be needed before progressing to conducting these tests.

Evaluation of a novel intervention to improve physical activity for adults with whiplash associated disorders: Protocol for a multiple-baseline, single case experimental study.

Half of individuals with a whiplash injury experience ongoing pain and disability. Many are insufficiently active for good health, increasing their risk of preventable morbidity and mortality, and compounding the effects of the whiplash injury. This paper describes a protocol for evaluating the efficacy of a physical activity promotion intervention in adults with whiplash associated disorders. A multiple-baseline, single case experimental design will be used to evaluate the effects of a physical activity (PA) intervention that includes evidence-based behaviour change activities and relapse prevention strategies for six adults with chronic whiplash. A structured visual analysis supplemented with statistical analysis will be used to analyse: accelerometer-measured PA, confidence completing PA in the presence of neck pain, and pain interference.

Retrospective descriptive observational study of patients who presented to an Australian hospital emergency department with neck soft tissue injury.

OBJECTIVE: To describe clinical presentation and management of neck soft tissue injury in an Australian ED. METHODS: This is a retrospective cohort study conducted in a tertiary hospital ED in Queensland, Australia. This study included all patients aged 18-65 years presenting with neck sprain/strain in 2016. Main outcome measures are patient demographics, comorbidities, presentation, acute management and follow up. RESULTS: Of 339 patients, 176 (52%) had cervical computed tomography (CT) scans and 3% plain radiographs. Two had fractures (CT yield of 2/176; 1.1%) and three were admitted with neurological symptoms, leaving 334 patients. Of 264 patients receiving medications in the ED, simple analgesia + oral opioid (146, 55.3%) was most frequently used, followed by simple analgesia (89, 33.7%) and opioid + benzodiazepine +/- simple analgesia (16, 6%). Opioids were prescribed for 169 (64%) (including i.v. opioids for 34 [12.9%] and for 85/97 (88%) with pain scores ≤4), and benzodiazepines for 22 (8.3%). Ten (3%) were referred for physiotherapy management in ED and eight (2.4%) for outpatient physiotherapy follow up. Of 113/334 (33.8%) receiving discharge prescription, 60 (53.1%) were prescribed oral opioid + simple analgesia, 37 (32.7%) oral opioids and seven (6.2%) opioids + benzodiazepines; 205 (61%) were discharged without a recorded follow-up plan. CONCLUSIONS: There is large practice variation in management of neck soft tissue injury in ED. Over half of the patients received CT scans with modest yield. Opioids were commonly used both in ED and on discharge. There is need for a standard management plan to be developed for patients presenting with acute neck soft tissue injury.

Use of and attitudes to the role of medication for acute whiplash injury: A preliminary survey of emergency department doctors.

OBJECTIVE: Describe current practice of medication prescribing for acute whiplash-associated disorders (WAD) in the ED and explore attitudes towards pregabalin prescription for WAD. METHODS: Questionnaire-based survey in two EDs collected data on demographics and self-reported medication prescribing for WAD. Comfort in various scenarios for pregabalin prescribing was rated. RESULTS: A total of 145/170 (85%) doctors responded; 42.8% were junior doctors. Self-reported medications prescribed were nonsteroidal anti-inflammatory drug (77.9% [95% confidence interval (CI) 70.1-84.2]), paracetamol (75.2% [95% CI 67.2-81.8]), opioids (43.5% [95% CI 35.3-51.9]) and benzodiazepines (11.0% [95% CI 6.6-17.6]). Most were comfortable to prescribe pregabalin in evidence-based or advised-by-specialists scenarios. CONCLUSIONS: Opioids appear to be over-prescribed. Further research into pregabalin prescription in ED is warranted.

Views and perceptions about locally manufactured medicines in Ethiopia: a qualitative study of physicians, patients and regulatory authorities.

BACKGROUND: Because of their cost, the use of locally produced, bioequivalent, generic drugs is universally recommended. In Ethiopia. while the government is committed to raising the market share and use of locally produced drugs, the process is hampered by the lack of a bioequivalence testing centre to strengthen the regulatory environment and deliver quality-assured local medicines. The purpose of this study is to assess the views and perceptions of key regulatory stakeholders, physicians and patients about locally produced generic medicines. METHODS: A descriptive qualitative study, using focus group discussions and key informant interviews, was conducted. Five key informant interviews (two senior regulatory authority members and 3 institutional review board members) as well as 4 focus group discussions (2 with physicians and 2 with patients) were held. Data were analysed using an inductive, thematic process. RESULTS: Four major themes emerged: awareness of lack of bioequivalence profiles associated with local medicines, perceptions about the quality and effectiveness of local medicines, quality and efficacy of imported medicines from developing countries and quality and efficacy of cheaper medicines. All institutional review board members were aware of bioequivalence issues. However, many physicians lacked detailed knowledge about bioequivalence, its clinical relevance and the lack of bioequivalence data for local medicines. All institutional review board members, physicians and male patients, but not female patients, were concerned about the quality and effectiveness of local medicines. Female patients were more confident about the locally produced drugs. In addition, some physicians and patients were not confident about the quality and effectiveness of cheaper drugs and drugs imported from developing countries. Government officials believed that local drugs are reliable. CONCLUSION: The success of promoting the use of inexpensive local medicines and changing the perception of the community depends not only on increasing the domestic market share held by local companies, but also on the capacity of the regulatory environment and companies to produce quality assured medicines and to overcome misconceptions. Among other initiatives, establishing an accredited bioequivalence centre in the country needs to be addressed urgently.

N-of-1 trials in the clinical care of patients in developing countries: a systematic review.

BACKGROUND: N-of-1 trials have a potential role in promoting patient-centered medicine in developing countries. However, there is limited academic literature regarding the use of N-of-1 trials in the clinical care of patients in resource-poor settings. OBJECTIVE: To assess the extent of use, purpose and treatment outcome of N-of-1 trials in developing countries. METHOD: A systematic review of clinical N-of-1 trials was conducted between 1985 and September 2015 using PubMed, Embase, CINAHL, Web of Science and the Cochrane Central Register of Controlled Trials. Grey literature databases and clinical trial registers were also searched. This review included randomized, multi-cycle, crossover within individual patient trials involving drug intervention. Quality assessment and data extraction were conducted by two independent reviewers. RESULT: Out of 131 N-of-1 trials identified, only 6 (4.5%) were conducted in developing countries. The major reason that N-of-1 trials were used was to provide evidence on feasibility, effectiveness and safety of therapies. A total of 72 participants were involved in these trials. Five of the studies were conducted in China and all evaluated Chinese traditional medicine. The remaining study was conducted in Brazil. The completion rate was 93%. More than half, 46 (69%) of subjects made medication changes consistent with trial results after trial completion. A number of threats to the validity of the included evidence limited the validity of the evidence. In particular, the estimated overall effect in four of the included studies could have been affected by the "carry over" of the previous treatment effect as no adequate pharmacokinetic evidence regarding traditional medicines was presented. CONCLUSION: The prevalence and scope of N-of-1 trials in developing countries is low. A coordinated effort among government, clinicians, researchers and sponsor organizations is needed to increase their uptake and quality in developing countries. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015026841 .