Kliininen näyttö korkean riskiluokan lääkinnällisille laitteille Euroopan näkökulmasta : systemaattinen kirjallisuuskatsaus

Kansallinen lainsäädäntö, mikä perustuu EU direktiiviin 93/42, on säädellyt korkean riskiluokan lääkinnällisiä laitteita Euroopassa aina näihin päiviin asti. Se edellyttää, että markkinoille päästäkseen laitteen tulee olla turvallinen, käyttötarkoitukseensa sopiva ja suorituskyvyltään hyväksyttävä. Kliinisen tehon osoitusta ei vaadita. Kliinisen näytön perustana oleva tieto ei ole julkisesti saatavilla, sillä Euroopassa kliinistä arviointitietoa ja kliinisen laitetutkimuksen tuloksia ei velvoiteta julkaistavaksi markkinoille pääsyn ehdoksi. Tämä on mahdollistanut laitteiden valmistajille nopeamman ja kustannuksiltaan edullisemman tien saattaa laite markkinoille Euroopassa ja kasvattanut laiteteollisuuden jalansijaa Euroopassa. Euroopan lainsäädännön heikkoudet kuitenkin katsotaan olevan yksi syy vuosituhannen alun laitteiden ympärillä tapahtuneisiin mittaviin skandaaleihin tehon ja turvallisuuden osalta. Tämän myötä on laadittu uusi lääkinnällisten laitteiden EU asetus 2027/745 ja se astuu voimaan kaikissa jäsenvaltioissa toukokuussa 2021. Tutkimuksen tavoitteena oli selvittää yleisesti, millaiselle kliiniselle näytölle Euroopassa kaupan olevat korkean riskiluokan lääkinnälliset laitteet perustuvat ja miten asiakokonaisuutta on tutkittu. Menetelmänä tässä tutkimuksessa käytettiin systemaattista kirjallisuuskatsausta. Haasteeksi muodostui se, että aiheesta oli löydettävissä hyvin niukasti aineistoa. Tämä johtuu todennäköisesti siitä, että kliinisen tiedon saatavuus markkinoille hyväksytyistä laitteista on rajallinen, koska julkista tietokantaa arviointiraporteista ei ole vielä olemassa Euroopassa eikä laitteen valmistaja välttämättä julkaise tutkimustuloksia. Asiakokonaisuutta on kuitenkin tutkittu muutamien Euroopan maiden korvattavuuspäätöksiä hyväksikäyttäen ja niitä hyödynnettiin tässä tutkimuksessa, kuten myös Yhdysvaltojen tietokannoista saatavia tietoja. Euroopassa kaupan olevia lääkinnällisiä laitteita on jätetty arvioitavaksi Yhdysvaltoihin, joten eurooppalaisten laitteiden tietoja löytyy Yhdysvaltojen julkisista lähteistä. Näiden tietojen avulla saadaan vahvempi näkemys sille, millaiselle tasolle Euroopassa myytävien laitteiden kliinisen näytön perusta pohjautuu. Tutkimusaineistosta saadun tiedon mukaan korkean riskiluokan lääkinnällisten laitteiden kliininen näyttö on valtaosin puutteellista ja laadultaan heikkotasoista. Tällä on negatiivisia vaikutuksia hoitopäätöksiä tekeviin lääkäreihin, laitetta käyttäviin potilaisiin kuin myös laitevalmistajiin. Kliinisten tutkimusten menetelmät eivät kaikilta osin noudata kultaista standardia eikä muiden menetelmien käyttöä ole selkeästi perusteltu. Uuden laiteasetuksen myötä vaatimukset tulevat uusille laitteille merkittävästi kiristymään ja kaupan olevien laitteiden kliinistä näyttöä tulee päivittää. Kliiniset tiedot tulevat lähitulevaisuudessa Eudamed-tietokantaan saataville. Myös ilmoitettujen laitosten ja viranomaisten ohjeistus kliinisille tutkimuksille käytettäville vaihtoehtoisille menetelmille odotetaan selkiytyvän. Uudet kliinisen näytön vaatimukset lisäävät kustannuksia valmistajan puolella. Voi myös olla, että päivityksiä ei kliinisen näytön osalta jostain syystä pystytä toteuttamaan aiotussa käyttötarkoituksessa turvallisuusnäkökulmasta katsottuna. Todennäköistä on, että tärkeitä laitteita poistuu Euroopan markkinoilta ja laiteteollisuus kärsii. Tässä tulisikin löytää yhteisymmärrys lainsäätäjien ja teollisuuden kanssa, jotta turvataan omavarainen eurooppalainen laitevalmistus ja elintärkeiden laitteiden saatavuus potilaiden käyttöön.The national legislation, based on EU Directive 93/42, has regulated the high-risk medical devices in Europe to this day. It requires that in order to enter the market, the device must be safe, suitable for the intended use and acceptable in performance. The demonstration of clinical efficacy is not required. The information on which clinical evidence is based, is not publicly available, as clinical evaluation data and the results of a clinical trial are not required as a condition of market access in Europe. This has given the opportunity for manufacturers for faster and more cost-effective pathway to bring the medical devices to market in Europe. This has boosted the activity of device industry in Europe. However, the weaknesses of European legislation are considered to be one of the reasons caused the large-scale device scandals (lack of safety and effectiveness) in the early 2000s. As a result, a new EU Regulation 2027/745 on medical devices has been created and will enter into force in all Member States in May 2021. The aim of this study was to create an overview of the clinical evidence on high-risk medical devices marketed in Europe and how the issue has been investigated. A systematic literature review was used as the method in this study. The challenge was that there was lack of material available on the subject in question. This is probably due to the limited availability on clinical information of marketed devices, as a public database (Eudamed) does not exist yet in Europe and the device manufacturer may not publish the results of clinical studies. This issue has been investigated by using some reimbursement assessment decisions could be found from few European countries. The level of clinical evidence of devices in the United States has been extensively investigated. Medical devices marketed in Europe have been submitted for registration to United States, so information on European devices can be found in United States public sources. This information will provide a stronger insight of the level of clinical evidence regarding the devices marketed in Europe and thus the publication has been justified to be included in this study. According to the information obtained from this study, the clinical evidence of high-risk medical devices is mostly incomplete and of poor quality. This has negative effects on physicians making treatment decisions, patients using the devices, as well as device manufacturers. Clinical trial methods do not fully comply with the gold standard and the use of other methods is not clearly justified. The requirements for new devices will be significantly tightened and the clinical evidence of already approved devices will need to be updated due to the new device regulation. Clinical data will be publicly available in Eudamed database in the near future. Guidance from Notified Bodies and Authorities regarding alternative methods for clinical trials expected to be also clarified. New requirements of clinical evidence will increase manufacturer´s costs. It may also be the case that, clinical evidence updates of current devices cannot be implemented from a safety point of view. It is likely that important devices will exit the European market and the industry will suffer. An agreement should be reached together with authorities and industry to ensure self-sufficient European device manufacturing and the promptly availability of vital devices for patients

Comparison of Diatoms and Dinoflagellates from Different Habitats as Sources of PUFAs

Recent studies have clearly shown the importance of omega-3 (ω-3) and omega-6 (ω-6) polyunsaturated fatty acids (PUFAs) for human and animal health. The long-chain eicosapentaenoic acid (EPA; 20:5ω-3) and docosahexaenoic acid (DHA; 22:6ω-3) are especially recognized for their nutritional value, and ability to alleviate many diseases in humans. So far, fish oil has been the main human source of EPA and DHA, but alternative sources are needed to satisfy the growing need for them. Therefore, we compared a fatty acid profile and content of 10 diatoms and seven dinoflagellates originating from marine, brackish and freshwater habitats. These two phytoplankton groups were chosen since they are excellent producers of EPA and DHA in aquatic food webs. Multivariate analysis revealed that, whereas the phytoplankton group (46%) explained most of the differences in the fatty acid profiles, habitat (31%) together with phytoplankton group (24%) explained differences in the fatty acid contents. In both diatoms and dinoflagellates, the total fatty acid concentrations and the ω-3 and ω-6 PUFAs were markedly higher in freshwater than in brackish or marine strains. Our results show that, even though the fatty acid profiles are genetically ordered, the fatty acid contents may vary greatly by habitat and affect the ω-3 and ω-6 availability in food webs

Allopurinol, dipyridamole and calcium channel blockers in the treatment of bipolar disorder - A nationwide cohort study

Background: Improved treatments for bipolar disorder (BD) are needed. Drug repurposing aims to find novel targets for drugs that have been used for other indications. This study investigated the risk of psychiatric hospitalization associated with use of calcium-channel blockers (CCBs; dihydropyridines, diltiazem, verapamil) and adenosine modulators (allopurinol, dipyridamole) in BD in within-individual design. Methods: Individuals diagnosed with BD (ICD-10: F30-F31) were identified from the inpatient, specialized outpatient, sickness absence, and disability pension registers during 1996-2018 in Finland (N = 60,045). The main outcome was hospitalization due to affective symptoms (ICD-10: F30-F39). Within-individual models in stratified Cox regression were used and adjusted hazard ratios (aHR) with 95 % confidence intervals (CIs) reported. Results: Use of CCBs was associated with a decreased risk of hospitalization due to affective symptoms (aHR 0.83, 95 % CI 0.78-0.88) when all CCBs were analyzed together. Of specific CCBs, use of diltiazem (0.71, 0.55-0.91) and dihydropyridines (0.83, 0.78-0.89) were associated with a decreased risk but verapamil was not (0.93, 0.73-1.19). Use of adenosine modulators in general was associated with a decreased risk of hospitalizations due to affective symptoms (0.87, 0.79-0.96). Both allopurinol (0.85, 0.74-0.97) and dipyridamole (0.89, 0.78-1.00) were associated with a marginally decreased risk. Thiazide diuretic use as a negative control was not associated with the risk of hospitalization due to affective symptoms (0.97, 0.83-1.13). Limitations: Due to the observational nature of this study, causation cannot be confirmed. Conclusions: Dihydropyridines and diltiazem were associated with a decreased risk of psychiatric hospitalization in bipolar disorder. Results for allopurinol and dipyridamole were inconclusive.Peer reviewe

The clinical course of schizophrenia in women and men-a nation-wide cohort study

Gender differences in schizophrenia have been reported in different aspect of the course of disease and may urge special clinical interventions for female patients. Current literature provides insufficient information to design guidelines for treating women with schizophrenia. We aim to quantify the clinical course of schizophrenia in men and women on premorbid hospitalizations and prescription drugs, age at diagnosis, pharmacological treatment, comorbidity, number of re-hospitalizations, and mortality. Our nationwide cohort study included all patients admitted for the first time to hospital during 2000-2014 for schizophrenia or schizo-affective disorder in Finland. Gender differences were compared with logistic regression, by calculating incidence rates, and mortality was assessed with Cox proportional hazard model. We included 7142 women and 9006 men with schizophrenia/schizo-affective disorder and found that both women (71%) and men (70%) had often been hospitalized for another psychiatric disorder in the 5 years before diagnosis. In women, the last psychiatric hospitalization before schizophrenia/schizo-affective diagnosis was often for mood disorders (62%, OR 2.56, 95% CI 2.28-2.87). Men were diagnosed earlier (mean 34.4 [SD12.6] vs. 38.2 [SD 13.8]) with peak incidence around 22, while incidence in women declining only slowly between age 18 and 65. During ten years follow-up, 69.5% of both genders needed at least one re-hospitalization, with slightly more hospitalizations in women. Women were less often prescribed clozapine or long-acting antipsychotics. Mortality was lower in women (HR = 0.54, 95% CI 0.50-0.60), with fewer suicide and cardiovascular deaths, but more cancer deaths. These results suggest a diagnostic delay for women, which might be shortened by screening women aged 20-65 participating in affective disorder programs. As number of hospitalizations is not lower for women, clinicians should take care not to undertreat women with schizophrenia

The role of sociodemographic and clinical factors in the initiation and discontinuation of attention deficit hyperactivity disorder medication among young adults in Sweden

IntroductionLong-term medication use is a recommended treatment for attention-deficit/hyperactivity disorder (ADHD), however, discontinuation is common. Non-medical factors which might influence initiation and discontinuation are understudied. Therefore, we investigated how different sociodemographic factors and comorbidities were associated with the initiation and discontinuation of ADHD medication use among young adults.Methods and resultsWe conducted a population-based prospective cohort study using individually linked administrative register data, in which we included all individuals residing in Sweden, between the age of 19 and 29 who were first diagnosed with ADHD between January 2006 and December 2016 (n = 59224). ADHD medication initiation was defined as the first prescription of ADHD medication in the period from 3 months before to 6 months after the cohort entry date. Those who initiated ADHD medication were followed up for medication use until discontinuation, death/emigration, or until 2019. Logistic and Cox regression models were used to investigate the associations between sociodemographics, health-related predictors and initiation, as well as discontinuation. Overall, 48.7% of the 41399 individuals initiated ADHD medication, most often methylphenidate (87%). Among the initiators, 15462 (77%) discontinued medication use during the follow-up (median time: 150 days). After mutually adjusting all other predictors, initiation was positively associated with older age, male sex, higher level of education, and negatively associated with living at home with parents, immigrant status, being unemployed during the year before inclusion, being on disability pension, having autism, substance use, schizophrenia-spectrum disorders, other mental disability/developmental disorders, cardiovascular diseases or previous accidents. Discontinuation was positively associated with being born abroad, living in big cities, being unemployed during the year before inclusion, having cancer, and negatively associated with a higher educational level, having depression, anxiety or stress-related disorder, autism spectrum disorder or diabetes.ConclusionBesides medical factors, sociodemographics, such as educational attainment and immigrant status might also play a role in the initiation and discontinuation of ADHD medication use among young adults newly diagnosed with ADHD

Real-world effectiveness of pharmacological treatments of opioid use disorder in a national cohort

Abstract Aim To investigate the real-world effectiveness of pharmacological treatments (buprenorphine, methadone) of opioid use disorder (OUD). Design A nationwide, register-based cohort study. Setting Sweden. Participants All residents aged 16?64 living in Sweden using OUD-medication from July 2005 to December 2016 (n=5757, 71.8% men) were identified from registers of prescriptions, inpatient and specialized outpatient care, causes of death, sickness absence and disability pensions. Measurements Main outcome: hospitalization due to OUD. Secondary outcomes: hospitalization due to any cause; death due to all, natural and external causes. Mortality was analysed with between-individual multivariate-adjusted Cox hazards regression model. Recurrent outcomes, such as hospitalizations, were analysed with within-individual analyses to eliminate selection bias. OUD-medication use vs. non-use was modelled with PRE2DUP (from prescription drug purchases to drug use periods) method. Findings Buprenorphine (Hazard Ratio [HR], 0.73; 95% confidence interval [CI, 0.54?0.97) and methadone (HR, 0.74; 95% CI, 0.59?0.93) use were associated with significantly lower risk of OUD-hospitalization, but not any-cause hospitalizations, compared with the time periods when the same individual did not use OUD-medication. The use of buprenorphine and methadone were both associated with significantly lower risk of all-cause mortality (HR, 0.45; 95% CI, 0.34?0.59, HR, 0.51; 95 CI, 0.41?0.63, respectively), compared with non-use of both medications. Similar results were found for risk of mortality due to external causes (HR, 0.39; 95% CI, 0.27?0.54, HR, 0.40; 95% CI, 0.29?0.53, respectively), but not for mortality due to natural causes. The risk of OUD-hospitalization and all-cause mortality was decreased in all duration categories of studied medications (365 days), except for methadone use less than 30 days. Conclusions The use of buprenorphine and methadone are both associated with a significantly lower risk of hospitalization due to opioid use disorder and death due to all and external causes, when compared with non-use.Peer reviewe

Optimal Doses of Specific Antipsychotics for Relapse Prevention in a Nationwide Cohort of Patients with Schizophrenia

Background and Hypothesis Optimal doses of most antipsychotics in the maintenance treatment of schizophrenia are unknown. We aimed to study the risk of severe relapse indicated by rehospitalization for different dose categories of 15 most frequently used antipsychotics in monotherapy in Finland. Study Methods We studied the risk of rehospitalization (Adjusted Hazard Ratio, aHR) associated with six antipsychotic monotherapy dose categories (as time-varying dose, measured in defined daily dose, DDDs/day) in a nationwide cohort of persons diagnosed with schizophrenia (n = 61 889), using within-individual analyses to eliminate selection bias. Study Results Among the 15 most widely used antipsychotics, 13 had a U- or J-shaped dose-response curve, showing the lowest risks of relapse for doses of 0.6-0.9 DDD/day, and especially at 1.4-Peer reviewe

Risk of head and traumatic brain injuries associated with antidepressant use among community-dwelling persons with Alzheimer’s disease : a nationwide matched cohort study

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Antidepressant use among immigrants with depressive disorder living in Finland : A register-based study

Publisher Copyright: © 2021 The Author(s)Background:: The aim of this study was to examine differences in the initiation and discontinuation of antidepressants between immigrants and the Finnish-born population diagnosed with depression in specialized health care. Methods:: The study utilized register-based data, which includes all immigrants living in Finland at the end of 2010 and matched Finnish-born controls. For this study, we selected individuals who had received a diagnosis of depression during 2011–2014 (immigrants n = 2244, Finnish-born n = 2773). Their antidepressant use was studied for a one-year period from initiation. A logistic regression was used to predict initiation and a Cox regression was used to predict discontinuation. Results:: Immigrants were more likely to initiate the use of antidepressants than the Finnish-born controls (adjusted OR = 1.25, 95% CI = 1.07–1.46), but they also discontinued the medication earlier than the Finnish-born controls (adjusted HR = 1.48, 95% CI = 1.31–1.68). Immigrants from Sub Saharan Africa, the Middle East and Northern Africa were most likely to discontinue antidepressants earlier. More severe depression, a longer length of residence in Finland and more intensive psychiatric treatment were associated with decreased risk of discontinuation. Limitations:: The registers do not provide information on the perceived reasons for the discontinuation. Conclusions:: Immigrants with depression initiate antidepressants more often than the Finnish-born population, but they also discontinue them earlier. Early discontinuation may be a sign of insufficient treatment suggesting that there could be a need for improvement in mental health care for immigrants in Finland.Peer reviewe