Development of multi-criteria decision analysis (MCDA) framework for off-patent pharmaceuticals – an application on improving tender decision making in Indonesia

Background

Off-patent pharmaceuticals (OPPs) hold vital importance in meeting public health objectives, especially in developing countries where resources are limited. OPPs are comprised of off-patent originals, branded generics and unbranded generics; nonetheless, these products are not identical and often there are differences in their equivalence, manufacturing quality standards and reliability of supply. This necessitates reconsideration of the lowest price policy objective in pharmaceutical decision making. The aim of this study was to develop a Multi-Criteria Decision Analysis (MCDA) framework through a pilot workshop to inform the national procurement of OPPs in Indonesia.

Methods

An initial list of potentially relevant criteria was identified based on previous work and a literature review. In a 2-day pilot policy workshop, twenty local experts representing different stakeholder groups and decision-making bodies selected the final criteria, approved the scoring function for each criterion, and assigned weights to each criterion.

Results

An MCDA framework was proposed for OPP drug decision making in developing countries, which included price and 8 non-price criteria. Based on the pilot policy workshop 6?+?1 criteria were considered relevant for Indonesia: pharmaceutical price (40% weight), manufacturing quality (18.8%), equivalence with the reference product (12.2%), product stability and drug formulation (12.2%), reliability of drug supply (8.4%), real world clinical or economic outcomes, such as adherence or non-drug costs (4.2%) and pharmacovigilance (3.6%).

Conclusions

According to the pilot policy workshop, other criteria apart from price need to be strengthened in the tendering process. The introduction of additional criteria for OPP procurement in an MCDA framework creates incentives for manufacturers to invest into improved manufacturing standards, equivalence proof, product quality, reliability of supply or even additional real-world data collection, which ultimately may result in more health gain for the society.

     

Density and morphology of corneal endothelial cell after phacoemulsification using ringer lactate versus balanced salt solution as irrigating solutions

AIM: To compare the difference in corneal endothelial cell density and morphology after phacoemulsification using ringer lactate (RL) and balanced salt solution (BSS) irrigating solutions. METHODS: The prospective randomized controlled trial study was conducted between February 2017 and April 2017 in Dr. YAP Eye Hospital, Yogyakarta, Indonesia. There were a total of 52 subjects (52 eyes) who were senile cataract patients further grouped into two, 26 patients undergoing the phacoemulsification procedure using RL irrigating solution and the other 26 patients with BSS irrigating solution, both conducted by one operator. On the 1, 7, and 28d post operative, an evaluation was done to measure the density and corneal endothelial cell morphology, as well as the variable of inflammation in the two groups. RESULTS: Fifty-two eyes had undergone phacoemulsification with posterior intraocular lens implantation. Both groups were evaluated for the endothelial cell reduction and corneal endothelial cell morphology change, along with postoperative inflammation. On the 28d postoperative, endothelial cell reduction in the BSS group (173.96 cell/mm2, 8.12%) was lower than the RL group (253.20 cell/mm2, 10.25%), percentage of corneal endothelial cell variation coefficient increase in the BSS group (2.92%, 8.36%) was lower compared to the RL group (3.42%, 9.96%), decrease of hexagonal cells of corneal endothelium cells presentation percentage in the BSS group (4.30%, 8.17%) was lower compared to the RL group (4.84%, 8.97%), and the percentage increase of central corneal thickness in the BSS group (4.69 μm, 0.89%) was almost equal to the RL group (4.53 μm, 0.90%). All of the results regarding difference in density and corneal cell endothelium morphology between the two groups did not reveal any statistically significant difference (P>0.05). Inflammatory variable in the two groups were even. CONCLUSION: BSS and RL were equal in their capability of maintaining endothelial cell loss and endothelial cell morphologic change in senile cataract patients after phacoemulsification.     

Differences in pain and inflammation between Diclofenac 0.1% and Nepafenac 0.1% after cataract surgery

AIM: To compare pain level and inflammation between preoperative topical Diclofenac 0.1% and Nepafenac 0.1% in patients undergoing cataract surgery. METHODS: This research was designed as prospective randomized clinical trial and conducted in June to August 2017 at Dr. Yap Eye Hospital. There were 56 subjects underwent phacoemulsification operation (single operator) and diagnosed as senile cataract and no adverse events were found. Subjects were divided into 2 groups according to preoperative eye drop medication, namely Diclofenac group and Nepafenac group. Participants and phaco-surgeon were blind regarding to the treatment. Inflammation parameters (at 1, 7 and 14d follow up) such as pain, conjunctiva hyperemic, blepharospasm, flare and cell in anterior chamber level as the primary outcome, whereas density and morphology of corneal endothelial cells as the secondary outcome. RESULTS: There were no statistically difference in conjunctiva hyperemic and blepharospasm level between 2 groups at 1d (P=0.284, effect size=0.29, 95%CI=-0.09 to 0.31; P=0.254, effect size=0.31, 95%CI=-0.13 to 0.49, respectively) and 7d (P=1.000 and P=0.556, effect size=0.18, 95%CI=-0.08 to 0.16, respectively) postoperatively. The pain scores (during surgery, 1d and 14d postoperative) in Nepafenac group was statistically lower than Diclofenac group (P=0.006, effect size=0.77, 95%CI=0.24 to 1.34; P=0.045, effect size=0.39, 95%CI=-0.10 to 0.62; and P=0.014, effect size=0.69, 95%CI=-0.06 to 0.50, respectively). The degree of flare and cell in Nepafenac group was lower at the 1d after phacoemulsification (P=0.029, effect size=0.59, 95%CI=0.02 to 0.36). Reduction of corneal endothelial density between 2 groups was not statistically significant, however the reduction of hexagonal cell percentage at 7d after phacoemulsification was lower than Nepafenac group (P=0.042, effect size=-0.55, 95%CI=-2.33 to -0.03). CONCLUSION: The pain and flare-cell levels in Nepafenac group are lower when compared with Diclofenac group.     

Role of p53 in irinotecan-induced intestinal cell death and mucosal damage

Irinotecan treatment of colorectal cancers results in high-grade intestinal mucositis in a large proportion of patients. The mechanisms behind irinotecan-induced mucosal injury, however, have yet to be fully explained. The aim of this study was to investigate the role of the p53 protein in the onset of intestinal damage following irinotecan treatment in two different settings. IEC-6 and FHs 74 intestinal cell lines were treated with irinotecan with and without a temporary p53 inhibitor, pifithrin-alpha, and examined for changes in proliferation and survival along with expression of p53 and related proteins. Forty tumour-bearing rats also underwent irinotecan treatment with and without pifithrin-alpha, and the effects on intestinal morphology, gene expression, apoptosis and other toxicities were assessed. Irinotecan caused a dose-dependent reduction in cell viability that was not prevented by pifithrin-alpha in either cell line. Rats responded to irinotecan with diarrhoea, weight loss, histopathological changes to the small and large intestine, increased crypt apoptosis, and a mild inflammatory response. Pifithrin-alpha reduced severity and duration of intestinal apoptosis; however, it did not significantly affect other parameters including p53 expression. Temporary inhibition of p53 activation does not markedly prevent intestinal cell death or mucositis following irinotecan treatment. Irinotecan may act through upregulation of proapoptotic proteins Bax and Bak to induce cell death.     

A comparison of valsartan and captopril in patients with essential hypertension in Indonesia

Adult Indonesian outpatients were randomised to receive either valsartan 80 mg once daily or captopril 25 mg twice daily for 8 weeks. The main criterion for tolerability was the incidence of adverse events. The primary efficacy variable was the change in mean sitting diastolic blood pressure (SDBP) from baseline to endpoint. No valsartan patients experienced dry cough, which was reported by 22 captopril patients (21.6%). Both drugs reduced mean SDBP and SSBP, with a trend in favour of valsartan. The percentage of valsartan patients whose BP normalised was higher than in captopril patients at week 4 (37% and 22%) and week 8 (45% and 34%), the difference being statistically significant at week 4 (p < 0.05). Valsartan 80 mg once daily is as effective as captopril 25 mg twice daily in reducing blood pressure in Indonesian patients, and has a better tolerability profile in respect of dry cough.     

Is the Glycoprotein Responsible for the Differences in Dispersal Rates between Lettuce Necrotic Yellows Virus Subgroups?

Lettuce necrotic yellows virus is a type of species in the Cytorhabdovirus genus and appears to be endemic to Australia and Aotearoa New Zealand (NZ). The population of lettuce necrotic yellows virus (LNYV) is made up of two subgroups, SI and SII. Previous studies demonstrated that SII appears to be outcompeting SI and suggested that SII may have greater vector transmission efficiency and/or higher replication rate in its host plant or insect vector. Rhabdovirus glycoproteins are important for virus–insect interactions. Here, we present an analysis of LNYV glycoprotein sequences to identify key features and variations that may cause SII to interact with its aphid vector with greater efficiency than SI. Phylogenetic analysis of glycoprotein sequences from NZ isolates confirmed the existence of two subgroups within the NZ LNYV population, while predicted 3D structures revealed the LNYV glycoproteins have domain architectures similar to Vesicular Stomatitis Virus (VSV). Importantly, changing amino acids at positions 244 and 247 of the post-fusion form of the LNYV glycoprotein altered the predicted structure of Domain III, glycosylation at N248 and the overall stability of the protein. These data support the glycoprotein as having a role in the population differences of LNYV observed between Australia and New Zealand.     

Therapeutic vaccines for tuberculosis—A systematic review

For eradication of tuberculosis (TB) by 2050, the declared aim of the Stop TB Partnership, novel treatment strategies are indispensable. The emerging epidemic of multi-drug resistant (MDR) TB has fuelled the debate about TB vaccines, as increasing numbers of patients can no longer be cured by pharmacotherapy. Of several proposed modalities, TB vaccines administered in therapeutic manner represents a promising alternative, despite the controversial history due to the occurrence of exacerbated immune response. A modified concept of immunotherapy is required in order to justify further exploration. In this paper we systematically reviewed the most advanced therapeutic vaccines for TB. We address the rationale of immunotherapeutic vaccination combined with optimized pharmacotherapy in active TB. We summarize preclinical and patient data regarding the five most advanced therapeutic vaccines currently in the pipeline. Of the five products that have been tested in animal models and in humans during active or latent TB, the quality of the published clinical reports of two of these products justify further studies in patients with active TB. This systematic review fuels further clinical evaluation eventually including head-to-head comparative studies.     

Meta‐analysis: Association between hepatitis B virus preS mutation and hepatocellular carcinoma risk

Previous observational studies suggested that hepatitis B virus (HBV) preS mutation plays an important role in the existence of HBV‐related hepatocellular carcinoma (HCC). However, the results are still debatable. With an increasing number of studies about this topic, this study employed a meta‐analysis to identify the association between HBV preS mutation and HCC risk. We searched for eligible studies from PubMed, ProQuest, CINAHL, ScienceDirect and Springer databases to assess the association between HBV mutation and HCC risk. This meta‐analysis was conducted using RevMan 5.3 to provide pooled estimate for odds ratio (ORs) with 95% confidence intervals (95% CIs). Twenty‐one clinical studies were included in this meta‐analysis study which consisted of 1738 participants with HBV‐related HCC and 3740 HBsAg‐positive patients without HCC. All studies used samples of Asian population. PreS deletion was the most common mutation found in all studies. We found that ORs of HBV overall preS deletion was associated with HCC (OR = 3.28; 95% CI = 2.32‐4.65; P < .00001; random‐effects model). Each preS1 and preS2 deletion was associated with increased risk of HCC, with OR 2.42 (95% CI = 1.25‐4.68, P = .008) and 3.36 (95% CI = 2.04‐5.55, P < .00001), respectively. PreS2 start codon mutation was also significantly associated with HCC risk (OR = 2.47; 95% CI: 1.15‐5.27; P = .02; random‐effect model). The result of this meta‐analysis suggested that HBV preS deletion (all, preS1 and preS2) and preS2 start codon mutation might contribute to the increased risk of HBV‐related HCC.