Medicinal Products For Human Use Research Articles

PHP162 - LICENCED ORPHAN MEDICINES EXPENDITURE IN TURKEY

Orphan medicines (OM) are medicinal products for human use that are used in the diagnosis, prevention or treatment of rare diseases that threaten life or cause disability. They are medications that are often neglected in terms of their development and their production, even if their benefits are definitely determined, their use is so minimal that they are not economically viable. It has seen that OM's expenditure increasing for few years. We aimed to find out number of licenced orphan medicines and show total orphan medicines expenditure in Turkey for the year 2017. We used IQVIA Turkey database for sales numbers. We divided orphan medicines based on therapeutic area and reimbursement status in order to define public expenditure for licenced orphan medicines. June 2017 OrphaNet database considered to select products. Licence and unlicenced medicines list obtained from Turkish Medicines and Medical Devices Agency web site. We found out that 29 molecules licenced while 34 of them bringing from abroad with direct import method and 35 of them are unlicenced and currently not available in the market. Total cost of licenced orphan products were 228 million € in 2017 while reimbursed direct import orphan products expenditure reached to 240 million € with low amount of box sales. On the other hand expenditure for licenced orphan products 108% increased since 2013. Orphan products expenditure has been increasing. Orphan products has higher price comparing with medicines due low amount of patient population. Licenced orphan products take 5% of total pharmaceutical expenditure in Turkey. There is no specific pricing regulation for orphan products in Turkey. Rare disease treatments are valuable and to have sustainable system, countries should implement special pricing and reimbursement process for orphan products. Public incentives for investors will support orphan products development which will meet with public health needs.

EXPERT EVALUATION OF PRECLINICAL STUDIES OF PRIMARY AND SECONDARY PHARMACODYNAMICS OF MEDICINES

The article dwells upon the results of comparative analysis of the Russian national requirements and EAEU regulations dealing with evaluation of preclinical pharmacological studies. It highlights historical aspects of elaboration of regulatory requirements and scientific and methodological recommendations for conducting and evaluating preclinical pharmacological studies. According to the EAEU Rules of registration and evaluation of medicinal products for human use, the Common Technical Document has to include information on primary pharmacodynamics, secondary pharmacodynamics, safety pharmacology studies, and pharmacodynamic drug interactions, which are subject to evaluation during examination of the preclinical study results. The national guideline on evaluation of medicines does not contain any clear indication of the subject of examination in primary and secondary pharmacodynamic studies, which can make it difficult to prepare a registration dossier in the format of a Common Technical Document. The article formulates basic approaches to expert evaluation of the results of preclinical studies of primary and secondary pharmacodynamics of medicines. It determines the basics of expert evaluation which covers methodological framework of the research, results of the research, characteristics of the safety profile, extrapolation of preclinical data, characteristics of risk factors and of the predictable clinical safety profile for patients.

Validation of the method for determination of related impurities in the active antiviral ingredient of enisamium iodide

The aim of the work. To validate a method for the related impurities determination in the enisamium iodide active pharmaceutical ingredient (API) by means of high-performance liquid chromatography (HPLC). To characterize the sensitivity of the method by establishing the limit of detection and limit of quantification for the following impurities: benzylamine, isonicotinic acid (raw materials for API synthesis), isonicotinic acid benzylamide (intermediate product of API synthesis) and unidentified impurities. To confirm the method compatibility with validation characteristics as recommended by the International Conference on Harmonization of Technical Requirements for the Registration of Medicinal Products for Human Use (ICH). Materials and methods. The liquid chromatograph Agilent 1200 equipped with degasser, four-channel pump, auto sampler, chromatographic column thermostat and diode array detector was used. The Zorbax Eclipse XDB-C18 chromatographic column with dimensions 150.0 ×4.6 mm filled by octadecylsilane sorbent with a particles size of 5 μm, was used. The mobile phase was a mixture of a buffer solution pH 2.5 containing sodium octane-1-sulfonate in an amount of 0.1 %: water : acetonitrile (30 : 44 : 26 v/v/v). The primary standards of Farmak JSC were used: enisamium iodide (b. 07-16) and isonicotinic acid benzylamide (b. 10413). Other materials and reagents were used with sufficient purity (Sigma-Aldrich). Results. Detection limits and limits of quantification for identified and unidentified impurities have been determined. Validation characteristics such as specificity, accuracy, precision, range of use, robustness, intermediate precision have been confirmed. The linearity has been confirmed within the range of 0.01–0.06 % for each of the impurities (with a maximum permitted content of each impurity of 0.05 %). The correlation coefficients of linear regression (r) between the entered and found values for each of the determined impurities are greater than 0.990 and the relative confidence intervals ( D z ) are at the level not more than 5.0 %. Stability of the test solution, reference solution and solution for system suitability test upon storage at room temperature for 48 hours have been confirmed. Conclusions. It has been experimentally proved that the described method can be used for quality control of enisamium iodide substance.

Physicochemical and Microbiological Assays for Quality Evaluation of a Brand of Mentha piperita Tisanes in Costa Rica Market: Employment of the Central American Technical Regulation

Mentha piperita is a natural hybrid of water mint (Mentha aquatica) and spearmint (Mentha spicata L.), that are consumed as tisanes. For that reason, the present work evaluated physicochemical and microbiological aspects for the quality control of a commercial brand of Mentha piperita herbal tea distributed in Costa Rica, using assays established by the Central American Technical Regulation (RTCA) 11.03.56.09 (Pharmaceutical products. Natural medicinal products for human use. Quality verification), and determined if they have uniformity for different batches of this brand. To verify the quality of three batches of this product, the following assays were done: Labeling requirements, organoleptic, minimum fill, foreign organic matter, loss on drying, total ash, acid-insoluble ash, lead and arsenic limits, microbial enumerations and specific microorganisms (E. coli and Salmonella sp.) assays. As conclusion, the batches were in compliance for all the assays, except for labeling test, since information corresponding to the primary (batch number and expiration date) and secondary packaging (qualitative-quantitative composition of active ingredients interactions and adverse effects) were not presented. Furthermore, one of the batches did not have information about the employment, contraindications and warnings. Also, the manufacturing company maintained a good reproducibility between one batch and another, and the improvements that can be made are in the product labeling and better controls in its filling.
 Keywords: Natural product, Mentha piperita, quality control, tisane, pharmacopoeia, Central American Technical Regulation.

Encorafenib and Binimetinib: First Global Approvals.

Encorafenib (Braftovi™), a BRAF inhibitor, and binimetinib (Mektovi®), a MEK inhibitor, are two orally bioavailable drugs developed by Array BioPharma. In June 2018 they each received their first global approval, in the USA, for use in combination, for patients with unresectable or metastatic melanoma with a BRAFV600E or -V600K mutation as detected by an FDA-approved test. Registration applications for encorafenib and binimetinib for use in combination in the treatment of BRAF-mutation-positive advanced melanoma have also been submitted in the EU, Australia, Switzerland and Japan, with the EMA Committee for Medicinal Products for Human Use adopting a positive opinion in July 2018 towards granting the drugs marketing authorizations in the EU. Encorafenib plus binimetinib combination therapy is also in ongoing phaseIII clinical development in the treatment of metastatic colorectal cancer. This article summarizes the milestones in the development of encorafenib and binimetinib leading to these first approvals for the treatment of BRAFV600E or -V600K-mutation-positive unresectable or metastatic melanoma.

European Medicines Agency: Approval of new glucose-lowering medicines for type 2 diabetes.

Since 2005 all new glucose‐lowering medicines to be used in Europe have required approval by the European Medicines Agency (EMA) through a centralised procedure [1]. This involves assessment of a detailed file of data generated during the preclinical studies and phase 1‐3 clinical trials, along with the proposed product label. The file is subject to internal review and some aspects may also receive external review, giving rise to questions that are referred back to the sponsor and may lead to additional studies. The assessment is considered by the Committee for Medicinal Products for Human Use (CHMP) and if approval is recommended then a marketing authorisation is usually granted by the European Commission.

Drug Registries and Approval of Drugs: Promises, Placebo, or a Real Success?

PurposeAs part of the approval process, regulatory authorities often require postauthorization studies that involve patient registries; it is unknown, however, whether such registry studies are adequately completed. We investigated whether registry studies for new drugs were performed as agreed at time of approval. MethodsThis study reviewed protocols and follow-up reports for 73 registry studies that were proposed for 43 drugs approved by the Committee for Medicinal Products for Human Use in Europe in the period 2007 to 2010. ResultsThe data lock point of January 1, 2016, was taken to allow a 5-year follow-up period for each drug after approval. At that time, 2 studies (3%) in registries had been finalized, 19 registries (26%) had not enrolled any patients, and 52 studies (71%) were ongoing. The median enrollment was 31% (interquartile range [IQR], 6–104) of the required number of patients for 41 registry studies that had a predefined sample size, 30% (IQR, 2–101) for nonimposed registries, and 61% (IQR, 18–144) for imposed registries. ImplicationsEnrollment of patients into postapproval registries is poor, although the results for imposed registries seem better. Currently, registries only have a limited impact on resolving gaps in the knowledge of a drug’s benefits and risks at time of marketing authorization.

The challenge in colistin dosing: Updating available recommendations

Polymyxins have been available since the 1960s, however, because of their adverse effects, their use has been reserved for the treatment of infections caused by multiresistant bacteria. The increase in the clinical experience acquired in recent years and the published medical literature have raised doubts about the information provided by the product, indicating the need to update dosage recommendations, pharmacokinetics and pharmacokinetic/pharmacodynamic information (PK/PD). In addition, differences in concentration and dose between the different products of colistin may lead to errors of indication/administration and pose a risk to patients. In 2013, the European Medicines Agency (EMA) commissioned the Committee for Medicinal Products for Human Use (CHPM) to review available data and to make updated recommendations on the use of colistin. This procedure yielded a first report in 2014. This review highlights critical safety and efficacy aspects, reviews the recent pharmacokinetic and stability advances, the available pharmaceutical forms in Chile, providing the schemes currently recommended by health care agencies and experts in the field.

BIOTECNOLOGIA E DESENVOLVIMENTO REGIONAL: O CASO DA INDÚSTRIA DE MEDICAMENTOS DE USO HUMANO E FITOTERÁPICOS NO BRASIL E NA REGIÃO DA AMAZÔNIA LEGAL

The article analyzes the influence of urban and scientific attributes on the localization of herbal medicines and medicinal products for human use in Brazil, with emphasis on the Legal Amazon region. In order to do so, we estimated the Poisson regression model of inflated zeros, which uses two processes to model the response variable, which are the counting model and the zeros model. The first refers to the municipalities that have industries of medicines for human use and industries of herbal medicines. Already in the second are modeled the municipalities that do not have industries of medicines for human use and industries of herbal medicines. The results suggest that for both types of industries the urban and scientific attributes are determinant for the location of these companies in Brazilian municipalities. The most attractive characteristics of these locations are the urban scale, the strategic location of the municipality, the ease of transportation and the technical-scientific scale.

Ertugliflozin: First Global Approval

Ertugliflozin (Steglatro™) is an orally active sodium glucose co-transporter type 2 inhibitor being developed by Merck and Pfizer as a treatment for type 2 diabetes mellitus (T2DM). Ertugliflozin as monotherapy and in combination with various other antidiabetic drugs was associated with improvements in glycaemic control and secondary outcome measures in the VERTIS phase III clinical trial program. Ertugliflozin and fixed-dose combinations of ertugliflozin and metformin (Segluromet™) and ertugliflozin and sitagliptin (Steglujan™) have recently been approved by the US FDA as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. These products have also received a positive opinion from the EU Committee for Medicinal Products for Human Use (CHMP). This article summarizes the milestones in the development of ertugliflozin leading to its first approval for T2DM.

Будущее за инфузионной гепатопротекцией?

Hepatoprotectors are one of the important categories of drugs prescribed to patients with acute and severe conditions accompanied by impairment of the liver function. In view of the importance of this problem, at the end of 2017 the Government of the Russian Federation approved a new list of vital and essential medicinal products for human use for 2018, which included the original drug developed by the Russian researchers - the infusion hepatoprotector Remaxol®.

Letermovir: First Global Approval.

Letermovir (Prevymis™) is an orally or intravenously administered cytomegalovirus (CMV) DNA terminase complex inhibitor being developed by Merck & Co., Inc., under a global license from AiCuris Anti-infective Cures GmbH. Letermovir has been approved in Canada and the USA for the prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of an allogeneic haematopoietic stem cell transplant (HSCT). In addition, letermovir has received a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use, and is under review in several countries, including Japan. This article summarizes the milestones in the development of letermovir leading to its first global approval in Canada as well as the USA for the prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of an allogeneic HSCT.

THE NEW REGULATIONS FOR THE APPROVAL OF MEDICINAL PRODUCTS IN IVORY COAST: APPLICATION OF REGULATION N ° 06/2010 / CM / WAEMU RELATING TO PROCEDURES FOR THE APPROVAL OF PHARMACEUTICAL PRODUCTS FOR HUMAN USE IN WAEMU MEMBER STATES.

Harmonization of procedures for the approval of medicines in the WAEMU area allows Member States to have astandard tool for the examination of applications for marketing authorization for medicinal products for human use.The objective of this study was to highlight the textual provisions adopted by a member state, Côte d'Ivoire foroptimal application of the Community norm. The methodology used consisted, on the basis of a reminder of the mainpoints of Regulation No. 06 / CM / UEMOA concerning the approval of medicinal products for human use, to showhow the national implementing decrees taken in Côte d'Ivoire the Regulation. However, the need for Member Statesto act more expeditiously with regard to the application of Community standards is clear.&nbsp

Immunogenicity considerations for antibody-drug conjugates: a focus on neutralizing antibody assays.

Immunogenicity considerations for antibody-drug conjugates: a focus on neutralizing antibody assays.

Immunogenicity and safety of a novel seasonal influenza preservative-free vaccine manufactured in Kazakhstan: Results of a randomized, comparative, phase II clinical trial in adults

ABSTRACTBackground: The study was aimed at comparative evaluation of seasonal influenza vaccine RIBSP versus commercial vaccine VAXIGRIP® for immunogenicity and safety in the course of clinical trial phase II on healthy volunteers aged 18–60 years. Methods: The trial involved 150 subjects in randomized 2:1 groups that received either RIBSP vaccine or comparator vaccine VAXIGRIP®. One dose (0.5 ml) of either vaccine contained 15 μg of hemagglutinin of each influenza virus strain recommended by WHO for the Northern hemisphere in 2016–2017 flu season. The observation period lasted 21 day. The trial was registered at ClinicalTrials.gov identifier NCT 03016143. Results: Assessment of immunogenic activity of the vaccine under study showed that in 21 day the portion of participants with 4-fold seroconversions was 87.0% to A/H1N1; 63.0% to A/H3N2 and 59.0% to B virus. Antibody titer increase factor in the group of subjects that received RIBSP vaccine was 23.3 for A/H1N1; 4.4 for A/H3N2 and 4.5 for B virus. The volunteers that received RIBSP vaccine demonstrated 95% seroprotection level against A/H1N1; 84% against A/H3N2 and 80% against B virus. RIBSP vaccine met the CHMP criteria of the Committee for Medicinal Products for Human Use (CPMP/BWP/214/96). In the course of evaluating the vaccine safety no serious undesirable effects were recorded. All changes of laboratory data were slight and single in most cases. All recorded local reactions have been light in character and these have been predicted reactions observed at vaccination against influenza. Conclusion: Comparison of the allantoic inactivated split vaccine obtained in vaccines RIBSP and VAXIGRIP®, showed similar immunogenic activity. Both vaccines were safe for the study participants.

Quality Issues Identified During the Evaluation of Biosimilars by the European Medicines Agency's Committee for Medicinal Products for Human Use.

The aim of this study was to identify trends in deficiencies raised during the EU evaluation of the quality part of dossiers for marketing authorisation applications of biosimilar medicinal products. All adopted day 120 list of questions on the quality module of 22 marketing authorisation applications for biosimilars submitted to the European Medicines Agency and concluded by the end of October 2015 was analysed. Frequencies of common deficiencies identified were calculated and summarised descriptions included. Frequencies and trends on quality deficiencies were recorded and presented for 22 biosimilar applications. Thirty-two 'major objections' for 9 products were identified from 14 marketing authorisation applications with 15 raised for drug substance and 17 for drug product. In addition, 547 'other concerns' for drug substance and 495 for drug product were also adopted. The frequencies and trends of the identified deficiencies together with their impact were discussed from a regulatory perspective and how these impact key manufacturing processes and key materials used in the production of biosimilars. This study provides an insight to the regulatory challenges prospective companies need to consider when developing biosimilars; it also helps elucidate common pitfalls in the development and production of biosimilars and in the submission of dossiers for their marketing authorisations. The results are expected to be of interest to pharmaceutical companies but also to regulators to obtain consistent information on medicinal products based on transparent rules safeguarding the necessary pharmaceutical quality of medicinal products.

Registries supporting new drug applications.

PurposeKnowledge of the benefits and risks of new drugs is incomplete at the time of marketing approval. Registries offer the possibility for additional, post‐approval, data collection. For all new drugs, which were approved in the European Union between 2007 and 2010, we reviewed the frequency, the type, and the reason for requiring a registry.MethodsThe European Public Assessment Reports, published on the website of the European Medicine Agency, were reviewed for drugs approved by the Committee for Medicinal Products for Human Use. We searched for key characteristics of these drugs, including therapeutic area (ATC1 level), level of innovation (the score is an algorithm based on availability of treatment and therapeutic effect), and procedural characteristics. In addition, we identified if these registries were defined by disease (disease registry) or exposure to a single drug (drug registry).ResultsOut of 116 new drugs approved in the predefined period, for 43 (37%), 1 to 6 registry studies were identified, with a total of 73 registries. Of these 46 were disease registries and 27 (single) drug registries. For 9 drugs, the registry was a specific obligation imposed by the regulators. The level of innovation and the orphan status of the drugs were determinants positively predicting post‐approval registries (OR 10.3 [95% CI 1.0‐103.9] and OR 2.8 [95% CI 1.0‐7.5], respectively).ConclusionsThe majority of registries required by regulators are existing disease registries. Registries are an important and frequently used tool for post‐approval data collection for orphan and innovative drugs.

Orphan Drug Regulation: A missed opportunity for children and adolescents with cancer

BackgroundOncology represents a major sector in the field of orphan drug development in Europe. The objective was to evaluate whether children and adolescents with cancer benefited from the Orphan Drug Regulation. MethodsData on orphan drug designations (ODDs) and registered orphan drugs from 8th August 2000 to 10th September 2016 were collected from the Community Register of medicinal products for human use. Assessment history, product information and existence of paediatric investigation plans were searched and retrieved from the European Medicine Agency website. ResultsOver 16 years, 272 of 657 oncology ODDs (41%) concerned a malignant condition occurring both in adults and children. The five most common were acute myeloid leukaemia, high-grade glioma, acute lymphoblastic leukaemia, graft-versus-host disease and soft-tissue sarcomas. 74% of 31 marketing authorisations (MAs) for an indication both in adults and children (26 medicines) had no information for paediatric use in their Summary of Product Characteristics (SmPC) at the time of the first MA. Furthermore, 68% still have no paediatric information in their most recently updated SmPC, at a median of 7 years after. Only 15 ODDs (2%) pertained to a malignancy occurring specifically in children and only two drugs received an MA: Unituxin for high-risk neuroblastoma and Votubia for sub-ependymal giant-cell astrocytoma. ConclusionThe Orphan Drug Regulation failed to promote the development of innovative therapies for malignancies occurring in children. Major delays and waivers occurred through the application of the Paediatric Medicines Regulation. The European regulatory environment needs to be improved to accelerate innovation for children and adolescents dying of cancer.

GCP and Quality in “Regulation (EU) 536/2014 on clinical trials on medicinal products for human use and repealing Directive 2001/20/EU”

Among the several new provisions foreseen by the EU Regulation (R) 2014/536 on Clinical Trials (CTs) repealing Directive (D) 2001/20/EC, this article focuses on the identification of possible critical points leading to potential incongruences regarding Good Clinical Practice (GCP). EU D foresees the obligation to be in compliance with GCP detailed guidelines, while the R foresees the obligation to be in compliance only with the GCP principles. Many of the GCP detailed aspects have been transposed in the R and the R provides to be in compliance with GCP quality standards. Nevertheless, other GCP aspects, which have direct or indirect ethical implication in CTs, will not be mandatory in the EU.

Rethinking the Appraisal and Approval of Drugs for Fracture Prevention.

Background: In January 2014, the EMA's Pharmacovigilance Risk Assessment Committee recommended that strontium ranelate no longer be used for osteoporosis. However, EMA's Committee for Medicinal Products for Human Use decided to restrict its use rather than ban it. Starting from this fact, evidence of drugs for fracture prevention over the last 30 years was reviewed and lessons to be learnt from this story are highlighted.Findings: The general belief that drug therapy may become a “solution” for fragility fractures is challenged. The key points of the article are as follows:Lessons 1–5: Bone density and morphometric vertebral compression are not reliable surrogate endpoints. In fact, clinically relevant endpoints are essential to assess harms and benefits in clinical trials. There is a need for assessing overall harm-benefit with well-designed trials, taking into account that drug therapy may not be more effective in high-risk patients. Lessons 6–10: While bisphosphonates and strontium ranelate show a questionable harm-benefit ratio on hip fracture prevention, denosumab results are inconclusive and no benefit has been proved coming from calcitonines or teriparatide. After decades of widespread use, effectiveness of drugs for osteoporosis remains uncertain, yet adverse effects are more apparent.Conclusions: Well-designed and large trials over prolonged follow-up periods, measuring clinically relevant outcomes as hip and other disabling fractures, are urgently needed in order to properly understand the harm-benefit ratio of commonly prescribed drugs. Regulatory agencies should be more transparent and make individual-patient data from all clinical trials publicly available, allowing for independent assessment and pooled analysis.