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Feltelius N.,Swedish Medical Products Agency | Gedeborg R.,Swedish Medical Products Agency | Holm L.,Swedish Medical Products Agency | Zethelius B.,Swedish Medical Products Agency
Upsala Journal of Medical Sciences | Year: 2017

Aim: The aim of this study was to describe content and procedures in some selected Swedish health care quality registries (QRs) of relevance to regulatory decision-making. Methods: A workshop was organized with participation of seven Swedish QRs which subsequently answered a questionnaire regarding registry content on drug treatments and outcomes. Patient populations, coverage, data handling and quality control, as well as legal and ethical aspects are presented. Scientific publications from the QRs are used as a complementary measure of quality and scientific relevance. Results: The registries under study collect clinical data of high relevance to regulatory and health technology agencies. Five out of seven registries provide information on the drug of interest. When applying external quality criteria, we found a high degree of fulfillment, although information on medication was not sufficient to answer all questions of regulatory interest. A notable strength is the option for linkage to the Prescribed Drug Registry and to information on education and socioeconomic status. Data on drugs used during hospitalization were also collected to some extent. Outcome measures collected resemble those used in relevant clinical trials. All registries collected patient-reported outcome measures. The number of publications from the registries was substantial, with studies of appropriate design, including randomized registry trials. Conclusions: Quality registries may provide a valuable source of post-marketing data on drug effectiveness, safety, and cost-effectiveness. Closer collaboration between registries and regulators to improve quality and usefulness of registry data could benefit both regulatory utility and value for health care providers. © 2017 Swedish Medical Products Agency. Published by Informa UK Limited, trading as Taylor & Francis Group.


Mani N.,University of California at Berkeley | Murray J.,U.S. Food and Drug Administration | Gulick R.M.,Cornell University | Josephson F.,Swedish Medical Products Agency | And 5 more authors.
AIDS | Year: 2012

The resounding success of combination antiretroviral efficacy for both treatment-naïve and treatment-experienced patients - with 70-90% viral suppression rates in recent studies - has made registration trials for new agents challenging. With the inevitable specter of drug resistance, new agents must have a pathway to approval. The Forum for Collaborative HIV Research obtained input from concerned stakeholders including industry, clinical sciences, community advocacy, and regulatory sciences (Food and Drug Administration and European Medicines Agency) to discuss how safety and efficacy of new agents could be demonstrated. Recognizing the shortfalls of superiority or noninferiority trials in this environment, a new trial design for treatment-experienced patients, minimizing the risk for drug resistance but allowing full assessment of safety, was proposed. The antiviral efficacy of an active investigational drug would be assessed by comparison to placebo as an add-on to a failing regimen in a short, 10-14-day study followed by institution of an optimized background regimen (OBR) in both arms with investigational drug given to all patients. The follow-on stage would assess dose response, safety, durability of initial response, and development of resistance. Additionally, a second safety trial could be conducted comparing patients randomized to the investigational agent with a new OBR to those on a new OBR and placebo. Finally, approval decisions could consider other long-term safety endpoints. Exposing treatment-naïve patients to investigational agents remains a controversial issue; stakeholders have different interpretations of risk-benefit for trials in this population that necessitate careful consideration before initiating trials in them. © 2012 Wolters Kluwer Health | Lippincott Williams and Wilkins.


Hsu V.,U.S. Food and Drug Administration | Vieira M.D.L.T.,U.S. Food and Drug Administration | Vieira M.D.L.T.,Federal University of Minas Gerais | Zhao P.,U.S. Food and Drug Administration | And 6 more authors.
Clinical Pharmacokinetics | Year: 2014

Background and Objectives: The kidney is a major drug-eliminating organ. Renal impairment or concomitant use of transporter inhibitors may decrease active secretion and increase exposure to a drug that is a substrate of kidney secretory transporters. However, prediction of the effects of patient factors on kidney transporters remains challenging because of the multiplicity of transporters and the lack of understanding of their abundance and specificity. The objective of this study was to use physiologically based pharmacokinetic (PBPK) modelling to evaluate the effects of patient factors on kidney transporters. Methods: Models for three renally cleared drugs (oseltamivir carboxylate, cidofovir and cefuroxime) were developed using a general PBPK platform, with the contributions of net basolateral uptake transport (T up,b) and apical efflux transport (T eff,a) being specifically defined. Results and Conclusion: We demonstrated the practical use of PBPK models to: (1) define transporter-mediated renal secretion, using plasma and urine data; (2) inform a change in the system-dependent parameter (≥10-fold reduction in the functional 'proximal tubule cells per gram kidney') in severe renal impairment that is responsible for the decreased secretory transport activities of test drugs; (3) derive an in vivo, plasma unbound inhibition constant of T up,b by probenecid (≤1 μM), based on observed drug interaction data; and (4) suggest a plausible mechanism of probenecid preferentially inhibiting T up,b in order to alleviate cidofovir-induced nephrotoxicity. © 2013 The Author(s).


Karolinska Represents Third Approved Study Site in Europe; First Patient Expected to be Enrolled in Phase I/II Study in First Quarter of 2017 ALACHUA, FL--(Marketwired - November 10, 2016) - CTD Holdings, Inc. ( : CTDH), a biotechnology company developing cyclodextrin-based products for the treatment of diseases with unmet medical need, today announced that the Swedish Medical Products Agency has approved CTD Holdings' Clinical Trial Application to conduct a Phase I/II clinical study at Karolinska University Hospital in Sweden evaluating Trappsol® Cyclo™ in patients with Niemann-Pick Type C (NPC) Disease, a rare and fatal illness tied to an autosomal recessive genetic defect. Karolinska represents the third site in Europe approved to conduct this study. CTD Holdings expects that the first patient in this Phase I/II clinical trial will be dosed in the first quarter of 2017. Trappsol® Cyclo™ is a parenteral grade of hydroxypropyl beta cyclodextrin, a donut-shaped molecule comprised of seven glucopyranose units. Its hydrophilic exterior allows it to move easily through the body, and its inner hydrophobic cavity allows it to capture and hold certain types of molecules. To date, intravenous Trappsol® Cyclo™ has been administered to 21 NPC patients worldwide, some for more than five years, via multiple Compassionate Use Programs. During this time, multiple patients have shown marked improvements in neurological symptoms, lung function or liver morphology, or had stabilization of disease progression, with no significant, unexpected, safety concerns. "We view this third site approval at such a prestigious institution in Europe, Karolinska University Hospital, as validation of the potential of intravenous Trappsol® Cyclo™ in treating NPC," said N. Scott Fine, Chief Executive Officer of CTD Holdings. "In addition to the Phase I/II study we are conducting in Europe, we also expect to begin enrolling patients in a U.S. Phase I study to evaluate the safety and impact of intravenous Trappsol® Cyclo™ on biomarkers of NPC Disease in the first quarter of 2017. NPC is a highly under-served orphan disease with an addressable market of over $400 million, and represents a significant opportunity for CTD Holdings." "NPC is a fatal disease that is difficult to diagnose and is consequently under-diagnosed," said Dr. Sharon Hrynkow, CTD's Senior VP for Medical Affairs. "There is currently only one approved treatment for the disease in Europe, and none in the U.S. Based on the Compassionate Use Program data garnered to date, we believe Trappsol® Cyclo™ administered intravenously has the potential to effectively treat NPC. We look forward to working with our colleagues in Sweden to further evaluate this promising drug candidate in this Phase I/II study." CTD Holdings received Orphan Drug designation for the use of Trappsol® Cyclo™ in NPC from the U.S. Food and Drug Administration and the European Medicines Agency. For further information on this trial and the U.S. trial, please visit www.ClinicalTrials.gov. About the Company: CTD Holdings, Inc. is a biotechnology company that develops cyclodextrin-based products for the treatment of disease. The company's Trappsol® Cyclo™, an orphan drug designated product in the United States and Europe, is used to treat Niemann-Pick Type C, a rare and fatal genetic disease. Additional indications for the active ingredient in Trappsol® Cyclo™ are in development. For additional information, visit the company's website: www.ctd-holdings.com Safe Harbor Statement: This press release contains "forward-looking statements" about the company's current expectations about future results, performance, prospects and opportunities. Statements that are not historical facts, such as "anticipates," "believes" and "expects" or similar expressions, are forward-looking statements. These statements are subject to a number of risks, uncertainties and other factors that could cause actual results in future periods to differ materially from what is expressed in, or implied by, these statements. The factors which may influence the company's future performance include the company's ability to obtain additional capital to expand operations as planned, success in achieving regulatory approval for clinical protocols, enrollment of adequate numbers of patients in clinical trials, unforeseen difficulties in showing efficacy of the company's biopharmaceutical products, success in attracting additional customers and profitable contracts, and regulatory risks associated with producing pharmaceutical grade and food products. These and other risk factors are described from time to time in the company's filings with the Securities and Exchange Commission, including, but not limited to, the company's reports on Forms 10-K and 10-Q. Unless required by law, the company assumes no obligation to update or revise any forward-looking statements as a result of new information or future events.


Neovius M.,Karolinska Institutet | Arkema E.V.,Karolinska Institutet | Olsson H.,Karolinska Institutet | Eriksson J.K.,Karolinska Institutet | And 13 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objective: To compare drug survival on adalimumab, etanercept and infliximab in patients with rheumatoid arthritis (RA). Methods: Patients with RA (n=9139; 76% women; mean age 56 years) starting their first tumour necrosis factor (TNF) inhibitor between 2003 and 2011 were identified in the Swedish Biologics Register (ARTIS). Data were collected through 31 December 2011. Drug survival over up to 5 years of follow-up was compared overall and by period of treatment start (2003-2005/2006-2009; n=3168/4184) with adjustment for age, sex, education, period, health assessment questionnaire (HAQ), disease duration, concomitant disease modifying antirheumatic drug (DMARD) treatment and general frailty (using hospitalisation history as proxy). Results: During 20 198 person-years (mean/median 2.2/1.7 years) of follow-up, 3782 patients discontinued their first biological (19/100 person-years; 51% due to inefficacy, 36% due to adverse events). Compared with etanercept, infliximab (adjusted HR 1.63, 95% CI 1.51 to 1.77) and adalimumab initiators had higher discontinuation rates (1.26, 95% CI 1.16 to 1.37), and infliximab had a higher discontinuation rate than adalimumab (1.28, 95% CI 1.18 to 1.40). These findings were consistent across periods, but were modified by time for adalimumab versus etanercept (p<0.001; between-drug difference highest the 1st year in both periods). The discontinuation rate was higher for starters in 2006-2009 than 2003-2005 (adjusted HR 1.12, 95% CI 1.04 to 1.20). The composition of 1-year discontinuations also changed from 2003-2005 vs 2006-2009: adverse events decreased from 45% to 35%, while inefficacy increased from 43% to 53% (p<0.001). Conclusions: Discontinuation rates were higher for infliximab compared with adalimumab and etanercept initiators, and for adalimumab versus etanercept during the 1st year. Discontinuation rates increased with calendar period, as did the percentage discontinuations due to inefficacy. © 2013 BMJ Publishing Group Ltd & European League Against Rheumatism.


Hellgren K.,Karolinska University Hospital | Smedby K.E.,Karolinska University Hospital | Feltelius N.,Karolinska University Hospital | Feltelius N.,Swedish Medical Products Agency | And 2 more authors.
Arthritis and Rheumatism | Year: 2010

Objective. Patients with rheumatoid arthritis (RA), in particular those with the most severe disease, are at increased risk of developing malignant lymphoma. Whether this increase is entirely a consequence of the RA disease and/or its treatment or is reflective of shared susceptibility to the two diseases remains unclear. We undertook this study to assess whether patients with RA are already at increased risk of lymphoma or of other cancers before the diagnosis of RA, and if the relative risk increases with time since RA diagnosis. Methods. Patients with incident RA (symptom duration <1 year) (n = 6,745) registered in the Swedish Early Arthritis Registry from 1997 through 2006 were identified. For each patient, 5 general population controls were randomly matched by sex, age, marital status, and residence (n = 33,657). For all study subjects, inclusion in the nationwide Swedish Cancer Register in 1958-2006 was determined. Relative risks (RRs) (with 95% confidence intervals [95% CIs]) of lymphoma and of cancer overall, before and after diagnosis of RA, were estimated using conditional logistic regression and Cox regression, respectively. Results. Before diagnosis of RA, there was no observed increase in the risk of lymphoma (RR [odds ratio] 0.67 [95% CI 0.37-1.23]) or other cancers (RR 0.78 [95% CI 0.70-0.88]). During the first 10 years following diagnosis of RA, the overall RR (hazard ratio) of lymphoma development was 1.75 (95 % CI 1.04-2.96). Conclusion. These findings indicate that overall, a history of cancer, including lymphoma, does not increase the risk of subsequent RA development. Shared susceptibility to RA and lymphoma may thus be of limited importance. In contrast, increased lymphoma risks were observed within the first decade following RA diagnosis. © 2010, American College of Rheumatology.


Magnusson U.,Swedish University of Agricultural Sciences | Ljungvall K.,Swedish Medical Products Agency
Reproductive Toxicology | Year: 2014

The scientific literature on altered onset of puberty predominantly involves studies on females. This paper reviews current knowledge on the role of environmental pollutants in dysregulation of male puberty in humans, laboratory rodents and farm animals. The methods used to determine the onset of puberty are well developed in humans and farm animals, and standardized across studies in humans. In laboratory rodents standardized external morphological endpoints are used. There is an increasing weight of evidence from epidemiological studies in humans, as well as from experiments in animals, indicating that environmental pollutants dysregulate puberty in males. Most data are from studies on "classical" persistent environmental pollutants. Assessing the effect of multichemical environmental pollution on dysregulation of puberty in humans is more challenging; further solid epidemiological data would likely contribute most to our understanding, especially if combined with systematically collected field-data from selected wildlife. © 2014 The Authors.


Hellgren K.,Karolinska University Hospital | Iliadou A.,Karolinska Institutet | Rosenquist R.,Uppsala University | Feltelius N.,Karolinska University Hospital | And 5 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Background: Benefits and risks of corticosteroid treatment in rheumatoid arthritis (RA) are debated. Patients with RA are at increased risk of malignant lymphomas. In a large case-control study of risk factors for lymphoma in RA, it was recently reported that steroid treatment was associated with decreased lymphoma risk. Objective: To further assess the nature of the association between steroid treatment in RA and the risk of lymphoma. Methods: In a cohort of 74 651 patients with RA, 378 patients with lymphoma and 378 matched RA controls were identified, and information on inflammatory activity and different aspects of steroid treatment (duration, therapeutic strategy and mode of administration) abstracted from their medical records. Lymphomas were reclassified (WHO classification) and examined for Epstein-Barr virus. Relative risks were assessed as adjusted odds ratios (ORs) through conditional logistic regression. Results: A total duration of oral steroid treatment of <2 years was not associated with lymphoma risk (OR=0.87; 95% CI 0.51 to 1.5), whereas total treatment >2 years was associated with a lower lymphoma risk (OR=0.43; 95% CI 0.26 to 0.72). RA duration at the initiation of oral steroids did not affect lymphoma risk. Intra-articular steroids were associated with a reduced lymphoma risk, but only when used as swift flare treatment (OR=0.22; 95% CI 0.13 to 0.37). Analyses by lymphoma subtype showed a reduced risk of diffuse large B-cell lymphoma (crude OR=0.59; 95% CI 0.37 to 0.94). Conclusion: In this RA population, use of steroids was associated with reduced lymphoma risk. Whether this association is a generic effect of steroids or specific to the studied population remains unknown.


Hellgren K.,Karolinska University Hospital | Smedby K.E.,Karolinska University Hospital | Backlin C.,Uppsala University | Sundstrom C.,Uppsala University | And 5 more authors.
Arthritis and Rheumatology | Year: 2014

Objective Data on lymphoma risk in ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are scarce. This study was undertaken to assess the risk of lymphoma in AS and PsA overall and in relation to therapies, including tumor necrosis factor inhibitor (TNFi), for which lymphoma risks are a concern. Methods Through the Swedish National Patient Register we assembled nationwide prevalence cohorts of patients with AS (n = 8,707) and patients with PsA (n = 19,283) for whom data were obtained between 2001 and 2010. Each cohort member was matched to 5 population comparator subjects. Linkage with the nationwide Cancer Register identified all lymphomas recorded from 2001 to 2010. Through the Swedish Biologics Register (Anti-Rheumatic Therapy in Sweden [ARTIS]), we identified patients exposed to TNFi in the AS cohort (n = 1,908) and the PsA cohort (n = 2,605) before lymphoma diagnosis. Hazard ratios (HRs) for lymphoma were estimated by Cox regression. Crude incidences of lymphoma in TNFi-exposed and TNFi-naive patients were compared. Results For AS patients, the HR of having lymphoma versus the general population was 0.9 (95% confidence interval [95% CI] 0.5-1.6) (14 lymphomas). For PsA patients, the corresponding HR was 1.2 (95% CI 0.9-1.7) (45 lymphomas). For PsA patients treated with methotrexate and/or sulfasalazine, the HR of having lymphoma was 1.7 (95% CI 1.0-3.1). The numbers and incidence of lymphoma were not materially different in TNFi-exposed versus TNFi-naive AS and PsA patients, although the numbers of lymphomas were small. Conclusion In contrast to rheumatoid arthritis, the average risks of lymphoma in AS or PsA are not elevated, although increased risks in a subset of PsA patients cannot be excluded. Our findings indicate that TNFi does not affect the risk of lymphoma in AS or in PsA. Copyright © 2014 by the American College of Rheumatology.


PubMed | Chimerix, Fred Hutchinson Cancer Research Center, Copenhagen University, Center for Drug Evaluation and Research and 6 more.
Type: | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2016

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2002. Since then, there have been major developments in its diagnosis and management. Therefore, the CMV Drug Development Forum consisting of scientists, clinicians, regulators, and industry representatives has produced an updated version incorporating recent knowledge with the aim to support clinical research and drug development. The main changes compared to previous definitions are the introduction of a probable disease category and to incorporate quantitative nucleic acid testing in some end-organ disease categories. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts between scientists, regulators, and industry can provide a platform for this work.

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