Inhibition of interleukin 6 (IL-6) signalling has been proposed as a potential cardioprotective strategy for patients with chronic kidney disease (CKD) but the direct renal effects of IL-6 inhibition are not established. A Mendelian randomization (MR) study was performed to investigate the association of genetically proxied inhibition of IL-6 signalling with estimated glomerular filtration rate (eGFR), CKD and blood urea nitrogen (BUN). Inverse variance weighted MR was used as the main analysis, with sensitivity analyses performed using simple median, weighted median and MR-Egger methods. There was no evidence for an association of genetically proxied inhibition of IL-6 signalling (scaled per unit decrease in natural log transformed C-reactive protein) with log eGFR (0.002, 95% confidence interval -0.004 – 0.008), BUN (0.088, 95% confidence interval -0.003 – 0.019) and CKD (odds ratio 1.018, 95% confidence interval 0.899 – 1.153). These findings suggest that inhibition of IL-6 signalling is unlikely to have a direct effect on renal function.

Routinely collected data has been increasingly used to evaluate and monitor long-term opioid therapy (LTOT) patterns, with very little guidance on how to measure LTOT from these data sources. We conducted a systematic review of studies published between Jan 2000 and Jul 2019 to catalogue LTOT definitions, the rationale for definitions, and LTOT rates in observational research using routinely collected data in non-surgical settings. We screened 4,056 abstracts, 209 full-text manuscripts and included 126 studies; mostly from the US (82%) and published between 2015 and 2019 (68%). We identified 78 definitions of LTOT, commonly operationalised as 90 days of use within a year (21%). Studies often used multiple criteria to derive definitions (63%), mostly based on measures of duration, such as supply days/days of use (67%), episode length (21%), or prescription fills within specified time periods (9%). Definitions were based on previous publications (63%), clinical judgment (17%), or empirical data (3%); 10% of studies applied more than one definition. LTOT definition was not provided with enough details for replication in 14 studies and 37 studies did not specify the opioids evaluated. Rates of LTOT ranged from 0.2% to 57% according to study design, population and definition used. We observed a substantial rise in studies evaluating LTOT with large variability in the definitions used and poor reporting of the rationale and implementation of the definitions. This variation impacts on research reproducibility, comparability of findings and the development of strategies aiming to curb therapy that is not guideline-recommended.

Introduction: Chagas disease (CD) is a worldwide problem, with over 8 million people infected in both rural and urban areas. CD was first described over a century ago, but only two drugs are currently available for CD treatment, benznidazole (BZN) and nifurtimox (NF). Treating CD infected patients, especially children and women of reproductive age, is vital in order to prevent long term sequelae such as heart and gastrointestinal disfunction, but this aim is still far from being accomplished. Currently, the strongest data to support benefit-risk considerations come from trials in children. Finally, treatment response biomarkers need further development as serology is being questioned as the best method to assess treatment response. Areas covered: This article is a narrative review on the pharmacology of drugs for CD, particularly BZN and NF. Data on drug biopharmaceutical characteristics, safety and efficacy of both drugs are summarized from a clinical perspective. Current data on alternative compounds under evaluation for CD treatment, and new possible treatment response biomarkers are also discussed. Conclusion: Early diagnosis and treatment of CD, especially in pediatric patients, is vital for an effective and safe use of the available drugs (i.e. BZN and NF). New biomarkers for CD are urgently needed for the diagnosis and evaluation of treatment efficacy, and to guide efforts from academia and pharmaceutical companies to accelerate the process of new drugs development.

Aim To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single subcutaneous (s.c.) dose using a conventional needle. Methods In this single-centre double-blind, placebo-controlled, double-dummy clinical trial in 24 healthy adults we compared 40 mg adalimumab (0.4 mL) administered i.d. using a hollow microneedle with a s.c. dose using a conventional needle. Primary parameters were pain, acceptability, and local tolerability; secondary parameters safety, pharmacokinetics and immunogenicity. We explored usability of optical coherence tomography (OCT), clinical photography, thermal imaging, and laser speckle contrast imaging (LSCI) to evaluate skin reaction after i.d. injections. In vitro protein analysis was performed to assess compatibility of adalimumab with the hollow microneedle device. Results While feasible and safe, injection pain of i.d. adalimumab was higher compared to s.c. adalimumab (35.4 vs. 7.9 on a 101-point VAS scale). Initial absorption rate and bioavailability were higher after i.d. adalimumab (Tmax=95h(47-120); F=129%(6.46%)) compared to s.c. adalimumab (Tmax=120h(96-221)). In 50% and 83% of the subjects anti-adalimumab antibodies were detected after i.d. and s.c. adalimumab, respectively. We observed statistically significantly more erythema and skin perfusion after i.d. adalimumab, compared to s.c. adalimumab and placebo injections (p<0.0001). Cytokine secretion after whole blood LPS challenge was comparable between administration routes. Conclusion Intradermal of adalimumab using hollowing microneedles was perceived as more painful, and less accepted than s.c. administration, however, yields a higher bioavailability with similar safety and pharmacodynamic effects.

Comment on “The changing face of paracetamol toxicity and new regimens for an old antidote acetylcysteine”Dear Editor,We have with interest read the recently published commentary by Isbister and Chiew1 in which current approaches for the treatment of paracetamol (PCM) poisoning with N-acetylcysteine (NAC) were described. While we appreciate the authors’ valuable comments on the challenges in managing this common poisoning, we noticed the omission of the Danish NAC regimen.NAC has been established as a highly efficient antidote in preventing PCM-induced hepatotoxicity when administered within 8 h of PCM ingestion.2 Treatment delays because of pending laboratory results do not harmfully affect the outcome if NAC is administered within 8 h. However, it is frequent occurring that patients get treated beyond that time in e.g. the UK,3 thus potentially decreasing the efficacy of NAC.In Denmark a 20-hour two-bag regime has been used for more than seven years.4 All patients suspected of poisoning with more than 6 g PCM are treated with NAC without risk stratification according to a nomogram. Patients deliberately poisoning themselves with PCM may not report reliable information of the time of ingestion and dose of PCM. If a nomogram is used without an accurate time of ingestion, the estimation of the risk of hepatotoxicity is unreliable. It is well documented that patients have been withheld treatment with NAC due to misinterpretation of the nomogram resulting in hepatotoxicity.5Concomitant overdosing of several drugs that delay the time to peak PCM concentration is common and may result in crossing from below to above the treatment line5 leaving line crossers who required treatment untreated. The same is relevant in cases of massive PCM overdosing alone (drug bezoar) or poisonings with extended-release PCM formulations (late PCM peak).6 Furthermore, it is well-known that the half-life of PCM in liver injury exceeds the expected 4 h used for treatment decision in the nomogram, thus further questioning the reliability of the nomogram as a risk stratification tool for patients suffering from liver diseases. Although the Danish regime further reduces the risk of hepatoxicity, because of incorrectly withheld or delayed NAC treatment compared to other regimes based on a nomogram, it comes at a cost of more patients being treated.We believe that all approaches deserve mention in order to identify the most effective and safe approach to this poisoning. Therefore, we should consider the effectiveness, duration and safety of choice of treatment including the incidence of anaphylactoid reactions to NAC while assuring that nobody is wrongly withhold NAC treatment. Not to mention, that the abovementioned approach is associated with a comparable incidence of anaphylactoid reactions when compared to other approaches.4,7 It is worth mentioning that the primary factor limiting a faster delivery of the antidote is the development of anaphylactoid reactions. It is to be shown if pre-administrations of antihistamines can reduce the dose-dependent side-effect leading to development of faster NAC regimes7.We declare no competing interests.Alaa Daoud (orcid: 0000-0002-8714-4028)a,b, Kim Peder Dalhoffa,b, Tonny Studsgaard Petersen (orcid: 0000-0002-9974-2738)a,baDepartment of Clinical Medicine, Faculty of Health and Medical science, Copenhagen University, Copenhagen, DenmarkbDepartment of Clinical Pharmacology and The Danish Poison Information Centre, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark*Correspondence to Alaa Daoud, Alaa.Ahmed.Daoud@regionh.dk1. Isbister GK, Chiew A. The changing face of paracetamol toxicity and new regimens for an old antidote acetylcysteine. British Journal of Clinical Pharmacology . n/a(n/a). doi:10.1111/bcp.144952. Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. Br Med J . 1979;2(6198):1097-1100. doi:10.1136/bmj.2.6198.10973. The College of Emergency Medicine. Paracetamol Overdose Clinical Audit 2013-14. Accessed September 7, 2020. https://www.rcem.ac.uk/docs/Previous%20Audits/CEM8120-Paracetamol%20Overdose%20national%20report.pdf4. Daoud A, Dalhoff KP, Christensen MB, Bøgevig S, Petersen TS. Two-bag intravenous N-acetylcysteine, antihistamine pretreatment and high plasma paracetamol levels are associated with a lower incidence of anaphylactoid reactions to N-acetylcysteine. Clinical Toxicology . 2020;58(7):698-704. doi:10.1080/15563650.2019.16758865. Mutsaers A, Green JP, Sivilotti MLA, et al. Changing nomogram risk zone classification with serial testing after acute acetaminophen overdose: a retrospective database analysis. Clinical Toxicology . 2019;57(6):380-386. doi:10.1080/15563650.2018.15293206. Bizovi KE, Aks SE, Paloucek F, Gross R, Keys N, Rivas J. Late Increase in Acetaminophen Concentration After Overdose of Tylenol Extended Relief. Annals of Emergency Medicine . 1996;28(5):549-551. doi:10.1016/S0196-0644(96)70119-17. Mullins ME, Yu M, O’Grady L, Khan S, Schwarz ES. Adverse reactions in patients treated with the one-bag method of N-acetylcysteine for acetaminophen ingestion. Toxicology Communications . 2020;4(1):49-54. doi:10.1080/24734306.2020.1770498

Health and specifically Medication Literacy is important in patient empowerment and in empowering patients and families as effective partners in ensuring optimal health outcomes. While there has is a reasonable body of evidence on this for adults, there has been very little work on medication literacy for children, specifically in terms of effective interventions. Adopting agreed upon nomenclature and developing and validating children's specific instruments -- such as infographics - will be important in moving forward, especially when these instruments can be actively incorporated into eHealth initiatives.

Introduction Irrational medicine use is proportionately higher in low and middle-income countries like Sierra Leone. This study aims at exploring the structure, functions, and challenges of Drug, and Therapeutics Committees (DTC) recently piloted in Sierra Leone. Method A two-phase mixed-method study design was used in this study. Firstly, a cross-sectional survey using an online questionnaire to assess the structure, indicators, and challenges of DTC . In phase two, a semi-structured interview was used to get deeper insights into the key issues that emerged from the survey. Participants were mainly pharmacists in-charge at the hospitals where the DTC program hasbeen established. MS Excel 2019 and NVivo version 12 were respectively used for data management and analysis. Results DTCs mostly had a minimum of ten members consisting of a mix of both medical and hospital administrative staff. The main functions of DTC are ensuring rational medicines use, monitoring, and reporting adverse drug reactions. All but one hospital had subcommittees that are either effective or nonfunctional. The main challenges in DTC functions and maintenance were funding (n=6), DTC decision implementation (n=4), and unmotivated members (n=4). Strategies suggested to improve DTC at public hospitals and nationwide include; resource allocation, monitoring, and evaluating DTC functions and capacity building of its members. Conclusion DTC present a compelling opportunity towards achieving rational medicines use at the hospital level in Sierra Leone. Nonetheless, lack of funding, operational resources, are significant limitations. Policymakers must note these drawbacks whilst expanding DTC programs to other hospitals in Sierra Leone.

Aim Patients on anti-tuberculosis (anti-TB) therapy are at risk of drug-induced liver injury (DILI). MicroRNA-122 (miR-122) and cytokeratin-18 (K18) are exploratory DILI biomarkers. To explore their utility in this global context, circulating miR-122 and K18 concentrations were measured in UK and Ugandan populations on anti-TB therapy for mycobacterial infection. Methods European patients receiving anti-TB therapy were recruited at the Royal Infirmary of Edinburgh, UK (ALISTER-ClinicalTrials.gov Identifier: NCT03211208). African patients with HIV-TB coinfection, receiving anti-TB and anti-retroviral therapy (ART), were recruited at the Infectious Diseases Institute, Kampala, Uganda (SAEFRIF-NCT03982277). Serial blood samples, demographic and clinical data were collected. MiR-122 was quantified using PCR. K18 was quantified using the M65 ELISA. Results The study had 235 participants (healthy volunteers (n=28); ALISTER: active TB (n=30), latent TB (n=88), non-tuberculous mycobacterial infection (n=25); SAEFRIF: HIV-TB coinfection (n=64)). In the absence of DILI, there was no difference in miR-122 and K18 across the groups. Both miR-122 and K18 correlated with alanine transaminase activity (ALT) (miR-122: r=0.52, 95%CI=0.42-0.61, P<0.0001. K18: r=0.42, 95%CI=0.34-0.49, P<0.0001). There were two DILI cases: baseline ALT was 18 and 28 IU/L, peak ALT 431 and 194 IU/L; baseline K18 58 and 219 U/L, peak K18 1247 and 3490 U/L; baseline miR-122 4 and 17 fM, peak miR-122 60 and 336 fM, respectively. Conclusion In European and African patients treated with anti-TB therapy miR-122 and K18 correlated with ALT and increased with DILI. Further work should determine the diagnostic and prognostic utility of miR-122 and K18 in this global context-of-use.

Aims: Hypophosphatemia is an increasingly recognized side-effect of ferric carboxymaltose (FCM) and possibly iron isomaltoside/ferric derisomaltose (IIM), which are used to treat iron deficiency. To determine frequency, severity, duration and risk factors of incident hypophosphatemia after treatment with FCM and IIM. Methods: A systematic literature search for articles indexed in EMBASE, PubMed and Web of Science in years 2005 to 2020 was carried out using the search terms ‘ferric carboxymaltose’ OR ‘iron isomaltoside’. Prospective clinical trials reporting outcomes on hypophosphatemia rate, mean nadir serum phosphate and/or change in mean serum phosphate from baseline were selected. Hypophosphatemia rate and severity were compared for studies on IIM vs. FCM after stratification for chronic kidney disease. Meta-regression analysis was used to investigate risk factors for hypophosphatemia. Results: Across the 42 clinical trials included in the meta-analysis, FCM induced a significantly higher incidence of hypophosphatemia than IIM (47%, 95% CI 36-58% vs. 4%, 95% CI 2-5%), and significantly greater mean decreases in serum phosphate (0.40 versus 0.06 mmol/L). Hypophosphatemia persisted at the end of the study periods (maximum 3 months) in up to 45% of patients treated with FCM. Meta-regression analysis identified low baseline serum ferritin and transferrin saturation, and normal kidney function as significant predictors of hypophosphatemia. Conclusion: FCM is associated with a high risk of hypophosphatemia, which does not resolve for at least 3 months in a large proportion of affected patients. More severe iron deficiency and normal kidney function are risk factors for hypophosphatemia.

The development of specific drug therapy for children was a paradigm changing event that transformed paediatric medical practice. However a series of tragedies involving drug treatment for children resulted in a gap developing between drug regulation and practice, with the majority of drugs used in child health care being used “off label” rendering children therapeutic orphans. Over the past two decades changes in drug regulation led by the US FDA and followed by the European Union’s EMA have led to substantial changes in how new drugs with potential use in children are studied and labelled. While these changes have substantially improved labeling for new drugs, there has been much less progress with older drugs. As well while the unique challenges of conducting clinical research in children have been addressed by novel clinical trial designs, many of these innovations have not been translated into approaches accepted for the drug approval process. The regulations applying to the need for paediatric studies currently are only applicable in the United States and the European Union, and there is less impetus for paediatric labeling in other jurisdictions. This impacts on a number of issues beyond labeling, including the availability of child-friendly formulations. Finally the impact of Brexit on paediatric drug studies in the UK remains unclear and subject to on-going negotiations between the UK government and the European Union.

Timely intravenous (IV) to oral antimicrobial switch (IV-oral-switch) is a key antimicrobial stewardship (AMS) strategy. A retrospective audit was undertaken to determine concordance with IV-oral-switch guidelines in the context of a long-standing, tightly regulated AMS program. Data from 107 general medical and surgical patients in an Australian hospital were analysed. Median duration of IV antimicrobial courses before switching to oral therapy was 3 days (interquartile range, 2.25-5.00). Timely IV-oral-switch occurred in 57% (n=61) of patients. The median delay to switching was 0 days (IQR 0 to 1.25). In most courses (92/106, 86.8%), the choice of oral alternative after switching was appropriate. In 45% (47/105) of courses, total duration of therapy (IV plus oral) exceeded the recommended duration by >1.0 day. Excessive IV antimicrobial duration was uncommon at a hospital with a tightly regulated AMS program. Total duration of therapy was identified as an AMS target for improvement.

AIM: We propose the use of in silico mathematical models to provide insights that optimize therapeutic interventions designed to eradicate respiratory infection during a pandemic. A modelling and simulation framework is provided using SARS-CoV-2 as an example, considering applications of both treatment and prophylaxis. METHODS: A target cell-limited model was used to quantify the viral infection dynamics of SARS-CoV-2 in a pooled population of 105 infected patients. Parameter estimates from the resulting model were used to simulate and compare the impact of various interventions against meaningful viral load endpoints. RESULTS: Robust parameter estimates were obtained for the basic reproduction number, viral release rate and infected-cell mortality from the infection model. These estimates were informed by the largest dataset currently available for SARS-CoV-2 viral time course. The utility of this model was demonstrated using simulations, which hypothetically introduced inhibitory or stimulatory drug mechanisms at various target sites within the viral life-cycle. We show that early intervention is crucial to achieving therapeutic benefit when monotherapy is administered. In contrast, combination regimens of two or three drugs may provide improved outcomes if treatment is initiated late. The latter is relevant to SARS-CoV-2, where the period between infection and symptom onset is relatively long. CONCLUSIONS: The use of in silico models can provide viral load predictions that can rationalize therapeutic strategies against an emerging viral pathogen.

Aims: Emodepside is an anthelmintic, originally developed for veterinary use. We investigated the safety, pharmacokinetics, relative bioavailability and dose linearity of four oral formulations of emodepside in healthy male subjects. Methods: Three randomised, parallel‐group, controlled, Phase I studies were conducted using various oral formulations, involving 79 subjects in ten cohorts in the single-ascending-dose study, 24 subjects in three ascending-dose cohorts in the multiple-ascending-dose study and 77 subjects in seven different cohorts in the relative bioavailability study. Pharmacokinetics and safety assessments were performed up to 21, 30 and 7 days, respectively. Results: As a liquid service formulation, emodepside was rapidly absorbed under fasting conditions, with dose-proportional increases in plasma concentrations at doses from 1 mg to 40 mg. The half-life during the first 24 hours after dosing was around 11 hours, followed by a terminal elimination half-life > 500 hours. Emodepside was less bioavailable in the fed state. The rate of absorption was slower and Cmax was lower with the amorphous solid dispersion tablets compared to the liquid service formulation. Emodepside was well tolerated overall with no major safety concerns. Conclusion: These Phase I studies with various dosage forms revealed a pharmacokinetic profile suggesting good tissue distribution of emodepside and a long terminal half‐life. A 15 mg dose with the gastrosoluble tablet is predicted to provide exposure that will achieve the target concentration for clinical efficacy. These data enabled us to select a field-adapted tablet formulation that will open the way for further clinical development of emodepside in individuals with onchocerchiasis.

Dose selection and optimization is an important topic in drug development to maximize treatment benefits for all patients. While exposure-response (E-R) analysis is a useful method to inform dose-selection strategy, in oncology, special considerations for prognostic factors are needed due to their potential to confound the E-R analysis for monoclonal antibodies. The current review focuses on three different approaches to mitigate the confounding effects for monoclonal antibodies in oncology: (1) cox-proportional hazards modeling and case-matching, (2) tumor growth inhibition-overall survival (TGI-OS) modeling, and (3) multiple dose level study design. In the presence of confounding effects, studying multiple dose levels may be required to reveal the true E-R relationship. However, it is impractical for pivotal trials in oncology drug development programs. Therefore, the strengths and weaknesses of the other two approaches are considered, and the favorable utility of TGI-OS modeling to address confounding in E-R analyses is described. In the broader scope of oncology drug development, this review discusses the downfall of the current emphasis on E-R analyses using data from single dose level trials, and proposes that development programs be designed to study more dose levels in earlier trials.

Objective Polypharmacy is common in people with diabetes and associated with the use of potentially inappropriate medication (PIM). This study aimed to assess trends in prevalence of polypharmacy and PIM in older and middle-aged people with diabetes. Methods A repeated cross-sectional study using the University Groningen IADB.nl prescription database was conducted. All people ≥45 years treated for diabetes registered in the period 2012-2016 were included. PIMs were assessed using Beers criteria for people ≥65 years old, and PRescribing Optimally in Middle-aged People’s Treatments (PROMPT) criteria for 45-64 years old. Chi-square tests and regression analysis were applied. Results The prevalence of polypharmacy increased from 56.5% to 58.2% during the study period. In 2016, the prevalence of polypharmacy was 36.9% in the group of 45-54 years old, 50.3% in 55-64 years old, and 66.2% in ≥65 years old. All age-groups showed significant increases. The prevalence of older people with at least one PIM decreased around 3%, while in the middle-aged group this prevalence increased around 1% with a highest level in 2015. The most common PIMs in both age groups were the use of long-term high-dose proton-pump-inhibitors, benzodiazepines, and strong opioids without laxatives. Of those, only benzodiazepines showed a decreasing trend. Conclusions Polypharmacy increased in older and middle-aged people with diabetes. While the prevalence of PIM decreased over time in older age, this trend was not observed in middle-aged people with diabetes. Efforts are needed to decrease the use of PIMs in populations already burdened with many drugs, notably at middle age

Aim. Repurposing strategies to address the COVID-19 pandemic have been accelerated. As both pregnant and pediatric patients are likely to be excluded from most planned investigations, the list of repurposed options and the available data on these drugs and vaccines provides a baseline risk assessment and identifies gaps for targeted investigation. Methods. Clinical trials have been searched and reviewed; twenty-three repurposed drugs and drug combinations and 9 candidate vaccines have been assessed regarding the availability of relevant data in pediatrics and pregnant women and to evaluate expected or unanticipated risk. Results. Thirteen of the repurposed drugs or drug combinations are indicated for use in pediatrics in some age category albeit for indications other than COVID-19; 10 of these are indicated for use in pregnant women. Even in cases where these drugs are indicated in the populations, source data from which safety and or dosing could be extrapolated for use in COVID-19 is sparse. Vaccine trials are ongoing and generally exclude pregnant women; only in a few instances have pediatric subgroups been planned for enrollment. Data from individual case studies and RWD may suggest that subpopulations of both pediatric patients and pregnant women may be more at risk, particularly those in an increased inflammatory state. Conclusion. In conjunction with more prospective collaboration, plans are evolving to ensure that we will be better prepared to address similar situations especially in pediatrics and pregnant women where experience is limited and actual practice relies heavily on leveraging data from other populations and indications.

Patients in sub-Saharan Africa generally have poor anticoagulation control. We review the potential reasons for this poor control, as well as the potential solutions. Challenges include the affordability and centralisation of anticoagulation care, problems with access to medicines and INR monitoring, the lack of locally-validated standardized dosing protocols, and low levels of anticoagulation knowledge among health care workers and patients. Increasing numbers of patients will need anticoagulation in the future because of the epidemiological transition in the region. We propose that locally-developed “warfarin care bundles” which address multiple anticoagulation challenges in combination may be the most appropriate solution in this setting currently.

Haemophilia A and B are rare bleeding disorders. Over the past decades, they have been transformed from debilitating diseases to manageable conditions. However, several challenges and unmet needs remain in the treatment of the haemophilia limiting the QoL of the patients. These challenges are now being addressed by EHL recombinant factors, rebalancing and substitution therapies. Gene therapy and genome editing show promise for a definite clinical cure. Herein, we provide an overview of new therapeutic opportunities for haemophilia and their advances and limitations. The database on human medicines from EMA was used and data from rare disease (orphan) designations and EPARs were retrieved for the analysis. Clinical Trial databases were used to query all active studies on haemophilia. Gene therapy medicinal products based on AAV and lentiviral vectors are in development and clinical trials have reported substantial success in ameliorating bleeding tendency in haemophilia patients. The prospect of gene editing for correction of the underlying mutation is on the horizon with considerable potential. We are entering an era of innovation and abundance in treatment options for those affected by bleeding disorders but issues still remain about the affordability and accessibility to patients, the long-term durability, safety and efficacy.