Innovative approaches to biologic development on the trail of CT-P13: biosimilars, value-added medicines, and biobetters.
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SUBMITTER: Kim H
PROVIDER: S-EPMC7889098 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background & objectives: Despite the wide interest surrounding drug repurposing, no common terminology has been yet agreed for these products and their full potential value is not always recognised and rewarded, creating a disincentive for further development. The objectives of the present study were to assess from a wide perspective which value drug repurposing might bring to society, but also to identify key obstacles for adoption of these medicines and to discuss policy recommendations. Methods: A preliminary comprehensive search was conducted to assess how the concept of drug repurposing was described in the literature. Following completion of the literature review, a primary research was conducted to get perspective of various stakeholders across EU member states on drug repurposing (healthcare professionals, regulatory authorities and Health Technology Assessment (HTA) bodies/payers, patients, and representatives of the pharmaceutical industry developing medicines in this field). Ad hoc literature review was performed to illustrate, when appropriate, statements of the various stakeholders. Results: Various nomenclatures have been used to describe the concept of drug repurposing in the literature, with more or less broad definitions either based on outcomes, processes, or being a mix of both. In this context, Medicines for Europe (http://www.medicinesforeurope.com/value-added-medicines/) established one single terminology for these medicines, known as value added medicines, defined as 'medicines based on known molecules that address healthcare needs and deliver relevant improvements for patients, healthcare professionals and/or payers'. Stakeholder interviews highlighted three main potential benefits for value added medicines: (1) to address a number of medicine-related healthcare inefficiencies related to irrational use of medicines, non-availability of appropriate treatment options, shortage of mature products, geographical inequity in medicine access; (2) to improve healthcare system efficiency; and (3) to contribute to sustainability of healthcare systems through economic advantages. Current HTA framework, generic stigma, and pricing rules, such as internal reference pricing or tendering processes in place in some countries, were reported as the current key hurdles preventing the full recognition of value added medicines' benefits, discouraging manufacturers from bringing such products to the market. Discussion & conclusions: There is currently a gap between increasing regulatory authority interest in capturing value added medicines' benefits and the resistance of HTA bodies/payers, who tend to ignore this important segment of the pharmaceutical field. This situation calls for policy changes to foster appropriate incentives to enhance value recognition of value added medicines and deliver the expected benefit to society. Policy changes from HTA perspective should include: absence of any legislative barriers preventing companies from pursuing HTA; HTA requirements proportionate to potential reward; HTA decision-making framework taking into account the specific characteristics of value added medicines; eligibility for early HTA dialogues; Policy changes from pricing perspective should encompass: tenders/procurement policies allowing differentiation from generic medicines; eligibility for early entry agreement; non-systematic implementation of external and internal reference pricing policies; recognition of indication-specific pricing. At the same time, the pharmaceutical industry should engage all the stakeholders (patients, healthcare providers, HTA bodies/payers) in early dialogues to identify their expectations and to ensure the developed value added medicines address their needs.
| S-EPMC5328340 | biostudies-literature
Project description:Adding subtraction single-photon emission computed tomography/computed tomography (SPECT/CT) to dual isotope (I-123 and Tc-99m-sestamibi) subtraction parathyroid scintigraphy is not widely implemented. We aimed to assess the added value of dual isotope subtraction SPECT/CT over single isotope SPECT/CT as an adjunct to dual isotope planar pinhole subtraction scintigraphy. Parathyroid scintigraphies from 106 patients with an estimated total of 415 parathyroid glands who (1) were diagnosed with primary hyperparathyroidism, (2) underwent dual isotope subtraction scintigraphy in the Department of Nuclear Medicine, Gentofte Hospital, Denmark throughout 2017 and (3) underwent subsequent parathyroidectomy, were included. The original dual isotope planar pinhole subtraction plus dual isotope subtraction SPECT/CT (dual/dual method) exams were retrospectively re-evaluated using only Tc-99m-sestamibi SPECT/CT (dual/single method). Statistics were calculated per parathyroid. Surgical results confirmed by pathology served as reference standard. The dual/dual method had higher sensitivity than the dual/single method (82% (95%CI 74%-88%) vs. 69% (95%CI 60%-77%)) while specificity, positive and negative predictive values (PPV and NPV) were similar (specificity 96% vs. 93%, PPV's 87% vs. 82% and NPV's 89% vs. 93%). Reader confidence was higher when employing the dual/dual method (p = 0.001). The dual/dual method can be considered superior to the dual/single method in the preoperative imaging in primary hyperparathyroidism.
| S-EPMC7555464 | biostudies-literature
Project description:ObjectivesTo assess the efficacy and safety of switching from the infliximab reference product (RP; Remicade) to its biosimilar CT-P13 (Remsima, Inflectra) or continuing CT-P13 in patients with rheumatoid arthritis (RA) for an additional six infusions.MethodsThis open-label extension study recruited patients with RA who had completed the 54-week, randomised, parallel-group study comparing CT-P13 with RP (PLANETRA; NCT01217086). CT-P13 (3 mg/kg) was administered intravenously every 8 weeks from weeks 62 to 102. All patients received concomitant methotrexate. Endpoints included American College of Rheumatology 20% (ACR20) response, ACR50, ACR70, immunogenicity and safety. Data were analysed for patients who received CT-P13 for 102 weeks (maintenance group) and for those who received RP for 54 weeks and then switched to CT-P13 (switch group).ResultsOverall, 302 of 455 patients who completed the PLANETRA study enrolled into the extension. Of these, 158 had received CT-P13 (maintenance group) and 144 RP (switch group). Response rates at week 102 for maintenance versus switch groups, respectively, were 71.7% vs 71.8% for ACR20, 48.0% vs 51.4% for ACR50 and 24.3% vs 26.1% for ACR70. The proportion of patients with antidrug antibodies was comparable between groups (week 102: 40.3% vs 44.8%, respectively). Treatment-emergent adverse events occurred in similar proportions of patients in the two groups during the extension study (53.5% and 53.8%, respectively).ConclusionsComparable efficacy and tolerability were observed in patients who switched from RP to its biosimilar CT-P13 for an additional year and in those who had long-term CT-P13 treatment for 2 years.Trial registration numberNCT01571219; Results.
| S-EPMC5284338 | biostudies-literature
Project description:PurposeThe aim of this study was to evaluate whether the addition of brain CT imaging data to a model incorporating clinical risk factors improves prediction of ischemic stroke recurrence over 5 years of follow-up.MethodsA total of 638 patients with ischemic stroke from three centers were selected from the Dutch acute stroke study (DUST). CT-derived candidate predictors included findings on non-contrast CT, CT perfusion, and CT angiography. Five-year follow-up data were extracted from medical records. We developed a multivariable Cox regression model containing clinical predictors and an extended model including CT-derived predictors by applying backward elimination. We calculated net reclassification improvement and integrated discrimination improvement indices. Discrimination was evaluated with the optimism-corrected c-statistic and calibration with a calibration plot.ResultsDuring 5 years of follow-up, 56 patients (9%) had a recurrence. The c-statistic of the clinical model, which contained male sex, history of hyperlipidemia, and history of stroke or transient ischemic attack, was 0.61. Compared with the clinical model, the extended model, which contained previous cerebral infarcts on non-contrast CT and Alberta Stroke Program Early CT score greater than 7 on mean transit time maps derived from CT perfusion, had higher discriminative performance (c-statistic 0.65, P = 0.01). Inclusion of these CT variables led to a significant improvement in reclassification measures, by using the net reclassification improvement and integrated discrimination improvement indices.ConclusionData from CT imaging significantly improved the discriminatory performance and reclassification in predicting ischemic stroke recurrence beyond a model incorporating clinical risk factors only.
| S-EPMC7966192 | biostudies-literature
Project description:ObjectiveCertain pulmonary diseases are associated with cardiovascular disease (CVD). Therefore we investigated the incremental predictive value of pulmonary, mediastinal and pleural features over cardiovascular imaging findings.MethodsA total of 10,410 patients underwent diagnostic chest CT for non-cardiovascular indications. Using a case-cohort approach, we visually graded CTs from the cases and from an approximately 10 % random sample of the baseline cohort (n = 1,203) for cardiovascular, pulmonary, mediastinal and pleural findings. The incremental value of pulmonary disease-related CT findings above cardiovascular imaging findings in cardiovascular event risk prediction was quantified by comparing discrimination and reclassification.ResultsDuring a mean follow-up of 3.7 years (max. 7.0 years), 1,148 CVD events (cases) were identified. Addition of pulmonary, mediastinal and pleural features to a cardiovascular imaging findings-based prediction model led to marginal improvement of discrimination (increase in c-index from 0.72 (95 % CI 0.71-0.74) to 0.74 (95 % CI 0.72-0.75)) and reclassification measures (net reclassification index 6.5 % (p < 0.01)).ConclusionPulmonary, mediastinal and pleural features have limited predictive value in the identification of subjects at high risk of CVD events beyond cardiovascular findings on diagnostic chest CT scans.Key points• Incidental cardiovascular findings on routine chest CT can predict cardiovascular disease • Non-cardiovascular chest CT abnormalities are associated with cardiovascular disease • Non-cardiovascular chest CT features have limited predictive value beyond cardiovascular features.
| S-EPMC4419189 | biostudies-literature
Project description:BackgroundMedicines that are based on known molecules and are further developed to address healthcare needs and deliver relevant improvement for patients, healthcare professionals and/or payers are called value-added medicines (VAMs). The evaluation process of VAMs is heterogeneous across countries, and it has been primarily designed for originator pharmaceuticals with confirmatory evidence collected alongside pivotal clinical trials. There is a mismatch between evidence requirements by public decision-makers and evidence generated by manufacturers of VAMs. Our objective was to develop a core evaluation framework for VAMs.MethodsPotential benefits offered by VAMs were collected through a systematic literature review and allocated to separate domains in an iterative process. The draft list of domains and their applicability were validated during two consecutive virtual workshops by health policy experts representing countries with different economic statuses, geographical and decision-making contexts.ResultsBased on 158 extracted studies, the final consensus on the evaluation framework resulted in 11 value domains in 5 main clusters, including unmet medical needs, health gain (measured by health care professionals), patient-reported outcomes, burden on households, and burden on the health care system.ConclusionsThe proposed framework could reduce the heterogeneity in value assessment processes across countries and create incentives for manufacturers to invest in incremental innovation. However, some domains may not be equally relevant or accepted in all countries, therefore the core framework needs thorough adaptation in specific jurisdictions.
| S-EPMC8406013 | biostudies-literature
Project description:The introduction of biological agents has revolutionized the management of many life-threatening and debilitating immune-mediated diseases. Because of the high cost of biological drugs and their patent expiration, the market has opened to biosimilar agents, copy versions of the originators, which can lead to reduced health care expenditure and increase treatment access worldwide. CT-P13 is the first biosimilar of infliximab (IFX) and has been approved for the same indications as its originator drug. It obtained regulatory approval by the European Medicines Agency in September 2013 and by the US Food and Drug Administration in April 2016. The Phase I and Phase III clinical trials conducted in ankylosing spondylitis and rheumatoid arthritis have demonstrated pharmacokinetic and efficacy equivalence with comparable safety and immunogenicity to IFX. For these reasons, the use of CT-P13 has been extrapolated also to inflammatory bowel disease. There have been some initial concerns regarding the use of CT-P13 in inflammatory bowel disease patients, because of the lack of randomized controlled trials. However, emerging real-world data have further confirmed the comparability between CT-P13 and its reference product in terms of efficacy, safety, and immunogenicity, in patients naïve to the anti-tumor necrosis factor alpha agents and after switching from IFX, and will be summarized in this review.
| S-EPMC5472432 | biostudies-literature
Project description:BackgroundTransient ischemic attack (TIA) is an important predictor for a pending stroke. Guidelines recommend a workup for TIA-patients similar to that of stroke patients, including an assessment of the extra- and intracranial arteries for vascular pathologies with direct therapeutic implications via computed tomography angiography (CTA). Aim of our study was a systematic analysis of TIA-patients receiving early CTA-imaging and to evaluate the predictive value of TIA-scores and clinical characteristics for ipsilateral vascular pathologies and the need of an invasive treatment.MethodsWe analysed clinical and imaging data from TIA patients being admitted to a tertiary university hospital between September 2015 and March 2018. Following subgroups were identified: 1) no- or low-grade vascular pathology 2) ipsilateral high-risk vascular pathology and 3) high-risk findings that needed invasive, surgical or interventional treatment. We investigated established TIA-scores (ABCD2-, the ABCD3- and the SPI-II score) and various clinical characteristics as predictive factors for ipsilateral vascular pathologies and the need for invasive treatment.ResultsOf 812 patients, 531 (65.4%) underwent initial CTA in the emergency department. In 121 (22.8%) patients, ipsilateral vascular pathologies were identified, of which 36 (6.7%) needed invasive treatment. The ABCD2-, ABCD3- and SPI-II-scores were not predictive for ipsilateral vascular pathologies or the need for invasive treatment. We identified male sex (OR 1.579, 95%CI 1.049-2.377, p = 0.029), a short duration of symptoms (OR 0.692, 95% CI 0.542-0.884, p = 0.003), arterial hypertension (OR 1.718, 95%CI 0.951-3.104, p = 0.073) and coronary heart disease (OR 1.916, 95%CI 1.184-3.101, p = 0.008) as predictors for ipsilateral vascular pathologies. As predictors for the need of invasive treatment, a short duration of symptoms (OR 0.565, 95%CI 0.378-0.846, p = 0.006), arterial hypertension (OR 2.612, 95%OR 0.895-7.621, p = 0.079) and hyperlipidaemia (OR 5.681, 95%CI 0.766-42.117, p = 0.089) as well as the absence of atrial fibrillation (OR 0.274, OR 0.082-0.917, p = 0.036) were identified.ConclusionMore than every fifth TIA-patient had relevant vascular findings revealed by acute CTA. TIA-scores were not predictive for these findings. Patients with a short duration of symptoms and a vascular risk profile including coronary heart disease, arterial hypertension and hyperlipidaemia most likely might benefit from early CTA to streamline further diagnostics and therapy.
| S-EPMC8722154 | biostudies-literature
Project description:Lymphatic mapping and sentinel lymphadenectomy (LM/SL) have been successfully used in pre-treatment nodal staging of gynaecological cancers. We hypothesised the added-value of LM/SL plus SPECT/CT in patients with early stage of cervical cancer and vulvar cancer. A prospective, single-center, diagnostic, open label, active control, non-randomized clinical trial has been conducted in 7 patients with FIGO IA-IB1 cervical cancer and 7 patients with FIGO stage I-II-IIIcN0 vulvar cancer. All patients underwent LM/SL plus SPECT/low-dose CT and complete lymph node dissection (CLND) according to the standard of care. In case of negative hematoxylin-eosin staining, serial sections of the SLNs were analysed by immunohistochemistry and high molecular weight cytokeratin. Primary outcome measures were the detection rate, the sensitivity (SV), the negative predictive value (NPV), the diagnostic accuracy (DA) for anatomic localisation of SLNs, and the impact on management of SPECT/CT guided LM/SL versus CLND. The secondary outcome measure was the patient tolerability and operating time of LM/SL guided SPECT/CT versus CLND. http://clinicaltrials.gov/show/NCT00773071 All 14 patients were enrolled into the 1-day research protocol with dual-tracer LM/SL and SPECT/CT. Additional SLNs were detected on SPECT/CT compared to conventional planar imaging. Hot and cold > 1cm SLNs were detected on SPECT/CT. Detection rate, SV, NPV, DA were 100% in both groups; false negative rate was 0%. Rate of SLN metastases was 28.5% in cervical cancer and 42.9% in vulvar cancer. Impact on treatment was 28.5% and 14.3% in cervical cancer and vulvar cancer patients, respectively. SPECT/CT was well tolerated by all patients and operating time for LM/SL was within 30 min. No adverse events were reported with a time frame of 1-to-3 years. In early stage of gynaecological cancers, SPECT/low-dose CT is technically feasible and of clinical added-value for LM/SL.
| S-EPMC3601478 | biostudies-literature
Project description:Data regarding double switching from originator infliximab (IFX) to IFX biosimilars in inflammatory bowel diseases (IBDs) are lacking. The purpose of this study was to evaluate the safety and efficacy of switching from originator IFX to CT-P13 and subsequently to SB2 (double switch) in patients with IBD. Patients undergoing IFX-double switch in eight Centers in Lombardy (Italy) from November 2018 to May 2019 were retrospectively analyzed. The IFX discontinuation rate, incidence and type of adverse events (AEs), and clinical remission rate were recorded. A comparison with a control group of patients with IBD single-switched from originator IFX to CT-P13 was performed, before and after an inverse probability of treatment weighting (IPTW)-based propensity score analysis. Fifty-two double-switched patients with IBD were enrolled. The 24- and 52-week proportions of patients continuing on IFX therapy following the second switch (CTP13 → SB2) were 98% (95% confidence interval [CI] 94%-100%) and 90% (95% CI 81%-99%), respectively. Four patients experienced a total of five AEs, all graded 1-3 according to Common Terminology Criteria for Adverse Events (CTCAE). No infusion reactions were observed. The 24-week and follow-up end clinical remission rates following the second switch were 94% and 88%, respectively. No differences were observed in the safety and efficacy outcomes by comparing the double-switch group with a single-switch group of 66 patients with IBD; all these results were confirmed by IPTW-adjusted analysis. The study suggests both the safety and efficacy of the double switch from originator IFX to CT-P13 and SB2 in patients with IBD is maintained. This strategy may be associated with potential cost implications.
| S-EPMC8742653 | biostudies-literature