Health technology assessment of drugs for rare diseases: insights, trends, and reasons for negative recommendations from the CADTH common drug review.

BACKGROUND: A shift in biochemical research towards drugs for rare diseases has created new challenges for the pharmaceutical industry, government regulators, health technology assessment agencies, and public and private payers. In this article, we aim to comprehensively review, characterize, identify possible trends, and explore reasons for negative reimbursement recommendations in submissions made to the Common Drug Review (CDR) for drugs for rare diseases (DRD) at the Canadian Agency for Drugs and Technologies in Health (CADTH), a publicly funded pan-Canadian health technology assessment agency. A public database (cadth.ca) was screened to identify DRD submissions to CDR. A diseases prevalence of ≤50 per 100,000 people was considered a rare disease. We calculated descriptive statistics for prevalence, study design, study size, treatment cost, reimbursement recommendation types, and reasons for negative reimbursement recommendations. RESULTS: From 2004 to 2015, 63 of 434 submissions to the CDR were for DRD (range: 1 submission in 2005 to 10 submissions in 2013). Most (74.6%) submissions included at least one double-blind randomized controlled trial (RCT). The average study size was 190 patients (range: 20 to 742). The average annual treatment cost was C$215,631 (range: $9,706 to $940,084). Reimbursement recommendations were positive for 54% of the submissions. Negative reimbursement recommendations were made due to a lack of clinical effectiveness (38.5%), insufficient evidence (30.8%), multiple reasons (23.1%), or lack of cost effectiveness/high cost (7.7%). CONCLUSION: The number of DRD submissions to CDR increased since 2013; from 4 to 5 per year between 2004 and 2012, to 10, 9, and 8 in 2013, 2014, and 2015 respectively. More than half of DRD submissions received positive reimbursement recommendation. Poor quality evidence and/or lack of supportive clinical evidence was at least partly responsible for a negative reimbursement recommendation in all cases. Although the average cost of DRD treatments was high, high cost was a reason for a negative reimbursement recommendation in only two (7.7%) of negative reimbursement recommendations.

Choice of therapy in patients with type 2 diabetes inadequately controlled with metformin and a sulphonylurea: a systematic review and mixed-treatment comparison meta-analysis.

BACKGROUND: Metformin and a sulphonylurea are often used in combination for the treatment of type 2 diabetes mellitus. We conducted a systematic review and meta-analysis to evaluate the comparative safety and efficacy of all available classes of antihyperglycemic therapies in patients with type 2 diabetes inadequately controlled with metformin and sulphonylurea combination therapy. METHODS: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS Previews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published in English from 1980 to November 2009. Additional citations were obtained from the grey literature and conference proceedings and through stakeholder feedback. Two reviewers independently selected the studies, extracted the data and assessed risk of bias. Key outcomes of interest were hemoglobin A1c, body weight, hypoglycemia, patients' satisfaction with treatment, quality of life, long-term diabetes-related complications, withdrawals due to adverse events, serious adverse events and mortality. Mixed-treatment comparison meta-analyses were conducted to calculate mean differences between drug classes for changes in hemoglobin A1c and body weight. When appropriate, pairwise meta-analyses were used to estimate differences for other outcomes. RESULTS: We identified 33 randomized controlled trials meeting the inclusion criteria. The methodologic quality of the studies was generally poor. Insulins (basal, biphasic, bolus), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues and thiazolidinediones (TZDs) all produced statistically significant reductions in hemoglobin A1c in combination with metformin and a sulphonylurea (-0.89% to -1.17%), whereas meglitinides and alpha-glucosidase inhibitors did not. Biphasic insulin, bolus insulin, and TZDs were associated with weight gain (1.85-5.00 kg), whereas DPP-4 inhibitors and alpha-glucosidase inhibitors were weight-neutral, and GLP-1 analogues were associated with modest weight loss. Treatment regimens containing insulin were associated with increased hypoglycemia relative to comparators, but severe hypoglycemia was rare across all treatments. INTERPRETATION: Third-line agents for the treatment of type 2 diabetes are similar in terms of glycemic control but differ in their propensity to cause weight gain and hypoglycemia. Longer-term studies with larger sample sizes are required to determine if any of the drug classes are superior with regard to reducing diabetes-related complications.

Second-line therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a systematic review and mixed-treatment comparison meta-analysis.

BACKGROUND: Although there is general agreement that metformin should be used as first-line pharmacotherapy in patients with type 2 diabetes, uncertainty remains regarding the choice of second-line therapy once metformin is no longer effective. We conducted a systematic review and meta-analysis to assess the comparative safety and efficacy of all available classes of antihyperglycemic therapies in patients with type 2 diabetes inadequately controlled on metformin monotherapy. METHODS: MEDLINE, EMBASE, BIOSIS Previews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published in English from 1980 to October 2009. Additional citations were obtained from grey literature and conference proceedings and through stakeholder feedback. Two reviewers independently selected studies, extracted data and assessed risk of bias. Key outcomes of interest were hemoglobin A1c, body weight, hypoglycemia, quality of life, long-term diabetes-related complications, serious adverse drug events and mortality. Mixed-treatment comparison and pairwise meta-analyses were conducted to pool trial results, when appropriate. RESULTS: We identified 49 active and non-active controlled randomized trials that compared 2 or more of the following classes of antihyperglycemic agents and weight-loss agents: sulfonylureas, meglitinides, thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, insulins, alpha-glucosidase inhibitors, sibutramine and orlistat. All classes of second-line antihyperglycemic therapies achieved clinically meaningful reductions in hemoglobin A1c (0.6% to 1.0%). No significant differences were found between classes. Insulins and insulin secretagogues were associated with significantly more events of overall hypoglycemia than the other agents, but severe hypoglycemia was rarely observed. An increase in body weight was observed with the majority of second-line therapies (1.8 to 3.0 kg), the exceptions being DPP-4 inhibitors, alpha-glucosidase inhibitors and GLP-1 analogues (0.6 to -1.8 kg). There were insufficient data available for diabetes complications, mortality or quality of life. INTERPRETATION: DPP-4 inhibitors and GLP-1 analogues achieved improvements in glycemic control similar to those of other second-line therapies, although they may have modest benefits in terms of weight gain and overall hypoglycemia. Further long-term trials of adequate power are required to determine whether newer drug classes differ from older agents in terms of clinically meaningful outcomes.

Efficacy of self-monitoring of blood glucose in patients with type 2 diabetes mellitus managed without insulin: a systematic review and meta-analysis.

BACKGROUND: Self-monitoring of blood glucose levels is commonly performed by patients with diabetes mellitus. However, there is debate surrounding the clinical utility and cost-effectiveness of this practice among patients with type 2 diabetes managed without insulin. We conducted a systematic review and meta-analysis to determine the effect of self-monitoring versus no self-monitoring, and the optimal frequency of self-monitoring, in this population. METHODS: MEDLINE, EMBASE, BIOSIS Previews, CINAHL and PsycINFO were searched for randomized controlled trials (RCTs) and observational studies published in English from January 1990 to March 2009. Additional citations were obtained through searches of the Internet and conference proceedings, and from stakeholder feedback. Two reviewers independently selected studies, extracted data and performed an assessment of the methodologic quality of the studies. Key outcomes of interest were hemoglobin A1c (HbA(1c)) concentration, hypoglycemia, quality of life, long-term complications of diabetes and death. Where appropriate, we pooled data using random-effects meta-analysis. RESULTS: We identified 1624 citations through the literature search and selected 25 articles for inclusion. We observed a statistically significant improvement in the HbA(1c) concentration across RCTs that compared self-monitoring of blood glucose levels with no self-monitoring among patients taking oral antidiabetes drug therapy (weighted mean difference --0.25%, 95% confidence interval -0.36% to -0.15%). Subgroup analysis indicated that results from RCTs that provided patients with education on how to interpret and apply self-monitoring test results were similar to those from RCTs that did not. On the basis of limited evidence, self-monitoring of blood glucose levels did not demonstrate consistent benefits in terms of quality of life, patient satisfaction, prevention of hypoglycemia or long-term complications of diabetes, or reduction of mortality. There was insufficient evidence pertaining to the optimal frequency of self-monitoring. INTERPRETATION: Self-monitoring of blood glucose levels was associated with a modest, statistically significant reduction in hemoglobin A1c concentrations, regardless of whether patients were provided with education on how to interpret and use the test results. Further studies are required to determine whether self-monitoring reduces the risk of long-term complications of diabetes and to identify patients most likely to benefit from self-monitoring.

Phosphoethanolamine is located at the 6-position and not at the 7-position of the distal heptose residue in the lipopolysaccharide from Neisseria meningitidis.

Previous studies on LPS from Neisseria meningitidis strains M992B, the immunotype L6 strain, NMB, the type strain, a candidate LPS vaccine strain 6275z, and an extensively used clinical strain M986 had suggested that the location of the phosphoethanolamine (PEtn) residue was the 7-position of the distal heptose residue (HepII) of the inner-core oligosaccharide (OS). In all cases, this was only established by chemical methods, methylation linkage analyses. In this study, we have used standard NMR techniques to unequivocally show that the PEtn residue is actually located at the 6-position and not at the 7-position of the HepII residue in all of these strains. The 6-PEtn transferase genes were sequenced and their translated amino acid sequences were shown to be greater than 96% identical to that of the Lpt6 transferase from the L4 immunotype strain, which has been shown to transfer PEtn to the 6-position of the distal heptose residue. We discuss the implications of these findings with respect to the immunotyping scheme for the meningococci and in the context of LPS-based vaccine development.