A survey of cost, access and outcomes for cannabinoid-based medicinal product use by Australians with endometriosis.

People with endometriosis use cannabis to manage their symptoms. This study aimed to identify costs, modes of administration, product composition, and self-reported effectiveness for those accessing medicinal cannabis in Australia. There were 192 survey responses analysed. Most (63.5%) used a 'cannabis clinic' doctor, incurring an initial consultation cost of $100-$200+ (10.2% Medicare bulk-billed) and median cannabinoid medicine costs of $300AUD per month. Cost was a major barrier to access, necessitating reducing dosage (76.1%) and/or consuming illicit cannabis (42.9%), despite a prescription. Most (77%) medical consumers used two or more cannabis products, with delta-9-tetrahydrocannabinol predominant oil and flower products most frequently prescribed.

Marketing Regulatory Oversight of Advanced Therapy Medicinal Products in Europe.

Advanced therapy medicinal products (ATMP) in the European Union (EU) are regulated by Regulation 1394/2007 and comprise gene and cell therapy and tissue-engineered products. Under this framework, ATMP are authorised by the centralised procedure, coordinated by the European Medicines Agency (EMA), whereas clinical trial authorisations remain at the remit of each National Competent Authority. The Committee for Advanced Therapies is responsible for the scientific evaluation of the marketing authorisation applications and for generating a draft opinion that goes to the Committee for Human Medicinal Products for a final opinion. For every application, data and information relating to manufacturing processes and quality control of the active substance and final product have to be submitted for assessment together with data from non-clinical and clinical safety and efficacy studies. Technical requirements for ATMP are defined in the legislation, and guidance for different products is available through several EMA/CAT guidelines.Due to the diverse and complex nature of ATMP, a need for some regulatory flexibility was recognised. Thus, a risk-based approach was introduced in Regulation 1394/2007 allowing adapted regulatory requirements. This has led, for instance, to the development of good manufacturing practice (GMP) guidelines specific for ATMP. This, together with enhanced regulatory support, has allowed an increasing number of successful marketing authorisation applications resulting in 25 licensed ATMP in the EU, mainly gene therapy medicinal products. The promise of messenger RNA and genome editing technologies as therapeutic tools make the future for these innovative medicinal products look even brighter.This chapter reviews the regulatory landscape together with some of the support initiatives developed for ATMP in the EU.

Outcome evaluation of capacity building and mentorship partnership (CBMP) program on data quality in the public health facilities of Amhara National Regional State, Ethiopia: a quasi-experimental evaluation.

BACKGROUND: Capacity Building and Mentorship Partnership (CBMP) is a flagship program designed by the Ethiopian Ministry of Health in collaboration with six local universities to strengthen the national health information system and facilitate evidence-informed decision making through various initiatives. The program was initiated in 2018. This evaluation was aimed to assess the outcome of CBMP on health data quality in the public health facilities of Amhara National Regional State, Ethiopia. METHODS: A matched comparison group evaluation design with a sequential explanatory mixed-method was used to evaluate the outcome of CBMP on data quality. A total of 23 health facilities from the intervention group and 17 comparison health facilities from a randomly selected district were used for this evaluation. The Organization for Economic Cooperation and Development (OECD) evaluation framework with relevance, effectiveness, and impact dimensions was used to measure the program's outcome using the judgment parameter. The program's average treatment effect on data quality was estimated using propensity score matching (PSM). RESULTS: The overall outcome of CBMP was found to be 90.75 %. The mean data quality in the intervention health facility was 89.06 % [95 %CI: 84.23, 93.88], which has a significant mean difference with the comparison health facilities (66.5 % [95 % CI: 57.9-75]). In addition, the CBMP increases the data quality of pilot facilities by 27.75 % points [95 %CI: 17.94, 37.58] on the nearest neighboring matching. The qualitative data also noted that there was a data quality problem in the health facility and CBMP improved the data quality gap among the intervention health facilities. CONCLUSIONS: The outcome of the CBMP was highly satisfactory. The program effectively increased the data quality in the health facilities. Therefore, the finding of this evaluation can be used by policymakers, program implementers, and funding organizations to scale the program at large to improve the overall health data quality for health outcome improvement.

Regulation of Clinical Trials with Advanced Therapy Medicinal Products in Germany.

In the European Union, clinical trials for Advanced Therapy Medicinal Products are regulated at the national level, in contrast to the situation for a Marketing Authorisation Application, in which a centralised procedure is foreseen for these medicinal products. Although based on a common understanding regarding the regulatory requirement to be fulfilled before conduct of a clinical trial with an Advanced Therapy Investigational Medicinal Product, the procedures and partly the scientific requirements for approval of a clinical trial application differ between the European Union Member States. This chapter will thus give an overview about the path to be followed for a clinical trial application and the subsequent approval process for an Advanced Therapy Investigational Medicinal Product in Germany and will describe the role of the stakeholders that are involved. In addition, important aspects of manufacturing, quality control and non-clinical testing of Advanced Therapy Medicinal Products in the clinical development phase are discussed. Finally, current and future approaches for harmonisation of clinical trial authorisation between European Union Member States are summarised.

[Strategic considerations on the design and choice of animal models for non-clinical investigations of cell-based medicinal products]. / Strategische Betrachtungen zur Konzeption und Wahl von Tiermodellen bei nicht-klinischen Prüfungen von zellbasierten Therapeutika.

For the development of medicinal products animal models are still indispensable to demonstrate efficacy and safety prior to first use in humans. Advanced therapy medicinal products (ATMP), which include cell-based medicinal products (CBMP), differ in their pharmacology and toxicology compared to conventional pharmaceuticals, and thus, require an adapted regime for non-clinical development. Developers are, therefore, challenged to develop particular individual concepts and to reconcile these with regulatory agencies. Guidelines issued by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA) and other sources can provide direction.The published approaches for non-clinical testing of efficacy document that homologous animal models where the therapeutic effect is investigated in a disease-relevant animal model utilizing cells derived from the same species are commonly used. The challenge is that the selected model should reflect the human disease in all critical features and that the cells should be comparable to the investigated human medicinal product in terms of quality and biological activity. This is not achievable in all cases. In these cases, alternative methods may provide supplemental information. To demonstrate the scientific proof-of-concept (PoC), small animal models such as mice or rats are preferred. During the subsequent product development phase, large animal models (i.e. sheep, minipigs, dogs) must be considered, as they may better reflect the anatomical or physiological situation in humans. In addition to efficacy, those models may also be suitable to prove some safety aspects of ATMP (e.g. regarding dose finding, local tolerance, or undesired interactions and effects of the administered cells in the target tissue). In contrast, for evaluation of the two prominent endpoints for characterizing the safety of ATMP (i.e. biodistribution, tumorigenicity) heterologous small animal models, especially immunodeficient mouse strains, are favourable due to their tolerance to the human cell therapy product. The execution of non-clinical studies under the principles of good laboratory practice (GLP) increases the acceptance of the results by authorities and the scientific community.

[Safety monitoring of cell-based medicinal products (CBMPs)]. / Überwachung der Sicherheit von Zelltherapeutika (CBMPs).

Cell-based medicinal products (CBMPs), a category of advanced-therapy medicinal products (ATMPs), are authorised for the European market by the European Commission by means of the centralized marketing authorisation. By conforming to the German Medicinal Products Act (Sec. 4b AMG), national authorisation can be granted by the Paul-Ehrlich-Institut in Germany exclusively for ATMPs not based on a routine manufacturing procedure. In both procedures, quality, efficacy, and safety are evaluated and the risk-benefit balance is assessed. For the centralised procedure, mainly controlled clinical trial data must be submitted, whereas the requirements for national procedures could be modified corresponding to the stage of development of the ATMP. After marketing authorization, the marketing authorization/license holder is obligated to report all serious adverse reactions to the competent authority and to provide periodic safety update reports. If necessary, post-authorization safety studies could be imposed. On the basis of these regulatory measures, the safety of advanced therapies can be monitored and improved.

Cannabis-Based Medicinal Products in the Management of Emotionally Unstable Personality Disorder (EUPD): A Narrative Review and Case Series.

Emotionally unstable personality disorder (EUPD) is a common mental health disorder, manifesting with a range of chronic and debilitating symptoms, including impaired social functioning, unstable mood, and risky impulsive or self-injurious behaviour. Whilst the exact aetiology has not been fully elucidated, implicated factors seem to include genetic factors, environmental causes such as trauma, and neurotransmitter deficits. The literature suggests that impaired functioning of the endocannabinoid system in key brain regions responsible for emotional processing and stress response may underlie the manifestation of EUPD symptoms. The National Institute for Health and Care Excellence (NICE) 2009 guidelines state that "no drugs have established efficacy in treating or managing EUPD", and yet, patients are commonly prescribed medication which includes antipsychotics, antidepressants, and mood stabilisers. Here we present a case series of seven participants diagnosed with EUPD and treated with cannabis-based medicinal products (CBMPs). Participants were given an initial assessment and followed up one month after CBMPs prescription. Improvement in symptoms was assessed by the completion of ratified rating scales by the participant and psychiatrist. Our results indicate that CBMPs were effective and well tolerated, as six participants reported a noticeable improvement in their symptoms and functioning. Although promising, further research is needed to ascertain the long-term tolerability, efficacy, and dosing strategy for CBMPs in EUPD.

A Multicriteria Decision Analysis Comparing Pharmacotherapy for Chronic Neuropathic Pain, Including Cannabinoids and Cannabis-Based Medical Products.

Background: Pharmacological management of chronic neuropathic pain (CNP) still represents a major clinical challenge. Collective harnessing of both the scientific evidence base and clinical experience (of clinicians and patients) can play a key role in informing treatment pathways and contribute to the debate on specific treatments (e.g., cannabinoids). A group of expert clinicians (pain specialists and psychiatrists), scientists, and patient representatives convened to assess the relative benefit-safety balance of 12 pharmacological treatments, including orally administered cannabinoids/cannabis-based medicinal products, for the treatment of CNP in adults. Methods: A decision conference provided the process of creating a multicriteria decision analysis (MCDA) model, in which the group collectively scored the drugs on 17 effect criteria relevant to benefits and safety and then weighted the criteria for their clinical relevance. Findings: Cannabis-based medicinal products consisting of tetrahydrocannabinol/cannabidiol (THC/CBD), in a 1:1 ratio, achieved the highest overall score, 79 (out of 100), followed by CBD dominant at 75, then THC dominant at 72. Duloxetine and the gabapentinoids scored in the 60s, amitriptyline, tramadol, and ibuprofen in the 50s, methadone and oxycodone in the 40s, and morphine and fentanyl in the 30s. Sensitivity analyses showed that even if the pain reduction and quality-of-life scores for THC/CBD and THC are halved, their benefit-safety balances remain better than those of the noncannabinoid drugs. Interpretation: The benefit-safety profiles for cannabinoids were higher than for other commonly used medications for CNP largely because they contribute more to quality of life and have a more favorable side effect profile. The results also reflect the shortcomings of alternative pharmacological treatments with respect to safety and mitigation of neuropathic pain symptoms. Further high-quality clinical trials and systematic comprehensive capture of clinical experience with cannabinoids is warranted. These results demonstrate once again the complexity and multimodal mechanisms underlying the clinical experience and impact of chronic pain.

The Effectiveness of the Capacity Building and Mentorship Program in Improving Evidence-Based Decision-making in the Amhara Region, Northwest Ethiopia: Difference-in-Differences Study.

BACKGROUND: Weak health information systems (HISs) hobble countries' abilities to effectively manage and distribute their resources to match the burden of disease. The Capacity Building and Mentorship Program (CBMP) was implemented in select districts of the Amhara region of Ethiopia to improve HIS performance; however, evidence about the effectiveness of the intervention was meager. OBJECTIVE: This study aimed to determine the effectiveness of routine health information use for evidence-based decision-making among health facility and department heads in the Amhara region, Northwest Ethiopia. METHODS: The study was conducted in 10 districts of the Amhara region: five were in the intervention group and five were in the comparison group. We employed a quasi-experimental study design in the form of a pretest-posttest comparison group. Data were collected from June to July 2020 from the heads of departments and facilities in 36 intervention and 43 comparison facilities. The sample size was calculated using the double population formula, and we recruited 172 participants from each group. We applied a difference-in-differences analysis approach to determine the effectiveness of the intervention. Heterogeneity of program effect among subgroups was assessed using a triple differences method (ie, difference-in-difference-in-differences [DIDID] method). Thus, the ß coefficients, 95% CIs, and P values were calculated for each parameter, and we determined that the program was effective if the interaction term was significant at P<.05. RESULTS: Data were collected using the endpoint survey from 155 out of 172 (90.1%) participants in the intervention group and 166 out of 172 (96.5%) participants in the comparison group. The average level of information use for the comparison group was 37.3% (95% CI 31.1%-43.6%) at baseline and 43.7% (95% CI 37.9%-49.5%) at study endpoint. The average level of information use for the intervention group was 52.2% (95% CI 46.2%-58.3%) at baseline and 75.8% (95% CI 71.6%-80.0%) at study endpoint. The study indicated that the net program change over time was 17% (95% CI 5%-28%; P=.003). The subgroup analysis also indicated that location showed significant program effect heterogeneity, with a DIDID estimate equal to 0.16 (95% CI 0.026-0.29; P=.02). However, sex, age, educational level, salary, and experience did not show significant heterogeneity in program effect, with DIDID estimates of 0.046 (95% CI -0.089 to 0.182), -0.002 (95% CI -0.015 to 0.009), -0.055 (95% CI -0.190 to 0.079), -1.63 (95% CI -5.22 to 1.95), and -0.006 (95% CI -0.017 to 0.005), respectively. CONCLUSIONS: The CBMP was effective at enhancing the capacity of study participants in using the routine HIS for decision-making. We noted that urban facilities had benefited more than their counterparts. The intervention has been shown to produce positive outcomes and should be scaled up to be used in other districts. Moreover, the mentorship modalities for rural facilities should be redesigned to maximize the benefits. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR202001559723931; https://tinyurl.com/3j7e5ka5.

Developing a circumpolar programme for the monitoring of Arctic terrestrial biodiversity.

The Arctic is undergoing biological and environmental changes, and a coordinated effort to monitor is critical to detect these changes. The Circumpolar Biodiversity Monitoring Programme (CBMP) of the Arctic Council biodiversity working group, Conservation of Arctic Flora and Fauna (CAFF), has developed pan-Arctic biodiversity monitoring plans that aims to improve the ability to detect and report on long-term changes. Whilst introducing this special issue, this paper also presents the making of the terrestrial monitoring plan and discusses how the plan follows the steps required for an adaptive and ecosystem-based monitoring programme. In this article, we discuss how data on key findings can be used to inform circumpolar and global assessments, including the State of the Arctic Terrestrial Biodiversity Report, which will be the first terrestrial assessment made by the CBMP. Key findings, advice for future monitoring and lessons learned will be used in planning next steps of pan-Arctic coordinated monitoring.

Arctic terrestrial biodiversity status and trends: A synopsis of science supporting the CBMP State of Arctic Terrestrial Biodiversity Report.

This review provides a synopsis of the main findings of individual papers in the special issue Terrestrial Biodiversity in a Rapidly Changing Arctic. The special issue was developed to inform the State of the Arctic Terrestrial Biodiversity Report developed by the Circumpolar Biodiversity Monitoring Program (CBMP) of the Conservation of Arctic Flora and Fauna (CAFF), Arctic Council working group. Salient points about the status and trends of Arctic biodiversity and biodiversity monitoring are organized by taxonomic groups: (1) vegetation, (2) invertebrates, (3) mammals, and (4) birds. This is followed by a discussion about commonalities across the collection of papers, for example, that heterogeneity was a predominant pattern of change particularly when assessing global trends for Arctic terrestrial biodiversity. Finally, the need for a comprehensive, integrated, ecosystem-based monitoring program, coupled with targeted research projects deciphering causal patterns, is discussed.

Status and trends of circumpolar peregrine falcon and gyrfalcon populations.

The peregrine falcon (Falco peregrinus) and the gyrfalcon (Falco rusticolus) are top avian predators of Arctic ecosystems. Although existing monitoring efforts are well established for both species, collaboration of activities among Arctic scientists actively involved in research of large falcons in the Nearctic and Palearctic has been poorly coordinated. Here we provide the first overview of Arctic falcon monitoring sites, present trends for long-term occupancy and productivity, and summarize information describing abundance, distribution, phenology, and health of the two species. We summarize data for 24 falcon monitoring sites across the Arctic, and identify gaps in coverage for eastern Russia, the Arctic Archipelago of Canada, and East Greenland. Our results indicate that peregrine falcon and gyrfalcon populations are generally stable, and assuming that these patterns hold beyond the temporal and spatial extents of the monitoring sites, it is reasonable to suggest that breeding populations at broader scales are similarly stable. We have highlighted several challenges that preclude direct comparisons of Focal Ecosystem Components (FEC) attributes among monitoring sites, and we acknowledge that methodological problems cannot be corrected retrospectively, but could be accounted for in future monitoring. Despite these drawbacks, ample opportunity exists to establish a coordinated monitoring program for Arctic-nesting raptor species that supports CBMP goals.