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1.  The views of stakeholders on controlled access schemes for high-cost antirheumatic biological medicines in Australia 
In Australia, government-subsidised access to high-cost medicines is "targeted" to particular sub-sets of patients under the Pharmaceutical Benefits Scheme to achieve cost-effective use. In order to determine how this access system could be improved, the opinions of key stakeholders on access to biological agents for rheumatoid arthritis were explored.
Thirty-six semi-structured interviews were conducted with persons from relevant stakeholder groups. These were transcribed verbatim, and analysed thematically.
Controlled access to expensive medicines was considered to be equitable and practical; however, there was disagreement as to the method of defining the target patient populations. Other concerns included timeliness of access, excessive bureaucracy, and the need for additional resources to facilitate the scheme. Collaboration between stakeholders was deemed important because it allows more equitable distribution of limited resources. The majority considered that stakeholder consultation should have been broader. Most wanted increased transparency of the decision-making process, ongoing and timely review of access criteria, and an increased provision of information for patients. More structured communication between stakeholders was proposed.
The Pharmaceutical Benefit Scheme is adapting to meet the changing needs of patients. Provision of subsidised access to high-cost medicines in a manner that is affordable for individuals and society, and that is equitable and efficiently managed is challenging. The views of stakeholders on targeted access to anti-rheumatic biological medicines in Australia acknowledged this challenge and provided a number of suggestions for modifications. These could serve as a basis to inform the debate on how to change the processes and policies so as to improve the scheme.
PMCID: PMC2231358  PMID: 18096055
2.  Differential Expression of NK Receptors CD94 and NKG2A by T Cells in Rheumatoid Arthritis Patients in Remission Compared to Active Disease 
PLoS ONE  2011;6(11):e27182.
TNF inhibitors (TNFi) have revolutionised the treatment of rheumatoid arthritis (RA). Natural killer (NK) cells and Natural Killer Cell Receptor+ T (NKT) cells comprise important effector lymphocytes whose activity is tightly regulated through surface NK receptors (NKRs). Dysregulation of NKRs in patients with autoimmune diseases has been shown, however little is known regarding NKRs expression in patients with TNFi-induced remission and in those who maintain remission vs disease flare following TNFi withdrawal.
Patients with RA were recruited for this study, (i) RA patients in clinical remission following a minimum of one year of TNFi therapy (n = −15); (2) Active RA patients, not currently or ever receiving TNFi (n = 18); and healthy control volunteers (n = 15). Patients in remission were divided into two groups: those who were maintained on TNFi and those who withdrew from TNFi and maintained on DMARDS. All patients underwent full clinical assessment. Peripheral blood mononuclear cells were isolated and NKR (CD94, NKG2A, CD161, CD69, CD57, CD158a, CD158b) expression on T-(CD3+CD56−), NK-(CD3−CD56+) and NKT-(CD3+CD56+) cells was determined by flow cytometry.
Following TNFi withdrawal, percentages and numbers of circulating T cells, NK cells or NKT cell populations were unchanged in patients in remission versus active RA or HCs. Expression of the NKRs CD161, CD57, CD94 and NKG2A was significantly increased on CD3+CD56-T cells from patients in remission compared to active RA (p<0.05). CD3+CD56-T cell expression of CD94 and NKG2A was significantly increased in patients who remained in remission compared with patients whose disease flared (p<0.05), with no differences observed for CD161 and CD57. CD3+CD56− cell expression of NKG2A was inversely related to DAS28 (r = −0.612, p<0.005).
High CD94/NKG2A expression by T cells was demonstrated in remission patients following TNFi therapy compared to active RA, while low CD94/NKG2A were associated with disease flare following withdrawal of therapy.
PMCID: PMC3216944  PMID: 22102879
3.  Effects of Disease-Modifying Antirheumatic Drugs on Non-Vertebral Fracture Risk in Rheumatoid Arthritis: a Population-based Cohort Study 
Several prior investigations demonstrate an improvement in bone mineral density associated with use of TNF inhibitors (TNFi). We compared the risk of osteoporotic fractures among patients with rheumatoid arthritis (RA) initiating a disease-modifying antirheumatic drug (DMARD).
A population-based cohort study was conducted using health care utilization data (1996–2008) from a Canadian province and a US commercial insurance plan. Patients with at least two RA diagnoses were identified and follow-up began with the first prescription for a DMARD. Drug regimens were categorized into three mutually exclusive hierarchical groups: 1) TNFi with or without non-biologic DMARDs (nbDMARD), 2) methotrexate (MTX) without a TNFi, or 3) other nbDMARD without a TNFi or MTX. Main outcomes were hospitalizations for fractures of the hip, wrist, humerus, or pelvis based on diagnoses and procedure codes.
The study cohort consisted of 16,412 RA patients with 25,988 new treatment episodes: 5,856 TNFi, 12,554 MTX, and 7,578 other nbDMARD. The incidence rate per 1,000 person-years for osteoporotic fracture were 5.11 (95% CI 3.50 – 7.45) for TNFi, 5.35 (95% CI 4.08–7.02) for MTX, and 6.38 (95% CI 3.78–10.77) for other nbDMARD. After multivariable adjustment for osteoporosis and fracture-related risk factors, the risk of non-vertebral osteoporotic fracture was not different in either TNFi (hazard ratio (HR) 1.07, 95% CI 0.57–1.98) or MTX (HR 1.18, 95% CI 0.60– 2.34) compared with nbDMARD.
Among subjects diagnosed with RA, the adjusted risk of non-vertebral fracture was similar across persons starting a TNFi, MTX, or other nbDMARD.
PMCID: PMC3725780  PMID: 22162140
rheumatoid arthritis; fracture; disease modifying antirheumatic drugs
4.  Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice 
Annals of the Rheumatic Diseases  2012;71(12):1950-1954.
To evaluate the safety and efficacy of tocilizumab in clinical practice in patients with rheumatoid arthritis (RA) with inadequate responses (IR) to disease-modifying antirheumatic drugs (DMARDs) or both DMARDs and tumour necrosis factor α inhibitors (TNFis).
Patients—categorised as TNFi-naive, TNFi-previous (washout) or TNFi-recent (no washout) —received open-label tocilizumab (8 mg/kg) every 4 weeks ± DMARDs for 24 weeks. Adverse events (AEs) and treatment discontinuations were monitored. Efficacy end points included American College of Rheumatology (ACR) responses, 28-joint disease activity score (DAS28) and European League Against Rheumatism responses.
Overall, 1681 (976 TNF-naive, 298 TNFi-previous and 407 TNFi-recent) patients were treated; 5.1% discontinued treatment because of AEs. The AE rate was numerically higher in TNFi-recent (652.6/100 patient-years (PY)) and TNFi-previous (653.6/100PY) than in TNFi-naive (551.1/100PY) patients. Serious AE rates were 18.0/100PY, 28.0/100PY and 18.6/100PY; serious infection rates were 6.0/100PY, 6.8/100PY and 4.2/100PY, respectively. At week 4, 36.5% of patients achieved ACR20 response and 14.9% DAS28 remission (<2.6); at week 24, 66.9%, 46.6%, 26.4% and 56.8% achieved ACR20/ACR50/ACR70 responses and DAS28 remission, respectively. Overall, 61.6% (TNFi-naive), 48.5% (TNFi-previous) and 50.4% (TNFi-recent) patients achieved DAS28 remission.
In patients with RA who were DMARD-IR/TNFi-IR, tocilizumab ± DMARDs provided rapid and sustained efficacy without unexpected safety concerns.
PMCID: PMC3595980  PMID: 22615456
5.  The funding and use of high-cost medicines in Australia: the example of anti-rheumatic biological medicines 
Subsidised access to high-cost medicines in Australia is restricted under national programs (the Pharmaceutical Benefits Scheme, PBS, and the Repatriation Pharmaceutical Benefits Scheme, RPBS) with a view to achieving cost-effective use. The aim of this study was to examine the use and associated government cost of biological agents for treating rheumatoid arthritis over the first two years of subsidy, and to compare these data to the predicted outcomes.
National prescription and expenditure data for the biologicals, etanercept, infliximab, adalimumab, and anakinra were collected and analysed for the period August 2003 to July 2005. Dispensing data on biologicals sorted by the metropolitan, rural and remote zones and by prescriber major specialty were also examined.
A total of 27,970 prescriptions for biologicals was reimbursed. The government expenditure was A$53.1 million, representing only 19% of that expected. Almost all prescriptions were reimbursed by the PBS (98%, A$52 million) and the remainder by the RPBS. Approximately 62% of the prescriptions were for concessional patients (A$32.9 million). There was considerable variability in the use of biologicals across Australian states and territories, usage roughly correlating with the per capita adjusted number of rheumatologists. The total number of prescriptions continued to increase over the study period. Etanercept was the most highly prescribed agent (74% by number of prescriptions), although its use was beginning to plateau. Use of adalimumab increased steadily. Use of infliximab and anakinra was considerably lower. The resultant health outcomes for individual patients are unknown. Prescribers from capital cities and other metropolitan centres provided a majority of prescriptions of biologicals (89%).
The overall uptake of biologicals for treating rheumatoid arthritis over the first two years of PBS subsidy was considerably lower than expected. Long-term safety concerns and the expanded clinical uses of these drugs emphasise the need for evaluation. It is essential that there is comprehensive, ongoing analysis of utilisation data, associated expenditure and, importantly, patient outcomes in order to enhance accountability, efficiency and equity of policies that allocate substantial resources to subsidising national access to high-cost medicines.
PMCID: PMC1828161  PMID: 17331230
6.  Dyslipidemia and Changes in Lipid Profiles Associated with Rheumatoid Arthritis and Initiation of Anti-TNF Therapy 
Arthritis care & research  2012;64(9):1282-1291.
To investigate the frequency of lipid testing in clinical practice and explore the relationship between rheumatoid arthritis (RA), dyslipidemia, and other cardiovascular (CV) risk factors, with RA treatment.
Patients in the retrospective database study were ≥18 years old and had ≥2 physician diagnoses for RA or osteoarthritis (OA) [comparator group] between March 2004-March 2008. Outcomes of interest included the percentage of RA and OA patients receiving lipid tests, lipid profiles (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], and high-density lipoprotein cholesterol [HDL-C]) of RA vs. OA patients, and lipid profiles of RA patients before and after initiation with a tumor necrosis factor inhibitor (TNFi). We used multivariable regression to control potential confounders between the cohorts.
Over a median 2+ year follow-up, fewer RA patients than OA patients had at least one lipid test (62% [95% CI, 60-64] vs. 68% [95% CI, 65-71]). Mean TC and LDL-C were each 4 mg/dL lower in the RA cohort (P<0.0001); HDL-C was similar between cohorts. Across the RA cohort, 25.2% of patients had suboptimal LDL-C levels (≥130 mg/dL). Among RA patients not using lipid-lowering therapy who initiated TNFi therapy (n=96), mean TC and LDL-C increased by 5.4 and 4.0 mg/dL, respectively.
RA patients were less likely to be tested for hyperlipidemia and had more favorable lipid profiles than OA patients. TNFi therapy modestly increased all lipid parameters. Additional studies are needed to determine the effect of traditional CV risk factors, inflammation, and the impact of biologics on CV outcomes in RA patients.
PMCID: PMC3404153  PMID: 22504829
7.  Access to high cost medicines in Australia: ethical perspectives 
Access to "high cost medicines" through Australia's Pharmaceutical Benefits Scheme (PBS) is tightly regulated. It is inherently difficult to apply any criteria-based system of control in a way that provides a fair balance between efficient use of limited resources for community needs and equitable individual access to care. We suggest, in relation to very high cost medicines, that the present arrangements be re-considered in order to overcome potential inequities. The biological agents for the treatment of rheumatoid arthritis are used as an example by which to discuss the ethical issues associated with the current scheme. Consideration of ethical aspects of the PBS and similar programs is important in order to achieve the fairest outcomes for individual patients, as well as for the community.
PMCID: PMC2412887  PMID: 18489760
8.  Comparative effectiveness and predictors of response to tumour necrosis factor inhibitor therapies in rheumatoid arthritis 
Rheumatology (Oxford, England)  2012;51(11):2020-2026.
Objectives. Adalimumab, etanercept and infliximab are effective TNF inhibitors (TNFis) in the treatment of RA, but no randomized clinical trials have compared the three agents. Prior observational data are not consistent. We compared their effectiveness over 1 year in a prospective cohort.
Methods. Analyses were performed on subjects’ first episode of TNFi use in the Rheumatic Diseases Portuguese Register, The primary outcome was the proportion of patients with European League Against Rheumatism good response sustained at two consecutive observations separated by 3 months during the first year of TNFi use. Comparisons were performed using conventional adjusted logistic regression, as well as matching subjects across the three agents using a propensity score. In addition, baseline predictors of treatment response to TNFi were identified.
Results. The study cohort included 617 RA patients, 250 starting etanercept, 206 infliximab and 161 adalimumab. Good response was achieved by 59.6% for adalimumab, 59.2% for etanercept and 51.9% for infliximab (P = 0.21). The modelled probability of good response did not significantly differ across agents (etanercept vs adalimumab OR = 0.97, 95% CI 0.55, 1.71; etanercept vs infliximab OR = 1.25, 95% CI 0.74, 2.12; infliximab vs adalimumab OR = 0.80, 95% CI 0.47, 1.36). Matched propensity score analyses also showed no significant treatment response differences. Greater educational attainment was a predictor of better response, while smoking, presence of ACPA, glucocorticoid use and worse physician assessment of disease activity at baseline each predicted a reduced likelihood of treatment response.
Conclusion. Over 1 year, we found no difference in effectiveness between adalimumab, etanercept and infliximab.
PMCID: PMC3475979  PMID: 22843791
RA; TNF inhibitors; comparative effectiveness; register; response predictors
9.  Comparison of remission criteria in a tumour necrosis factor inhibitor treated rheumatoid arthritis longitudinal cohort: patient global health is a confounder 
Arthritis Research & Therapy  2013;15(6):R221.
Our objectives were to assess the frequency and sustainability of American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) and Disease Activity Score (DAS)28(4v)–C-reactive protein (CRP) remission 12 months after the initiation of tumour necrosis factor inhibitor (TNFi) therapy in a rheumatoid arthritis (RA) cohort.
Data were collected of 273 biologic naive RA patients at baseline, then 3, 6 and 12 months post-TNFi therapy. Remission status was calculated using DAS28(4v)-CRP <2.6 and ACR/EULAR Boolean criteria. Response was scored using EULAR criteria.
Mean (range) patient age was 59.9 (7.2-85.4) years with disease duration of 13.4 (1.0-52.0) years. Responder status maintained from 3–12 months (86%, 82.4%), laboratory/clinical parameters (erythrocyte sedimentation rate (ESR), CRP, patient global health (PGH), DAS28(4v)-CRP) also showed sustained improvement (P < 0.05). DAS28 remission was reached by 102 subjects at 1 year, 27 patients were in Boolean remission, but 75 missed it from the DAS28 remission group. Patients in remission were younger (P = 0.041) with lower baseline tender joint count (TJC)28 and PGH than those not in remission (P = 0.001, P = 0.047). DAS28 remission patients were older (P = 0.026) with higher 12 months PGH and subsequently higher DAS28 than Boolean remission patients (P < 0.0001). Patients not achieving Boolean remission due to missing one subcriteria most frequently missed PGH ≤1 criteria (79.8%).
Only 10% of this TNFi treated cohort achieved remission according to the new ACR/EULAR criteria, which requires lower disease activity. More stringent criteria may ensure further resolution of disease activity and better longterm radiographic outcome, which supports earlier intervention with biologic therapy in RA.
PMCID: PMC3978469  PMID: 24365061
10.  Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement 
Annals of the Rheumatic Diseases  2012;72(4):583-589.
Suppression of the immunoinflammatory cascade by targeting interleukin 6 (IL-6) mediated effects constitutes a therapeutic option for chronic inflammatory diseases. Tocilizumab is the only IL-6 inhibitor (IL-6i) licensed for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), but also other agents targeting either IL-6 or its receptor are investigated in various indications.
To review published evidence on safety and efficacy of IL-6i in inflammatory diseases.
We performed systematic literature searches in Medline and Cochrane, screened EULAR and American College of Rheumatology meeting-abstracts, and accessed
Comprehensive evidence supports the efficacy of tocilizumab in RA in DMARD-naïve patients, and after DMARD- and TNFi-failure. Randomised comparisons demonstrate superiority of tocilizumab in JIA, but not ankylosing spondylitis (AS). Other indications are currently investigated. Additional IL-6i show similar efficacy; safety generally appears acceptable.
IL-6i is effective and safe in RA and JIA, but not in AS. Preliminary results in other indications need substantiation.
PMCID: PMC3595140  PMID: 23144446
Rheumatoid Arthritis; Juvenile Idiopathic Arthritis; Treatment; DMARDs (biologic)
11.  Biologic and oral disease-modifying antirheumatic drug monotherapy in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2013;72(12):1897-1904.
Clinical evidence demonstrates coadministration of tumour necrosis factor inhibitor (TNFi) agents and methotrexate (MTX) is more efficacious than administration of TNFi agents alone in patients with rheumatoid arthritis, leading to the perception that coadministration of MTX with all biologic agents or oral disease-modifying antirheumatic drugs is necessary for maximum efficacy. Real-life registry data reveal approximately one-third of patients taking biologic agents use them as monotherapy. Additionally, an analysis of healthcare claims data showed that when MTX was prescribed in conjunction with a biologic agent, as many as 58% of patients did not collect the MTX prescription. Given this discrepancy between perception and real life, we conducted a review of the peer-reviewed literature and rheumatology medical congress abstracts to determine whether data support biologic monotherapy as a treatment option for patients with rheumatoid arthritis. Our analysis suggests only for tocilizumab is there evidence that the efficacy of biologic monotherapy is comparable with combination therapy with MTX.
PMCID: PMC3841743  PMID: 23918035
Rheumatoid Arthritis; Treatment; DMARDs (biologic)
12.  Patient’s access to healthcare and treatment in rheumatoid arthritis: the views of stakeholders in Portugal 
The access to healthcare and treatment by rheumatoid arthritis (RA) patients, particularly to biologics, differs significantly among European countries.
We aimed to explore the views and experiences of Portuguese healthcare stakeholders on key barriers which limit the access to treatment, and ultimately to biologics, by RA patients and to find potential solutions (leverage points) to overcome the identified barriers.
This was a qualitative research consisting of semi-structured face-to-face interviews with key stakeholders in RA framework. Thirty four individuals from eight groups of stakeholders were interviewed: rural and urban general practitioners (GPs), rheumatologists, hospital managers, hospital pharmacists, budget holders, representatives from the Portuguese Rheumatology Society and the RA Patient Association. Interviews were conducted between May and June 2011. Conventional content analysis with research triangulation was used.
The key barriers identified were related to the accessibility to primary healthcare services, difficulties in RA diagnosis among GPs, inefficient referral to secondary healthcare and controlled process of biologics prescription in public hospitals. The leverage points identified included the improvement of epidemiological and clinical knowledge about RA in Portugal, a better understanding of the disease among patients and GPs, the clarification of biologics benefits among budget holders and a raised awareness of the current treatment guidelines. In order to further address the leverage points, the following key initiatives were proposed: optimization of RA national registry; dissemination of information on rheumatic symptoms in primary care facilities and among the general public; increase interaction between rheumatologists and GPs through clinical discussions of successfully treated patients or workshops; broader utilization of disease diagnosis and monitoring tools, such as DAS28, and implementation of hospital–based research to collect real-world data.
Most of the key barriers limiting the access to treatment, including biologics, in RA in Portugal are upstream of rheumatology practice. Our findings suggest that future actions should be focused on the primary care level to improve referral to rheumatologists. In addition, the collection of real-world data seems essential to characterise the RA population, to improve disease management and to increase compliance with current treatment guidelines.
PMCID: PMC3849024  PMID: 24067096
Rheumatoid arthritis; Biologics; Access to treatment; Qualitative research; Stakeholders
13.  Assessing the impact of the Australia-United States Free Trade Agreement on Australian and global medicines policy 
On 1 January 2005, a controversial trade agreement entered into force between Australia and the United States. Though heralded by the parties as facilitating the removal of barriers to free trade (in ways not achievable in multilateral fora), it also contained many trade-restricting intellectual property provisions and others uniquely related to altering pharmaceutical regulation and public health policy in Australia. The latter appear to have particularly focused on the world-respected process of federal government reimbursement after expert cost-effectiveness evaluation, popularly known as the Pharmaceutical Benefits Scheme ('PBS'). It remains uncertain what sort of impacts – if any – the Australia-United States Free Trade Agreement ('AUSFTA') will have on PBS processes such as reference pricing and their important role in facilitating equitable and affordable access to essential medicines.
This is now the field of inquiry for a major three year Australian Research Council ('ARC')-funded study bringing together a team of senior researchers in regulatory theory from the Australian National University and pharmacoeconomics from the University of Newcastle. The project proposes to monitor, assess and analyse the real and potential impacts of the AUSFTA in this area, providing Australian policy-makers with continuing expertise and options.
To the extent that the AUSFTA medicines provisions may represent an important precedent in a global strategy by industry on cost-effectiveness evaluation of pharmaceuticals, the study will also be of great interest to policy makers in other jurisdictions.
PMCID: PMC1276805  PMID: 16209703
14.  Improvements in health-related quality of life after treatment with tocilizumab in patients with rheumatoid arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week randomized controlled RADIATE study 
Rheumatology (Oxford, England)  2012;51(10):1860-1869.
Objective. To investigate the effect of tocilizumab on patient-reported outcomes (PROs) in RA patients with inadequate responses to TNF inhibitors (TNFis).
Methods. In a Phase III randomized controlled trial, 489 patients received 4 or 8 mg/kg tocilizumab or placebo every 4 weeks plus MTX for 24 weeks. Mean changes from baseline over time and proportions of patients reporting improvements greater than or equal to minimum clinically important differences (MCIDs) in PROs were analyzed.
Results. At week 24, 8 mg/kg resulted in significantly greater improvements vs placebo in pain, global assessment of disease activity (P = 0.001), Health Assessment Questionnaire-Disability Index (HAQ-DI; P < 0.0001), Functional Assessment of Chronic Illness Therapy-Fatigue (P = 0.0150) and Medical Outcomes Survey Short Form 36 (SF-36 v2) Physical Component Summary (PCS; P = 0.0003) scores, all greater than MCID; 4 mg/kg resulted in greater improvements in pain (P = 0.0100), HAQ-DI (P = 0.0030) and SF-36 PCS (P = 0.0020) scores. Tocilizumab-associated improvements were evident as early as week 2. At week 24, more tocilizumab-treated than control patients reported improvements greater than or equal to MCID in SF-36 domain scores and related PROs (50.9–84.9% vs 35.0–51.7%) and achieved ACR50 responses and/or Disease Activity Score 28 (DAS28) remission with PRO improvements greater than or equal to MCID (36.2–51.2% vs 10–20.7% and 10.7–37.5% vs 0.0–3.4%, respectively).
Conclusion. Tocilizumab treatment in patients with inadequate responses to TNFis resulted in rapid and sustained improvements in multiple PROs that were statistically significant and clinically meaningful, consistent with previous efficacy reports.
Trial Registration.,, NCT00106522.
PMCID: PMC3448882  PMID: 22753773
rheumatoid arthritis; tocilizumab; health-related quality of life; patient-reported outcomes; randomized controlled trial
15.  Making our offices universally accessible: guidelines for physicians 
OBJECTIVE: To develop recommendations for office-based physicians who wish to make their offices accessible to all patients. OPTIONS: Include taking steps to make offices more accessible, or not; offices may be accessible to varying degrees. OUTCOMES: Outcomes of accessibility involve patient-care, economic, ethical and legal issues. Stakeholders in these outcomes include patients, physicians, government and society. EVIDENCE: Data were obtained from a series of searches of MEDLINE, CINAHL and Healthstar (previously Health) databases for articles on disability and family medicine, primary (health) care and family practice, and on access and offices, and health services accessibility, and from a telephone survey of 50 stakeholders. VALUES: A high value was placed on services to persons with disabilities and on stakeholder input. Universal accessibility was valued as an overall goal; improved accessibility was also highly valued. BENEFITS, HARMS AND COSTS: Benefits to patients include improved access to care as guaranteed by the Canada Health Act and in keeping with provincial Human Rights Codes. Benefits to physicians include contact with a broader patient population and freedom from fear of litigation. Costs of improved accessibility vary depending on individual circumstances and on whether an office is being built or renovated; some improvement costs are minimal. RECOMMENDATIONS: All physicians should take measures to improve practice accessibility. Improved access should be considered in each of the following areas: transportation and entrance to the facility, entrance to the office, waiting rooms, rest rooms, examination rooms, general building features and other features. VALIDATION: No similar guidelines exist. To assess the content validity of these guidelines, the authors had a draft document reviewed by 18 stakeholders. All specific recommendations met the minimum criterion of adherence to current legislation, including national and provincial building codes. The specific recommendations are endorsed by the Canadian Paraplegic Association (national and Ontario offices), the DisAbled Women's Network (Ontario) and the Centre for Independent Living (Toronto). SPONSORS: Development of these guidelines was supported in part by the Department of Family and Community Medicine, Toronto Hospital, Toronto, Ont.
PMCID: PMC1232828  PMID: 9068570
16.  Inflammatory pathways of importance for management of inflammatory bowel disease 
Inflammatory bowel disease (IBD) is a group of chronic disorders of the gastrointestinal tract comprising Crohn’s disease (CD) and ulcerative colitis (UC). Their etiologies are unknown, but they are characterised by an imbalanced production of pro-inflammatory mediators, e.g., tumor necrosis factor (TNF)-α, as well as increased recruitment of leukocytes to the site of inflammation. Advantages in understanding the role of the inflammatory pathways in IBD and an inadequate response to conventional therapy in a large portion of patients, has over the last two decades lead to new therapies which includes the TNF inhibitors (TNFi), designed to target and neutralise the effect of TNF-α. TNFi have shown to be efficient in treating moderate to severe CD and UC. However, convenient alternative therapeutics targeting other immune pathways are needed for patients with IBD refractory to conventional therapy including TNFi. Indeed, several therapeutics are currently under development, and have shown success in clinical trials. These include antibodies targeting and neutralising interleukin-12/23, small pharmacologic Janus kinase inhibitors designed to block intracellular signaling of several pro-inflammatory cytokines, antibodies targeting integrins, and small anti-adhesion molecules that block adhesion between leukocytes and the intestinal vascular endothelium, reducing their infiltration into the inflamed mucosa. In this review we have elucidated the major signaling pathways of clinical importance for IBD therapy and highlighted the new promising therapies available. As stated in this paper several new treatment options are under development for the treatment of CD and UC, however, no drug fits all patients. Hence, optimisations of treatment regimens are warranted for the benefit of the patients either through biomarker establishment or other rationales to maximise the effect of the broad range of mode-of-actions of the present and future drugs in IBD.
PMCID: PMC3886034  PMID: 24415859
Anti-tumor necrosis factor; Biologics; Crohn’s disease; Pro-inflammatory cytokines; Signaling pathways; Treatment; Ulcerative colitis
17.  Reducing Clinical Trial Monitoring Resource Allocation and Costs Through Remote Access to Electronic Medical Records 
Journal of Oncology Practice  2012;9(1):e13-e16.
Remote access to patient medical records for source data verification is feasible and is potentially an avenue through which resources can be more efficiently used.
With electronic medical records (eMRs), the option now exists for clinical trial monitors to perform source data verification (SDV) remotely. We report on a feasibility study of remote access to eMRs for SDV and the potential advantages of such a process in terms of resource allocation and cost.
The Clinical Trials Unit at the Peter MacCallum Cancer Centre, in collaboration with Novartis Pharmaceuticals Australia, conducted a 6-month feasibility study of remote SDV. A Novartis monitor was granted dedicated software and restricted remote access to the eMR portal of the cancer center, thereby providing an avenue through which perform SDV.
Six monitoring visits were conducted during the study period, four of which were performed remotely. The ability to conduct two thirds of the monitoring visits remotely in this complex phase III study resulted in an overall cost saving to Novartis. Similarly, remote monitoring eased the strain on internal resources, particularly monitoring space and hospital computer terminal access, at the cancer center.
Remote access to patient eMRs for SDV is feasible and is potentially an avenue through which resources can be more efficiently used. Although this feasibility study involved limited numbers, there is no limit to scaling these processes to any number of patients enrolled onto large clinical trials.
PMCID: PMC3545670  PMID: 23633977
18.  Improving Access to Medicines in Low and Middle Income Countries: Corporate Responsibilities in Context 
Southern Med Review  2012;5(2):3-8.
More than two billion people in low- and middle-income countries (LMIC) lack adequate access to essential medicines. In this paper, we make strong public health, human rights and economic arguments for improving access to medicines in LMIC and discuss the different roles and responsibilities of key stakeholders, including national governments, the international community, and non-governmental organizations (NGOs). We then establish a framework of pharmaceutical firms’ corporate responsibilities - the “must,” the “ought to,” and the “can” dimensions - and make recommendations for actionable business strategies for improving access to medicines. We discuss controversial topics, such as pharmaceutical profits and patents, with the goal of building consensus around facts and working towards a solution. We conclude that partnerships and collaboration among multiple stakeholders are urgently needed to improve equitable access to medicines in LMIC.
PMCID: PMC3606933  PMID: 23535994
Pharmaceutical Products; Health Policy; Health Financing; Health Systems
19.  Strengthening the admissions process in health care professional education: focus on a premier Pacific Island medical college 
Relying solely on measures of intellectual aptitude and academic performance in university admissions can be disadvantageous to underprivileged students. The Fiji School of Medicine primarily uses such measures to evaluate and select student applicants, and the introduction of supplementary assessments could provide better access for students from disadvantaged backgrounds. This study examined the need for supplementary assessments in the admission process, types of additional assessments needed, and stakeholders’ views on a multi-entry multi-exit strategy currently in use at the Fiji School of Medicine. A survey of the key stakeholders was conducted in February and March 2012 using closed and open ended questionnaire. One hundred and twenty-two validated questionnaires were self-administered by key stakeholders from the College of Medicine, Nursing and Health Sciences (CMNHS) and Fiji Ministries of Education and Health, with a response rate of 61%. Returned questionnaires were analysed quantitatively and qualitatively. Sixty-five percent of respondents supported the introduction of supplementary assessments, 49% favoured admissions test, and 16% preferred assessing non-academic factors. Many respondents supported the School’s multi-entry multi-exit strategy as a ‘good policy’ that provided ‘flexibility’ and opportunity for students, but should be better regulated. These findings demonstrate the need for supplementary assessments in the selection process and for continued support for the use of multi-entry multi-exit strategy at the school.
PMCID: PMC3545630  PMID: 23330054
Criteria, school admission; Equity; Fiji School of Medicine; Educational policy; Noncognitive factors
20.  Achieving universal health care coverage: Current debates in Ghana on covering those outside the formal sector 
Globally, extending financial protection and equitable access to health services to those outside the formal sector employment is a major challenge for achieving universal coverage. While some favour contributory schemes, others have embraced tax-funded health service cover for those outside the formal sector. This paper critically examines the issue of how to cover those outside the formal sector through the lens of stakeholder views on the proposed one-time premium payment (OTPP) policy in Ghana.
Ghana in 2004 implemented a National Health Insurance Scheme, based on a contributory model where service benefits are restricted to those who contribute (with some groups exempted from contributing), as the policy direction for moving towards universal coverage. In 2008, the OTPP system was proposed as an alternative way of ensuring coverage for those outside formal sector employment. There are divergent stakeholder views with regard to the meaning of the one-time premium and how it will be financed and sustained. Our stakeholder interviews indicate that the underlying issue being debated is whether the current contributory NHIS model for those outside the formal employment sector should be maintained or whether services for this group should be tax funded. However, the advantages and disadvantages of these alternatives are not being explored in an explicit or systematic way and are obscured by the considerable confusion about the likely design of the OTPP policy. We attempt to contribute to the broader debate about how best to fund coverage for those outside the formal sector by unpacking some of these issues and pointing to the empirical evidence needed to shed even further light on appropriate funding mechanisms for universal health systems.
The Ghanaian debate on OTPP is related to one of the most important challenges facing low- and middle-income countries seeking to achieve a universal health care system. It is critical that there is more extensive debate on the advantages and disadvantages of alternative funding mechanisms, supported by a solid evidence base, and with the policy objective of universal coverage providing the guiding light.
PMCID: PMC3532243  PMID: 23102454
Universal health care coverage; National health insurance; Policy objective; Policy options; Those outside formal sector employment; Tax funding; One-time premium payment; Ghana
21.  Graduate entry to medicine in Iran 
In Iran medical students are selected from high school graduates via a very competitive national university entrance exam. New proposals have been seriously considered for admitting students from those with bachelor degrees. We assessed the opinions of different stakeholders on the current situation of admission into medicine in Iran, and their views on positive and negative aspects of admitting graduates into medicine.
We conducted five focus group discussions and seven in-depth interviews with stakeholders including medical students, science students, university professors of basic sciences, medical education experts, and policy makers. Main themes were identified from the data and analyzed using content analysis approach.
Medical students believed "graduate admission" may lead to a more informed choice of medicine. They thought it could result in admission of students with lower levels of academic aptitude. The science students were in favor of "graduate admission". The education experts and the professors of basic science all mentioned the shortcomings of the current system of admission and considered "graduate admission" as an appropriate opportunity for correcting some of the shortcomings. The policy makers pointed out the potential positive influences of "graduate admission" on strengthening basic science research. They thought, however, that "graduate admission" may result in lengthening the overall duration of medical education, which is already long in Iran (over 7 years). On the whole, the participants thought that "graduate admission" is a step in the right direction for improving quality of medical education.
"Graduate admission" has the potential to correct some of shortcomings of medical education. Unlike other countries where "graduate admission" is used mainly to admit students who are mentally mature, in Iran the main objective seems to be strengthening basic sciences.
PMCID: PMC2571089  PMID: 18847497
22.  Intestinal-Specific TNFα Overexpression Induces Crohn’s-Like Ileitis in Mice 
PLoS ONE  2013;8(8):e72594.
Background and Aim
Human and animal studies have clearly established tumor necrosis factor (TNF)α as an important mediator of Crohn’s disease pathogenesis. However, whether systemic or only local TNFα overproduction is required for the development of chronic intestinal inflammation and Crohn’s disease remains unclear. The aim of this study was to assess the contribution of intestinal epithelial-derived TNFα to the development of murine Crohn’s-like ileitis.
We adapted the well-established TNF∆ARE/+ mouse model of Crohn’s disease (which systemically overexpresses TNFα) to generate a homozygous mutant strain that overexpress TNFα only within the intestinal epithelium. Intestinal-specific TNFi∆ARE/i∆ARE mice were examined for histopathological signs of gut inflammation and extraintestinal manifestations of Crohn’s disease. The mucosal immune phenotype was characterized, and the contribution of specific lymphocyte populations to the pathogenesis of TNFi∆ARE/i∆ARE ileitis was assessed.
TNFi∆ARE/i∆ARE mice had increased mucosal and systemic TNFα levels compared to wild-type controls (P<0.001), as well as severe chronic ileitis with increased neutrophil infiltration and villous distortion, but no extraintestinal manifestations (P<0.001 vs. wild-type controls). The gut mucosal lymphocytic compartment was also expanded in TNFi∆ARE/i∆ARE mice (P<0.05), consisting of activated CD69+ and CD4+CD62L- lymphocytes (P<0.05). FasL expression was significantly elevated in the mesenteric lymph nodes of TNFi∆ARE/i∆ARE mice (P<0.05). Adoptive transfer of mucosal TNFi∆ARE/i∆ARE lymphocytes resulted in ileitis in immunologically naïve severe combined immunodeficiency recipients (P<0.05 vs. wild-type controls), indicating an effector phenotype that was associated with increased production of both Th1 (IFNγ) and Th2 (IL-5, IL-13) cytokines.
Intestinal epithelial-derived TNFα is sufficient for the induction of Crohn’s-like ileitis, but not for the occurrence of extraintestinal manifestations, in TNFi∆ARE/i∆ARE mice. These effects were associated with generation of effector lymphocytes within the intestinal mucosa and dysregulated apoptosis. Thus, targeted intestinal blockade of TNFα may provide an effective means to neutralize gut-derived TNFα with reduced side effects.
PMCID: PMC3748077  PMID: 23977323
23.  Medicines information provided by pharmaceutical representatives: a comparative study in Australia and Malaysia 
BMC Public Health  2010;10:743.
Pharmaceutical representatives provide medicines information on their promoted products to doctors. However, studies have shown that the quality of this information is often low. No study has assessed the medicines information provided by pharmaceutical representatives to doctors in Malaysia and no recent evidence in Australia is present. We aimed to compare the provision of medicines information by pharmaceutical representatives to doctors in Australia and Malaysia.
Following a pharmaceutical representative's visit, general practitioners in Australia and Malaysia who had agreed to participate, were asked to fill out a questionnaire on the main product and claims discussed during the encounter. The questionnaire focused on provision of product information including indications, adverse effects, precautions, contraindications and the provision of information on the Pharmaceutical Benefit Scheme (PBS) listings and restrictions (in Australia only). Descriptive statistics were produced. Chi-square analysis and clustered linear regression were used to assess differences in Australia and Malaysia.
Significantly more approved product information sheets were provided in Malaysia (78%) than in Australia (53%) (P < 0.001). In both countries, general practitioners reported that indications (Australia, 90%, Malaysia, 93%) and dosages (Australia, 76%, Malaysia, 82%) were frequently provided by pharmaceutical representatives. Contraindications, precautions, drug interactions and adverse effects were often omitted in the presentations (range 25% - 41%). General practitioners in Australia and Malaysia indicated that in more than 90% of presentations, pharmaceutical representatives partly or fully answered their questions on contraindications, precautions, drug interactions and adverse effects. More general practitioners in Malaysia (85%) than in Australia (60%) reported that pharmaceutical representatives should have mentioned contraindications, precautions for use, drug interaction or adverse effects spontaneously (P < 0.001). In 48% of the Australian presentations, general practitioners reported the pharmaceutical representatives failed to mention information on PBS listings to general practitioners.
Information on indications and dosages were usually provided by pharmaceutical representatives in Australia and Malaysia. However, risk and harmful effects of medicines were often missing in their presentations. Effective control of medicines information provided by pharmaceutical representatives is needed.
PMCID: PMC3018442  PMID: 21118551
24.  USDA Stakeholder Workshop on Animal Bioinformatics: Summary and Recommendations 
An electronic workshop was conducted on 4 November–13 December 2002 to discuss current issues and needs in animal bioinformatics. The electronic (e-mail listserver) format was chosen to provide a relatively speedy process that is broad in scope, cost-efficient and easily accessible to all participants. Approximately 40 panelists with diverse species and discipline expertise communicated through the panel e-mail listserver. The panel included scientists from academia, industry and government, in the USA, Australia and the UK. A second ‘stakeholder’ e-mail listserver was used to obtain input from a broad audience with general interests in animal genomics. The objectives of the electronic workshop were: (a) to define priorities for animal genome database development; and (b) to recommend ways in which the USDA could provide leadership in the area of animal genome database development. E-mail messages from panelists and stakeholders are archived at Priorities defined for animal genome database development included: (a) data repository; (b) tools for genome analysis; (c) annotation; (d) practical application of genomic data; and (e) a biological framework for DNA sequence. A stable source of funding, such as the USDA Agricultural Research Service (ARS), was recommended to support maintenance of data repositories and data curation. Continued support for competitive grants programs within the USDA Cooperative State Research, Education and Extension Service (CSREES) was recommended for tool development and hypothesis-driven research projects in genome analysis. Additional stakeholder input will be required to continuously refine priorities and maximize the use of limited resources for animal bioinformatics within the USDA.
PMCID: PMC2447412  PMID: 18629125
25.  The Pharmaceutical Benefits Scheme 2003–2004 
The Pharmaceutical Benefits Scheme (PBS) grew by 8% in 2003–04; a slower rate than the 12.0% pa average growth over the last decade. Nevertheless, the sustainability of the Scheme remained an ongoing concern given an aging population and the continued introduction of useful (but increasingly expensive) new medicines. There was also concern that the Australia-United States Free Trade Agreement could place further pressure on the Scheme. In 2003, as in 2002, the government proposed a 27% increase in PBS patient co-payments and safety-net thresholds in order to transfer more of the cost of the PBS from the government to consumers. While this measure was initially blocked by the Senate, the forthcoming election resulted in the Labor Party eventually supporting this policy. Recommendations of the Pharmaceutical Benefits Advisory Committee to list, not list or defer a decision to list a medicine on the PBS were made publicly available for the first time and the full cost of PBS medicines appeared on medicine labels if the price was greater than the co-payment. Pharmaceutical reform in Victorian public hospitals designed to minimise PBS cost-shifting was evaluated and extended to other States and Territories. Programs promoting the quality use of medicines were further developed coordinated by the National Prescribing Service, Australian Divisions of General Practice and the Pharmacy Guild of Australia. The extensive uptake of computerised prescribing software by GPs produced benefits but also problems. The latter included pharmaceutical promotion occurring at the time of prescribing, failure to incorporate key sources of objective therapeutic information in the software and gross variation in the ability of various programs to detect important drug-drug interactions. These issues remain to be tackled.
PMCID: PMC548296  PMID: 15679896

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