Evaluating health policy and legal responses : how to reduce barriers and improve access to orphan drugs for rare diseases in Canada

Abstract : Rare diseases are debilitating conditions often leading to severe clinical manifestations for affected patients. Orphan drugs have been developed to treat these rare diseases affecting a small number of individuals. Incentives in the legal framework aimed to recoup the research and development cost of orphan drugs for pharmaceutical companies have been implemented in the United States and the European Union. At the present time, Canada is still lacking a legal and policy framework for orphan drugs. Several problems at the federal and provincial levels remain: lack of research funds for rare diseases, discrepancies on orphan drug policies between provinces, difficulties to access and reimburse these high price drugs. Recommendations and measures are proposed, such as a pan-Canadian (national) scientific committee to establish evidence-based guidelines for patients to access orphan drugs uniformly in all provinces with a disease specific registry, a formal agreement for a centralized Canadian public funding reimbursement procedure, and increasing the role of “guardian” for prices by the Patented Medicines Review Board in Canada. These recommendations and measures will be beneficial for the implementation of a policy framework for orphan drugs in Canada.

Chromatographic analysis and survey studies to evaluate the emerging drugs of synthetic cannabinoids in Scotland and Saudi Arabia

Synthetic cannabinoid receptor agonists or more commonly known as synthetic cannabinoids (SCs) were originally created to obtain the medicinal value of THC but they are an emerging social problem. SCs are mostly produced coated on herbal materials or in powder form and marketed under a variety of brand names, e.g. “Spice”, “K2”. Despite many SCs becoming controlled under drug legislation, many of them remain legal in some countries around the world. In Scotland, SCs are controlled under the Misuse of Drugs Act 1971 and Psychoactive Substances Act 2016 that only cover a few early SCs. In Saudi Arabia, even fewer are controlled. The picture of the SCs-problem in Scotland is vague due to insufficient prevalence data, particularly that using biological samples. Whilst there is evidence of increasing use of SCs throughout the world, in Saudi Arabia, there is currently no data regarding the use of products containing SCs among Saudi people. Several studies indicate that SCs may cause serious toxicity and impairment to health therefore it is important to understand the scale of use within society. A simple and sensitive method was developed for the simultaneous analysis of 10 parent SCs (JWH-018, JWH-073, JWH-250, JWH-200, AM-1248, UR-144, A-796260, AB-FUBINACA, 5F-AKB-48 and 5F-PB-22) in whole blood and 8 corresponding metabolites (JWH-018 4-OH pentyl, JWH-073 3-OH butyl, JWH-250 4-OH pentyl, AM-2201 4-OH pentyl, JWH-122 5-OH pentyl, JWH-210 5-OH pentyl, 5F-AKB-48 (N-4 OH pentyl), 5F-PB-22 3-carboxyindole)in urine using LLE and LC-MS/MS. The method was validated according to the standard practices for method validation in forensic toxicology (SWGTOX, May 2013). All analytes gave acceptable precision, linearity and recovery for analysing blood and urine samples. The method was applied to 1,496 biological samples, a mixture of whole blood and urine. Blood and/or urine samples were analysed from 114 patients presenting at Accident and Emergency in Glasgow Royal Infirmary, in spring 2014 and JuneDecember 2015. 5F-AKB-48, 5F-PB-22 and MDMB-CHMICA were detected in 9, 7 and 9 cases respectively. 904 urine samples from individuals admitted to/liberated from Scottish prisons over November 2013 were tested for the presence of SCs. 5F-AKB-48 (N-4 OH pentyl) was detected in 10 cases and 5F-PB-22 3-carboxyindole in 3 cases. Blood and urine samples from two post-mortem cases in Scotland with suspected ingestion of SCs were analysed. Both cases were confirmed positive for 5F-AKB-48. A total of 463 urine samples were collected from personnel who presented to the Security Forces Hospital in Ryiadh for workplace drug testing as a requirement for their job during July 2014. The results of the analysis found 2 samples to be positive for 5F-PB-22 3carboxyindole. A further study in Saudi Arabia using a questionnaire was carried out among 3 subpopulations: medical professionals, members of the public in and around smoking cafes and known drug users. With regards to general awareness of Spice products, 16%, 11% and 22% of those participants of medical professionals, members of the public in and around smoking cafes and known drug users, respectively, were aware of the existence of SCs or Spice products. The respondents had an overall average of 4.5% who had a friend who used these Spice products. It is clear from the results obtained in both blood and urine testing and surveys that SCs are being used in both Scotland and Saudi Arabia. The extent of their use is not clear and the data presented here is an initial look into their prevalence. Blood and urine findings suggest changing trends in SC use, moving away from JWH and AM SCs to the newer 5F-AKB-48, 5-F-PB-22 and MDMBCHMICA compounds worldwide. In both countries 5F-PB-22 was detected. These findings clarify how the SCs phenomenon is a worldwide problem and how the information of every country regarding what SCs are seized can help and is not specific for that country. The analytes included in the method were selected due to their apparent availability in both countries, however it is possible that some newer analytes have been used and these would not have been detected. For this reason it is important that methods for testing SCs are updated regularly and evolve with the ever-changing availability of these drugs worldwide. In addition, there is little published literature regarding the concentrations of these drugs found in blood and urine samples and this work goes some way towards understanding these.

Use of aromatic and medicinal plants, drugs and herbal products in Bragança city

Herbal therapy is characterized by the use of aromatic and medicinal plants (AMP) in different pharmaceutical forms for therapeutic purposes. The present study aims to characterize the use of AMP, drugs and herbal products in Bragança city. For this, a cross-sectional study was conducted through application of a questionnaire to 404 subjects of both gender and aged between 18 and 89 years. AMP were therapeutically used by 53.7% mainly due “to be natural” (43.9%) while 33.8% use drugs and/ or herbal products mainly “because it is good for health” (53.5%). The AMP most used were Cidreira (n=149) and Camomila (n=117) and concerning drugs and/ or herbal products Valdispert® (n=48) and Daflon® 500 (n=41) were the most reported. Overall, the reported uses of AMP, drugs and herbal products were correct, according to the reported in literature. The use of AMP is motivated by self-knowledge (55.4%) while drugs and/ or herbal products are used mostly by medical prescription (44.1%). AMP were obtained by own cultivation (44.1%) and drug and/ or herbal products in pharmacies (89.0%). Of all users, about 90% not combined these products with conventional drugs and it was identified just one potential occurrence of drug interactions related with the use of Hipericão. The occurrence of adverse effects was noted after the use of AMP Sene (11.8%), Hipericão (9.1%) and Ginkgo Biloba (8.3%). The use of these products is a common practice among the residents of Bragança city, which use a wide diversity of AMP and plant-based products.

Interactions between drugs and drug-nutrient in enteral nutrition: a review based on evidences

Introduction: Enteral nutrition (EN) provides calories, macronutrients and micronutrients in adequate quantity and quality to meet the patient's needs. Some drugs when crushed and diluted may have their properties altered, including the reduction of bioavailability causing the reduction of the serum concentration of the drug; tube obstruction; drug-drug interaction or drug-nutrient interaction. Methods: The study was conducted through review of submitted articles in the databases of the Virtual Health Library (VHL): MEDLINE (National Library of Medicine, USA), Lilacs (Latin American and Caribbean Literature on Health Sciences) PUBMED - NCBI (National Center for Biotechnology Information) and COCHRANE. Results: For this survey, 42 articles were identified during database searching. After applying the inclusion and exclusion criteria, 08 articles were selected, obtained from the MEDLINE and Lilacs. Discussion: Some interactions were found such as the aluminium hydroxide and lactulose with the enteral nutrition, which may result in a precipitation and reduction of drug bioavailability. Mineral oil will alter the absorption of fat-soluble vitamins and reduces the tube light. Others results were found as phenytoin, warfarin, captopril and furosemide with enteral nutrition may reduce the maximum serum concentration. Conclusion: Drug interactions are more common in day-to-day activities than health professionals may suppose. Knowledge on the matter may also assist in reducing cases of obstruction of tubes, through which enteral nutrition and medications are administered. Thus, the multidisciplinary team, acting together, may have more beneficial effects to the patient.

Application of a policy framework for the public funding of drugs for rare diseases

BACKGROUND: In many countries, decisions about the public funding of drugs are preferentially based on the results of randomized trials. For truly rare diseases, such trials are not typically available, and approaches by public payers are highly variable. In view of this, a policy framework intended to fairly evaluate these drugs was developed by the Drugs for Rare Diseases Working Group (DRDWG) at the request of the Ontario Public Drug Programs. OBJECTIVE: To report the initial experience of applying a novel evaluation framework to funding applications for drugs for rare diseases. METHODS: Retrospective observational cohort study. MEASURES: Clinical effectiveness, costs, funding recommendations, funding approval. KEY RESULTS: Between March 2008 and February 2013, eight drugs were evaluated using the DRDWG framework. The estimated average annual drug cost per patient ranged from 28,000 to 1,200,000 Canadian dollars (CAD). For five drugs, full evaluations were completed, specific funding recommendations were made by the DRDWG, and funding was approved after risk-sharing agreements with the manufacturers were negotiated. For two drugs, the disease indications were determined to be ineligible for consideration. For one drug, there was insufficient natural history data for the disease to provide a basis for recommendation. For the five drugs fully evaluated, 32 patients met the predefined eligibility criteria for funding, and five were denied based on predefined exclusion criteria. CONCLUSIONS: The framework improved transparency and consistency for evaluation and public funding of drugs for rare diseases in Ontario. The evaluation process will continue to be iteratively refined as feedback on actual versus expected clinical and economic outcomes is incorporated. © 2014 Society of General Internal Medicine.

Characterization of TRIB2-mediated resistance to anti-cancer drugs

Dissertação de Mestrado, Oncobiologia: Mecanismos Moleculares do Cancro, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2016

Inhibition of HIV cell-to-cell fusion by antiretroviral drugs and neutralizing antibodies

Poster presented at the 7th iMed.ULisboa Postgraduate Students Meeting. Lisbon, 15 July 2015

Erectile dysfunction: prevalence, risk factors and involvement of antihypertensive drugs intervention

Purpose: To explore the literature regarding prevalance, risk factors and the involvement of antihypertensive drugs in erectile dysfunction (ED). Methods: Original research articles, reviews, editorials and case reports published in English language on the prevalence of sexual/erectile dysfunction in hypertensive men taking antihypertensive drugs and risk factors were identified through a search of four bibliographic databases, namely, PubMed, EMBASE, CINAHL and EBSCO Health. Results: Recent analyses suggest that hypertensive men of almost all age groups suffer from ED but it is more prevalent in elderly male patients. The involvement of β-blockers was found to be controversial. Nevertheless, some evidence had been found regarding the use of propranolol in high doses. Conclusion: The present review indicates the need for research to unravel the role of β-blockers in the manifestation of ED in hypertensive males, whom there are no contributory factors such as sedentary lifestyle, aging, stress and anxiety, etc.

In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs

Introduction: The In vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance.