Biopharmaceutical innovation and industrial developments in South Korea, Singapore and Taiwan

South Korea, Singapore and Taiwan are well known as export-oriented developmental states which for decades employed industrial policy to target particular industries for government support. In the past fifteen years, these three countries all identified the biopharmaceutical industry as a strategic sector. This article explores, through economic analysis, the rationale for this decision and the strategies chosen for linking into the global bio-economy with the objective of catching up in biopharmaceuticals. The paper identifies three comparative advantages enjoyed by these countries in the biopharma sector: (1) public investments in basic research; (2) private investments in phase 1 clinical trials; and (3) a potentially significant contract research industry managing latter-stage clinical trials. Governments employ a range of industrial policies, consistent with these comparative advantages, to promote the biopharmaceutical industry, including public investment in biomedical hubs, research funding and research and development (R&D) tax credits. We argue that the most important feature of the biopharmaceutical industry in these countries is the dominant role of the public sector. That these countries have made progress in innovative capabilities is illustrated by input measures such as R&D expenditure as share of gross domestic product, number of patents granted and clinical trials, and volume of foreign direct investment. In contrast, output indicators such as approval of new chemical entities suggest that the process of catching up has only just commenced. Pharmaceutical innovation is at the stage of mainly generating inputs to integrated processes controlled by the globally incumbent firms.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 2 new and emerging therapies and their efficacy

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.

A phase II multicentered, single-blind, randomized, controlled trial of the stroke self-management program

Background and Purpose—The benefits of chronic disease self-management programs for stroke survivors are uncertain because individuals with severe impairments have been excluded from previous research. We undertook a phase II randomized controlled trial to determine whether a self-management program designed for survivors (SSMP; 8 weeks) was safe and feasible compared to standard care (control) or a generic self-management program (generic; 6 weeks).
Methods—Stroke survivors were recruited from 7 South Australian hospitals via a letter or indirectly (eg, newspapers). Eligible participants were randomized at a 1:1:1 ratio of 50 per group. Primary outcomes were recruitment, participation, and participant safety. Secondary outcomes were positive and active engagement in life using the Health Education Impact Questionnaire and characteristics of quality of life and mood at 6 months from program completion.
Results—Of 315 people screened, 149 were eligible and 143 were randomized (48 SSMP, 47 generic, 48 control); mean age was 69 years (SD, 11) and 59% were female. Demographic features were similar between groups and 41% had severe cognitive impairment; 57% accessed the interventions, with 52% SSMP and 38% generic completing >50% of sessions (P=0.18). Thirty-two participants reported adverse events (7 control, 12 generic, 13 SSMP; P=0.3; 34% severe); however, none was attributable to the interventions. Potential benefits for improved mood were found.
Conclusions—SSMP was safe and feasible. Benefits of the stroke-specific program over the generic program included greater participation and completion rates. An efficacy trial is warranted given the forecast growth in the stroke population and improved survival trends.

Getting your life back on track after stroke : a phase II multi-centered, single-blind, randomized, controlled trial of the Stroke Self-Management Program vs. the Stanford Chronic Condition Self-Management Program or standard care in stroke survivors

Background Self-management is seen as a primary mechanism to support the optimization of care for people with chronic diseases such as symptomatic vascular disease. There are no established and evidence-based stroke-specific chronic disease self-management programs. Our aim is to evaluate whether a stroke-specific program is safe and feasible as part of a Phase II randomized-controlled clinical trial.
Methods Stroke survivors are recruited from a variety of sources including: hospital stroke services, local paper advertisements, Stroke South Australia newsletter (volunteer peer support organization), Divisions of General Practice, and community service providers across Adelaide, South Australia. Subjects are invited to participate in a multi-center, single-blind, randomized, controlled trial. Eligible participants are randomized to either;
• standard care,
• standard care plus a six week generic chronic condition self-management group education program, or,
• standard care plus an eight week stroke specific self-management education group program.
Interventions are conducted after discharge from hospital. Participants are assessed at baseline, immediate post intervention and six months.
Study Outcomes The primary outcome measures determine study feasibility and safety, measuring, recruitment, participation, compliance and adverse events.
Secondary outcomes include:
• positive and active engagement in life measured by the Health Education Impact Questionnaire,
• improvements in quality of life measured by the Assessment of Quality of Life instrument,
• improvements in mood measured by the Irritability, Depression and Anxiety Scale,
• health resource utilization measured by a participant held diary and safety.

Conclusion The results of this study will determine whether a definitive Phase III efficacy trial is justified.

A multi-vector, multi-envelope HIV-1 vaccine

The St. Jude Children's Research Hospital (St. Jude) HIV-1 vaccine program is based on the observation that multiple, antigenically distinct HIV-1 envelope protein structures are capable of mediating HIV-1 infection. A cocktail vaccine comprising representatives of these diverse structures (immunotypes) is therefore considered necessary to elicit lymphocyte populations that prevent HIV-1 infection. This strategy is reminiscent of that used to design a currently licensed and successful 23-valent pneumococcus vaccine. Three recombinant vector systems are used for the delivery of envelope cocktails (DNA, vaccinia virus, and purified protein) and each of these has been tested individually in phase I safety trials. A fourth clinical trial, in which diverse envelopes and vectors are combined in a prime-boost vaccination regimen, has been FDA-approved and is expected to commence in 2007. This trial will continue to test the hypothesis that a multivector, multi-envelope vaccine can elicit diverse 8- and T-cell populations that can prevent HIV-1 infections in humans.

N-acetyl cysteine for depressive symptoms in bipolar disorder - a double blind, randomized, placebo-controlled trial

Background: Treatment-resistant subthreshold depression is a major problem in bipolar disorder. Both depression and bipolar disorderare complicated by glutathione depletion. We hypothesized that treatment with N-acetyl cysteine (NAC), a safe, orally bioavailable precursor of glutathione, may improve the depressive component of bipolar disorder.

Methods: A randomized, double-blind, multicenter, placebo-controlled study of individuals (n 75) with bipolar disorder in the maintenance phase treated with NAC (1 g twice daily) adjunctive to usual medication over 24 weeks, with a 4-week washout. The two primary outcomes were the Montgomery Asberg Depression Rating Scale (MADRS) and time to a mood episode. Secondary outcomes included the Bipolar Depression Rating Scale and 11 other ratings of clinical status, quality of life, and functioning.

Results: NAC treatment caused a significant improvement on the MADRS (least squares mean difference [95% confidence interval]: 8.05 [13.16, 2.95], p .002) a n d most secondary scales at end point. Benefit was evident by 8 weeks on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale and at 20 weeks on the MADRS. Improvements were lost after washout. There was no effect of NAC on time to a mood episode (log-rank test: p .968) and no significant between-group differences inadverse events. Effect sizes at end point were medium to high for improvements in MADRS and 9 of the 12 secondary readouts.

Conclusions: NAC appears a safe and effective augmentation strategy for depressive symptoms in bipolar  disorder.

Qualitative methods in early-phase drug trials : data and methods from a trial of N-acetylcysteine in schizophrenia

Objective: The pharmacokinetic profile of a drug often gives little indication of its potential therapeutic application, with many therapeutic uses of drugs being discovered serendipitously while being studied for different indications. As hypothesis-driven, quantitative research methodology is exclusively used in early-phase trials, unexpected but important phenomena may escape detection. In this context, this study aimed to examine the potential for integrating qualitative research methods with quantitative methods in early-phase drug trials. To our knowledge, this mixed methodology has not previously been applied to blinded psychopharmacologic trials.

Method: We undertook qualitative data analysis of clinical observations on the dataset of a randomized, double-blind, placebo-controlled trial of N-acetylcysteine (NAC) in patients with DSM-IV-TR–diagnosed schizophrenia (N = 140). Textual data on all participants, deliberately collected for this purpose, were coded using NVivo 2, and emergent themes were analyzed in a blinded manner in the NAC and placebo groups. The trial was conducted from November 2002 to July 2005.

Results: The principal findings of the published trial could be replicated using a qualitative methodology. In addition, significant differences between NAC- and placebo-treated participants emerged for positive and affective symptoms, which had not been captured by the rating scales utilized in the quantitative trial. Qualitative data in this study subsequently led to a positive trial of NAC in bipolar disorder.

Conclusions: The use of qualitative methods may yield broader data and has the potential to complement traditional quantitative methods and detect unexpected efficacy and safety signals, thereby maximizing the findings of early-phase clinical trial research.

Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer

Background: Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.

Patients and methods: We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m2 dose every three weeks

Results: Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6–99 weeks) and 1-year survival was 71%.

Conclusions: The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.

Do cognitive, language, or physical impairments affect participation in a trial of self-management programs for stroke?

BACKGROUND: Research studies may have limited generalizability when survivors of stroke with physical, language, or cognitive impairments are excluded. AIMS: To assess whether presence of cognitive, language, or global impairments affects participation in self-management programs.

METHODS: Stroke survivors were recruited in South Australia from seven hospitals or via advertisements into a randomized controlled trial (1:1:1 ratio) of a Stroke Self-Management Program, the Stanford chronic condition self-management program, or standard care. Impairment status was measured using: Cognistat (cognition), Frenchay Aphasia assessment (language), modified Rankin Score (mRS; where score 3-5 = global disability).

PRIMARY OUTCOMES: participation (i.e. booked, accessed, and completed a program (defined as attending ≥ 50% of sessions)) and safety (i.e. adverse events). Outcomes were compared by impairment status. RESULTS: Among 315 people screened 143/149 eligible were randomized (median age 71 years; 41% male; with impairments: 62% cognitive, 34% language, 64% global disability). Participation did not differ by cognitive or language impairment status (cognitive 75%, no cognitive 68%, p = 0.54; language 78%, no language 69%, p = 0.42). However, participation did vary by global impairment status (global disability 61%, no disability 96%, p < 0.001). Participants with cognitive impairment experienced more adverse events (severe n = 9 versus no cognitive impairment n = 1).

CONCLUSION: Survivors of stroke with cognitive, language, or global impairments are able to participate in self-management programs and should be included in these types of research studies or programs. Reduced participation by those with global disability and the possibility of more adverse events in people with cognitive impairments needs to be considered.

Safety and efficacy of routine postoperative ibuprofen for pain and disability related to ectopic bone formation after hip replacement surgery (HIPAID): a randomised control trial

Objectives To determine the benefits and risks of a non-steroidal anti-inflammatory drug (NSAID) as prophylaxis for ectopic bone formation in patients undergoing total hip replacement (or revision) surgery.
Design Double blind randomised placebo controlled clinical trial, stratified by treatment site and surgery (primary or revision).
Setting 20 orthopaedic surgery centres in Australia and New Zealand.
Participants 902 patients undergoing elective primary or revision total hip replacement surgery.
Intervention 14 days' treatment with ibuprofen (1200 mg daily) or matching placebo started within 24 hours of surgery.
Main outcome measures Changes in self reported hip pain and physical function 6 to 12 months after surgery (Western Ontario and McMaster University Arthritis index).
Results There were no significant differences between the groups for improvements in hip pain (mean difference -0.1, 95% confidence interval -0.4 to 0.2, P = 0.6) or physical function (-0.1, -0.4 to 0.2, P = 0.5), despite a decreased risk of ectopic bone formation (relative risk 0.69, 0.56 to 0.83) associated with ibuprofen. There was a significantly increased risk of major bleeding complications in the ibuprofen group during the admission period (2.09, 1.00 to 4.39).
Conclusions These data do not support the use of routine prophylaxis with NSAIDs in patients undergoing total hip replacement surgery.
Trial registration NCT00145730.

Efficacy and safety of vertebroplasty for treatment of painful osteoporotic vertebral fractures: a randomised controlled trial [ACTRN012605000079640]

Background: Vertebroplasty is a promising but as yet unproven treatment for painful osteoporotic vertebral fractures. It involves radiographic-guided injection of various types of bone cement directly into the vertebral fracture site. Uncontrolled studies and two controlled quasi-experimental before-after studies comparing volunteers who were offered treatment to those who refused it, have suggested an early benefit including rapid pain relief and improved function. Conversely, several uncontrolled studies and one of the controlled before-after studies have also suggested that vertebroplasty may increase the risk of subsequent vertebral fractures, particularly in vertebrae adjacent to treated levels or if cement leakage into the adjacent disc has occurred. As yet, there are no completed randomised controlled trials of vertebroplasty for osteoporotic vertebral fractures. The aims of this participant and outcome assessor-blinded randomised placebo-controlled trial are to i) determine the short-term efficacy and safety (3 months) of vertebroplasty for alleviating pain and improving function for painful osteoporotic vertebral fractures; and ii) determine its medium to longer-term efficacy and safety, particularly the risk of further fracture over 2 years.

Design: A double-blind randomised controlled trial of 200 participants with one or two recent painful osteoporotic vertebral fractures. Participants will be stratified by duration of symptoms (< and ≥ 6 weeks), gender and treating radiologist and randomly allocated to either the treatment or placebo. Outcomes will be assessed at baseline, 1 week, 1, 3, 6, 12 and 24 months. Outcome measures include overall, night and rest pain on 10 cm visual analogue scales, quality of life measured by the Assessment of Quality of Life, Osteoporosis Quality of Life and EQ-5D questionnaires; participant perceived recovery on a 7-point ordinal scale ranging from 'a great deal worse' to 'a great deal better'; disability measured by the Roland-Morris Disability Questionnaire; timed 'Up and Go' test; and adverse effects. The presence of new fractures will be assessed by radiographs of the thoracic and lumbar spine performed at 12 and 24 months.

Discussion: The results of this trial will be of major international importance and findings will be immediately translatable into clinical practice.

Trial registration: Australian Clinical Trial Register # [ACTRN012605000079640]

Immunostimulatory principles from Chlorella pyrenoidosa – part 1 : isolation and biological assessment in vitro

Our proprietary preparation obtained by extraction of Chlorella pyrenoidosa cells, ONC-107 (Respondin™), was recently found to selectively boost antibody response to the influenza vaccine in a human clinical trial. Respondin™ is a potent stimulator of mouse B cell proliferation and an activator of macrophages. Bioactivity-guided resolution concluded that Respondin™ is composed of a mixture of immunostimulatory principles of different chemical nature. A combination of size exclusion, anion exchange and hydrophobic interaction chromatography revealed that the bulk of the immunostimulatory activity resides in polysaccharide/protein complexes with molecular masses larger than 100 kDa that are composed primarily of galactose, rhamnose and arabinose.

Efficacy and safety of vertebroplasty for treatment of painful osteoporotic vertebral fractures : a randomised double-blind placebo-controlled trial

Background: Vertebroplasty has become a common treatment for painful osteoporotic vertebral fractures despite limited evidence to support its use. The primary aim of this study was to determine its short-term efficacy and safety in this patient population.

Methods: In a multicentre randomized placebo-controlled trial, participants with one or two painful osteoporotic vertebral fractures < 12 months duration confirmed active by MRI were randomly assigned, stratified by center, gender and duration of symptoms (< or ≥ 6 weeks), to receive vertebroplasty or sham treatment. Primary outcome was overall pain (0–10 scale) at 3 months. Participants, investigators (other than the interventional radiologist) and outcome assessors were blinded to treatment assignment.

Results: 78 participants were enrolled and 73 (36/38 active, 37/40 placebo, 94%) completed 3-month follow up. Vertebroplasty did not show any statistically significant advantage in any measured outcome with 95% confidence intervals indicating no plausible practically important benefits of vertebroplasty over placebo. At 1 week, 1 and 3 months, there were significant improvements in overall pain in both treatment groups (mean improvement (SD): 1.5 (2.5), 2.1 (2.8), 2.3 (2.6), and 1.7 (3.3), 2.5 (2.9), 1.9 (3.4) in the active and placebo groups respectively). Similar improvements in both groups were observed for night and rest pain, function, quality of life and perceived improvement. Eight incident clinical vertebral fractures (3 active, 5 placebo) occurred during 3-month follow up.

Conclusion: We found no evidence of a beneficial effect of vertebroplasty over sham treatment for painful osteoporotic vertebral fractures, 1 week, 1 and 3 months following treatment. [Australian Clinical Trial Register number, ACTRN012605000079640]

Maximising the benefits of radio frequency identification technology (RFID) integration in clinical contexts : a linear conduit

Radio Frequency Identification Technology (RFIO) has been explored for various process enhancements in clinical contexts, particularly hospitals, for asset tracking. The technology has been accepted in such environments, as it is inexpensive and, in principle, uncomplicated to integrate with other clinical support systems. It is perceived to offer many benefits to currently resource critical/strained clinical environments. This research investigation focuses on the exploitation of the potential of the technology, to enhance processes in clinical environments. In this paper, the researchers aimed to uncover if the technology, as presently deployed, has been able to achieve its potential and, in particular, if it has been fully integrated into processes in a way that maximises the benefits that were perceived. This research is part of a larger investigation that aims to develop a meta-model for integration of RFIO into processes in a form that will maximise benefits that may be achievable in clinical environments. As the first phase of the investigation, the key learning from a clinical context (hospital), which has deployed RFIO and attempted to integrate it into the processes, to enable better efficiencies, is presented in this paper. The case method has been used as a methodological framework. Two clinical contexts (hospitals) are involved in the larger project, which constitutes two phases. In Phase 1, semi structured interviews were conducted with a selected number of participants involved with the RFIO deployment project, before and after, in clinical context 1 (hereinafter named as CCl). The results were then synthesised drawing a set of key learning, from different viewpoints (implementers and users), as reported in this paper. These results outline a linear conduit for a new proposed implementation (CC2). On completion of the phase II, the researchers aim to construct a meta-model for maximising the potential of RFIO in clinical contexts. This paper is limited to the first phase that aims to draw key learning to inform the linear conduit.

Evaluation of a community pharmacy-based intervention for improving patient adherence to antihypertensives: a randomised controlled trial

Background
The majority of patients using antihypertensive medications fail to achieve their recommended target blood pressure. Poor daily adherence with medication regimens and a lack of persistence with medication use are two of the major reasons for failure to reach target blood pressure. There is no single intervention to improve adherence with antihypertensives that is consistently effective. Community pharmacists are in an ideal position to promote adherence to chronic medications. This study aims to test a specific intervention package that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications - Hypertension Adherence Program in Pharmacy (HAPPY).

Methods/Design
The HAPPY trial is a multi-centre prospective randomised controlled trial. Fifty-six pharmacies have been recruited from three Australian states. To identify potential patients, a software application (MedeMine CVD) extracted data from a community pharmacy dispensing software system (FRED Dispense®). The pharmacies have been randomised to either 'Pharmacist Care Group' (PCG) or 'Usual Care Group' (UCG). To check for 'Hawthorne effect' in the UCG, a third group of patients 'Hidden Control Group' (HCG) will be identified in the UCG pharmacies, which will be made known to the pharmacists at the end of six months. Each study group requires 182 patients. Data will be collected at baseline, three and six months in the PCG and at baseline and six months in the UCG. Changes in patient adherence and persistence at the end of six months will be measured using the self-reported Morisky score, the Tool for Adherence Behaviour Screening and medication refill data.

Discussion
To our knowledge, this is the first research testing a comprehensive package of evidence-based interventions that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications. The unique features of the HAPPY trial include the use of MedeMine CVD to identify patients who could potentially benefit from the service, control for the 'Hawthorne effect' in the UCG and the offer of the intervention package at the end of six months to patients in the UCG, a strategy that is expected to improve retention.

Trial Registration
Australian New Zealand Clinical Trial Registry ACTRN12609000705280