Norwegian Medicines Agency

BACKGROUNDPertussis remains a serious threat to young infants. In Norway, infants receive an acellular pertussis vaccine (aP) according to a 2 + 1 schedule at 3, 5 and 12 months of age, delivered as a hexavalent vaccine.AIMWe aimed to study susceptibility to pertussis in mothers and infants to guide decisions regarding vaccination in pregnancy.METHODSIn this prospective observational study, we included 366 mother/infant pairs during 2020–2023, collecting blood samples from mothers in late pregnancy, cord blood at delivery and from infants before their first and after their third vaccine dose. We retrieved health registry data on vaccination and pregnancy-related information. IgG antibody levels against pertussis-antigens, diphtheria and tetanus were measured using a multiplex immunoassay.RESULTSOf the pregnant women, 48% (174/366) had low levels of antibodies against pertussis toxin (PT) defined as below 5 IU/mL. Maternal antibodies declined in infants from birth until first vaccination, leaving 72% (154/215) of infants with anti-PT IgG levels below 5 IU/mL. All infants responded well to vaccination and we found no evidence of blunting from high levels (> 40 IU/mL) of maternal antibodies against PT. Infants of mothers who received an aP-containing booster vaccine within 2 years before pregnancy displayed low anti-PT IgG levels, with 58% (15/26) having levels below 5 IU/mL.CONCLUSIONA high proportion of pregnant women and their infants under 3 months of age had low anti-PT antibody levels, indicating high susceptibility to pertussis. The results support the introduction of vaccination against pertussis during pregnancy in Norway.

Withdrawal statement The authors have withdrawn their manuscript because the draft version contains incomplete data and includes some errors in the analysis and reported findings. Due to these inaccuracies, the results presented are unreliable and should not be cited or used. We are working to resolve the data issues and will provide an updated version when the corrections are complete. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

To support informed decision making, clear descriptions of the beneficial and harmful effects of a treatment are needed by various stakeholders. The current paradigm is to generate evidence sequentially through different experiments. However, data generated later, perhaps through observational studies, can be difficult to compare with earlier randomized trial data, resulting in confusion in understanding and interpretation of treatment effects. Moreover, the scientific questions these later experiments can serve to answer often remain vague. We propose Flexible Augmented Clinical Trial for Improved eVidence gEneration (FACTIVE), a new class of study designs enabling flexible augmentation of confirmatory randomized controlled trials with concurrent and close-to-real-world elements. Our starting point is to use clearly defined objectives for evidence generation, which are formulated through early discussion with health technology assessment (HTA) bodies and are additional to regulatory requirements for authorization of a new treatment. These enabling designs facilitate estimation of certain well-defined treatment effects in the confirmatory part and other complementary treatment effects in a concurrent real-world part. Each stakeholder should use the evidence that is relevant within their own decision-making framework. High quality data are generated under one single protocol and the use of randomization ensures rigorous statistical inference and interpretation within and between the different parts of the experiment. Evidence for the decision making of HTA bodies could be available earlier than is currently the case.

Model-informed drug development (MIDD) approaches receive wide regulatory acceptance in the European Medicines Agency (EMA) to support new drug development. For generic drugs, the European regulators have not reached a common position on how to use these methods. This commentary expands on the existing EMA regulatory framework for bioequivalence and physiological based pharmacokinetic (PBPK) modeling to propose conditions where mechanistic models could support or potentially waive clinical bioequivalence (BE)/bioavailability (BA) studies.

Akershus Castle is one of Norway's most important historical monuments and is listed with the highest grade of protection. The earlier medieval castle from around the year 1300 is an arena for the Norwegian state and in use for such as government dinners and receptions. The castle is also an important tourist destination and is used for public events like concerts, etc. Until today, people in wheelchair have had to be carried into the buildings due to stairs and differences in levels inside. In the autumn of 2021 five measures that make large parts of the castle accessible, were completed. Making public buildings accessible has high priority in Norway. Having achieved this at Akershus Castle is of great symbolic value. During the process of defining the projects extent and measures the method values-based conservation was applied. This was done through involving several stakeholders in assessing and quantifying an array of values and criteria. On this basis it was possible to define the project, achieve the permits from the heritage authorities and get acceptance from the organisations representing people with disabilities. The result has been very well received by the public, stakeholders and by the cultural heritage authorities.

BackgroundBack pain is an extensive burden to our healthcare system, yet few studies have explored modifiable prognostic factors associated with high costs related to healthcare utilization, especially among older back pain patients. The aims of this study were to identify modifiable prognostic factors for high costs related to healthcare utilization among older people seeking primary care with a new episode of back pain; and to replicate the identified associations in a similar cohort, in a different country.MethodsData from two cohort studies within the BACE consortium were used, including 452 and 675 people aged ≥55 years seeking primary care with a new episode of back pain. High costs were defined as costs in the top 25th percentile. Healthcare utilization was self-reported, aggregated for one-year of follow-up and included: primary care consultations, medications, examinations, hospitalization, rehabilitation stay and operations. Costs were estimated based on unit costs collected from national pricelists. Nine potential modifiable prognostic factors were selected based on previous literature. Univariable and multivariable binary logistic regression models were used to identify and replicate associations (crude and adjusted for selected covariates) between each modifiable prognostic factor and high costs related to healthcare utilization.ResultsFour modifiable prognostic factors associated with high costs related to healthcare utilization were identified and replicated: a higher degree of pain severity, disability, depression, and a lower degree of physical health-related quality of life. Kinesiophobia and recovery expectations showed no prognostic value. There were inconsistent results across the two cohorts with regards to comorbidity, radiating pain below the knee and mental health-related quality of life.ConclusionThe factors identified in this study may be future targets for intervention with the potential to reduce high costs related to healthcare utilization among older back pain patients.Trial registrationClinicalTrials.gov NCT04261309, 07 February 2020. Retrospectively registered.

The Norwegian department of agriculture decided to re-evaluate the Regulation No. 951 of 4 July 2003 on fertilizers and soil improvers of organic origin. The Norwegian Food Safety Authority (NFSA) requested VKM for a statement on the use of manure from farms where grey water and human waste (sewage) is disposed of directly to the farm manure cellar.
 Consideration was given to differences in risk according to the types of domestic wastewater, the species of animal from which the manure derived, the extent and type of sanitary facilities, the crops to which the amended manure is applied, and the effects of storage on infection risk.
 According to current legislation, sewage sludge cannot be spread on land where vegetables, potatoes, berries or fruit are grown. Furthermore, sewage cannot be spread on meadows or used for horticultural purposes. In private gardens, parks, playgrounds and similar residential areas, sewage may be used only as a component in a fertiliser, and not applied at the surface. Use of sewage as a fertilizer for the cultivation of grains is permitted. Sewage can also be used when establishing vegetation along roads and embankments.
 VKM concludes that manure cellars, to which wastewater, from private household use, and sewage from toilets in the outbuildings are drained, may contain pathogens from humans, in addition to those pathogens originating from animals. The quantity and species of pathogens in this sewage-amended manure would reflect the species and prevalence of pathogens in the population using the facilities. Although the prevalence of intestinal pathogens in the Norwegian human population is relatively low, it should be noted that farms in Norway often provide tourist accommodation, camping facilities, and may house migrant short-term employees during the summer season during which labour requirements are increased. Thus non-Norwegian populations may also use toilet facilities on these farms, and thus when considering the risk of human pathogens, consideration should also be given to people from countries where the prevalence of such pathogens may be higher.
 As many viruses and parasites are host-specific, the risk of contamination of produce with human pathogens from such manure is likely to be greater than from manure which has not been amended with untreated sewage.
 Pathogen survival is affected by storage, but it should be noted that some pathogens have robust and environmentally resistant transmission stages (e.g. parasite oocysts, cysts and eggs), a proportion of which may survive for prolonged periods in stored manure.

In the light of the recent findings of the tapeworm Echinococcus multilocularis (EM) in four red foxes from three different locations in Sweden, the Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen; VKM), Panel of Biological Hazards (Faggruppe hygiene og smittestoffer) took the initiative to undertake a risk assessment regarding the probability of this parasite being introduced to mainland Norway and thus becoming a threat to public health in the country.
 EM is a small tapeworm that resides in the intestine of carnivores (e.g. foxes, dogs) that function as final hosts for the adult tapeworm. The infection here gives few or no symptoms. Adult tapeworms produce eggs that are released in the faeces of the carnivores and may be ingested by mammals, usually rodents or lagomorphs1, which act as intermediate hosts. In the intermediate hosts, the larval form of the tapeworm produces cysts, predominantly in the liver, where they proliferate and may invade the surrounding tissues. If the infected intermediate host is eaten by a susceptible final host, the adult tapeworm develops in the intestine and the lifecycle is completed.
 EM is of public health significance as humans may act as accidental intermediate hosts if they ingest eggs, either through contaminated foods or water, or from contact with infected final hosts (dogs, foxes) or their faeces. In untreated patients the disease is often fatal (10 year survival rate of 29 %), and in treated patients the 10 year survival rate is 80 %. The anthelmintic treatment is long-term (for several years, possibly life-long) and expensive. Liver transplantation may be required.
 Conclusions: Based on the fact that EM is endemic in many European countries, that the incidence in endemic countries is increasing, and that the areas of endemicity are expanding it seems likely that EM will be imported into Norway at some point, perhaps within the next 10 years.
 Given the high numbers of pets crossing the border between Sweden and Norway and the paucity of checks regarding compliance with treatment legislation, this seems to be a likely route of entry of EM to Norway, should this occur. Introduction of checks may reduce this likelihood.
 Under the current monitoring conditions, VKM find it less likely that EM will be detected upon the first introduction to Norway. EM will probably only be detected once the prevalence in foxes is greater than 1%. The red fox population size is estimated to be between 70 000 to 120 000 animals. This means between 700 to 1200 red foxes would need to be infected before EM infection is likely to be detected under the current monitoring program. If EM is identified early enough after introduction, then it might be possible to avoid the establishment of EM in Norway and/or to limit the region of endemicity. This is dependent on optimal detection techniques and sufficient monitoring.
 VKM considers that it is unlikely that EM will be imported to Norway via contaminated produce (berries, fruits and mushrooms).
 Norway’s strong ‘outdoor’ culture, in which hunting, camping, berry-picking and other outdoor activities play a significant role, may place the Norwegian population at greater likelihood of contracting EM than populations in other European countries. However, it should be noted that even in countries with endemic EM, human echinococcosis is, apparently, relatively rare.