Products For Human Use Research Articles

Protein and Peptide Biopharmaceuticals: An Overview.

Bioactive proteins and peptides are recognised as novel therapeutic molecules with varying biological properties for potential medical applications. Development of protein and peptidebased therapeutic products for human use is growing steadily as they continue to receive an increasing rate of approval by the United States Food and Drugs Administration (US FDA). In this short review, we describe the current status and methodologies involved in the synthesis of protein and peptide biopharmaceuticals with an emphasis on the drivers and restrains to their exploitation in the therapeutic products sector.

CURRENT ENVIRONMENT FOR INTRODUCING HEALTH TECHNOLOGY ASSESSMENT IN GREECE

The aim of this study was to describe the current regulatory environment in Greece to evaluate the potential introduction of health technology assessment (HTA) for medicinal products for human use. Data sources consist of national legislation on pricing and reimbursement of health technologies to identify the potential need of establishing HTA and its relevant structure. The pricing procedure regarding medicinal products for human use is based on an external reference pricing mechanism which considers the average of the three lowest Euorpean Union prices. Currently, a formal HTA procedure has not been applied in Greece, and the only prerequisite used for the reimbursement of medicinal products for human use is their inclusion in the Positive Reimbursement List. To restrict pharmaceutical expenditure, a variety of measures-such as clawback mechanisms, rebates, monthly budget caps per physician, generics penetration targeting-have been imposed, aiming mainly to regulate the price level rather than control the introduction of medicinal products for human use in the Greek pharmaceutical market. Greece has the opportunity to rapidly build capacity, implement, and take advantage of the application of HTA mechanisms by clearly defining the goals, scope, systems, context, stakeholders, and methods that will be involved in the local HTA processes, taking into account the country's established e-prescription system and the recently adapted legislative framework.

Clinical Research: Good News Coming from Ca2+/cAMP Signaling Interaction

Clinical research plays an important role in medical sciences by determining the safety and efficiency of medications, devices and diagnostic products for human use. Our discovery of the interactions between intracellular signaling pathways as mediated by Ca2+ and cAMP (Ca2+/cAMP signaling interaction) in neurotransmission could help improve clinical research. This discovery emerged from classical neurotransmission studies using rodent vas deferens as a model. In addition, the concept of Ca2+-dependent muscle contraction (Ca2+ influx triggers muscle contraction) is amply accepted. Thus, Ca2+ channel blockers (CCB) should reduce muscle contraction. Nonetheless, using this model, some studies performed since 1975 reported that reduction of Ca2+ influx by low concentrations of CCB (verapamil, diltiazem or nifedipine) produced a paradoxical increase of the contractions mediated sympathetic nerves, a phenomenon known as “calcium paradox”. Recent studies using adrenal chromaffin cells have also demonstrated that CCB caused a paradoxical increase of the catecholamine release. Because these compounds are blocking the L-type voltage-activated Ca2+ channels (VACC), an augmented nerve-mediated response due to increased neurotransmitter release was an unexpected outcome. In 2013, we revealed that the Ca2+/cAMP signaling interaction could properly explain the so-called “calcium paradox”. The original paper published by us in Cell Calcium (2013) has appeared four times in ScienceDirect TOP 25 Hottest Articles lists. In conclusion, these findings may significantly impact on cardiovascular and neurodegenerative diseases, cancer, stem cell-based therapies and many other diseases, and may stimulate the development of new pharmacological strategies to combat these diseases.

Timeline of Authorization and Reimbursement for Oncology Drugs in Italy in the Last 3 Years

Introduction The main purpose of this analysis was to quantify the time elapsed between the validation date of European Medicines Agency (EMA) centralized procedure and the first purchase of a product by at least 1 Italian health care structure, evaluating different variables that affect the process, the number of products approved by the Committee for Medicinal Products for Human Use (CHMP) that are available on the Italian market (July 2016), and the impact of the Cnn class for oncology drugs in Italy. Methods A panel of oncology products has been defined, which considered drugs approved by the EMA between January 2013 and December 2015, and authorized for the treatment of oncology diseases, excluding generics. Data were obtained via the EMA website by the Agenzia Italiana del Farmaco (AIFA; the Italian Medicine Agency) meeting reports, by official administrative acts of marketing authorization, and the date of the first purchase (first day of the first handling month). Results The mean time of EMA evaluation for the considered panel of medicines was about 441 days (standard deviation (SD) 108; range 266-770); the average approval time for AIFA was about 248 days (SD 131; range 85-688). Interestingly, the mean AIFA evaluation time decreased significantly from 264 days for products submitted to AIFA assessment in 2013-2014 to 219 days for products evaluated in 2015-2016. Focusing on the regional access, both the timing and the number of drugs available for patients were widely different from region to region. Discussion A reduction in the approval time in the last 2 years has been observed in Italy. However, several variables influence the efficiency of the process and need to be addressed to make the access to drugs timely and efficient.

Nivolumab-Induced Rapid Tumor Remission of Pulmonary Adenocarcinoma

We The immune checkpoint modulator, nivolumab (BMS-936558/ONO-4538), is the first PD-1 inhibitor to gain regulatory approval, for the treatment of patients with unresectable melanoma. Nivolumab received FDA approval for the treatment of melanoma in December 2014. On 24 April 2015, the Committee for Medical Products for Human Use of the European Medicine Agency recommended approval of Nivolumab for metastatic melanoma as a monotherapy. In March 2015, the US FDA approved it for the treatment of squamous non-small cell lung cancer. This case reports about a patient with metastatical pulmonary adenocarcinoma who benefited from the therapy with nivolumab. Already after 10 weeks of treatment with nivolumab, we registered rapid tumor remission.

Influence of Different Processing Methods on Aflatoxin Level in <i>Ogi</i> Slurry Produced from Millet (<i>Pennisetum typhoideum</i>)

The global shortage of cereal foods arising from improper processing and preservation methods adopted in some of our industries could be the sources of contamination of various food products which could lead to devastating health disorder. From this study, millet grains were subjected to different processing methods such as fermentation, alkaline boiling, oven drying and sun drying. The microorganisms associated with the processed samples were isolated and identified using standard microbiological and biochemical methods. The extraction, detection and quantification of aflatoxin from ogi slurry were quantified using thin layer chromatography. The sample fermented with ethanol and water showed higher fungal count 37.33cfu/ml while the sample fermented in sodium hypochloride shown no growth of Aspergillus flavus with fermentation time at initial inoculation. The milled fermented oven dry sample showed higher colony counts 14.50 cfu/g when compared to milled sun-dry and alkaline boiling fermented samples. The aflatoxin level of the ogi slurry ranged from 0.00ppb to 0.02ppb. Samples fermented with water and ethanol showed high effect in removal of aflatoxin B and G produced by toxigenic Aspergillus flavus while the alkaline boiling showed less effect on aflatoxin B1 and B2. Aflatoxin G1 and G2 were completely removed/destroyed from the sample fermented with ordinary water with aflatoxin level 0.00ppb. The sample subjected to oven dry and sun-dry showed complete removal/reduction in aflatoxin B1 and G1. The reduction in aflatoxin level of ogi slurry produced from millet using different processing methods showed its permissible level below the standard as recommended by National Agency for Food Drug Administration and Control (NAFDAC) and European Union which could be promising prior to this methods in controlling the level of contaminant in our food products for human use.

Crime against Humanity<br/>—Uncovering Two Decades of Corruption in the FDA Regarding DMD Treatment

The world needs to know the facts as to how the FDA “protects” the public health by assuring the safety, effectiveness, and security of human drugs and biological products for human use. Recent uproar has surfaced over the FDA’s approval process on the unproven Duchenne Muscular Dystrophy (DMD) drug, Exondys 51 (Sarepta Therapeutics, Cambridge, MA, USA), but what many people do not know are the unlawful events that occurred nearly two decades ago on a proven and promising treatment for DMD.

Randomized, double-blind, multi-center, phase III clinical trial to evaluate the immunogenicity and safety of MG1109 (egg-based pre-pandemic influenza A/H5N1 vaccine) in healthy adults

ABSTRACTConsidering the pandemic potential of avian influenza A/H5N1, development of an effective and well-tolerated vaccine is an essential part of pandemic preparedness plans. This phase III, randomized, double-blind study was conducted to assess the immunogenicity and safety profile of an alum-adjuvanted, whole virion, pre-pandemic influenza A/H5N1 vaccine (MG1109). Healthy individuals were randomly assigned, in a 3:1 ratio, to receive two doses of either MG1109 or placebo containing alum gel. Immunogenicity was determined by hemagglutination inhibition (HI) and microneutralization (MN) assays. Solicited and unsolicited adverse events were assessed after vaccination. Among 420 enrolled subjects, 418 were available for safety analysis, and 298 MG1109 recipients were available for per-protocol immunogenicity analyses. According to the HI assays, after two vaccine doses, all three of the Committee for Medicinal Products for Human Use (CHMP) criteria were met against the vaccine strain for all age groups: seroprotection rate = 74.8% (95% CI: 69.9 – 79.8), seroconversion rate = 67.8% (95% CI: 62.5–73.1), and geometric mean titer ratio (GMTR) = 5.9 (95% CI: 5.4 – 6.4). According to the MN assays, the GMTR was 2.4 (95% CI: 2.1 – 2.7) and 7.0 (95% CI: 6.3 – 7.9) three weeks after the first and second vaccine doses, respectively. Solicited local and systemic adverse events were mostly mild to moderate and were not significantly different between MG1109 and placebo recipients. In conclusion, two-dose administration of alum-adjuvanted H5N1 pre-pandemic influenza vaccine (MG1109) was highly immunogenic and tolerable in adults.

A Guidance Manual for the Toxicity Assessment of Traditional Herbal Medicines

Herbal remedies have been used for thousands of years in worldwide traditional medicines for their potential health benefits. Although they are generally presumed safe unless a significant risk has been identified in humans, increasing number of case reports notify acute or chronic intoxications resulting from their use. This study aims to produce a scientific guide for the evaluation of traditional herbal medicines (THMs) in terms of their toxicity risks based on the published regulatory documents. For this purpose recommended in vitro and in vivo toxicity tests on medicinal products for human use issued by the international regulatory bodies are overviewed and they are then adopted to be used for the toxicity assessment of THMs. Accordingly, based on compilation of these issued regulations, the following tests are recommended for the toxicity assessment of THMs; in vitrocytotoxicity, genotoxicity, acute and repeated dose toxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance tests, toxicokinetic studies, and additional toxicity tests including safety pharmacology, immunotoxicity and antigenicity, endocrine system toxicity, gastro-intestinal toxicity, renal and hepatotoxicity, and drug interaction studies. This study describes and discusses the applicability of these tests for the risk assessment in THMs.

Scale-Up of Protein Purification: Downstream Processing Issues.

Separation science continues to occupy the central position in the overall strategy for the downstream processing and purification of therapeutic protein products for human use. Increasing product titers from mammalian cell culture and new emerging classes of biopharmaceuticals has presented a challenge to the industry to identify ways of improving the robustness and economics of chromatography processes. In commercial manufacturing, there is always a need to increase the scale of the chromatography operations which are typically developed and optimized in small-scale laboratory experiments. This review discusses the key factors in the chromatography process that need to be considered as the scale of the purification step is increased in order to maintain the purity and integrity of the product purified at smaller scale.

Medicamentos Não Sujeitos a Receita Médica de Dispensa Exclusiva em Farmácia em Portugal: Uma Oportunidade de Acesso Sub-Aproveitada?

In 2013 medicinal products for human use not subject to medical prescription dispensed exclusively in pharmacy, a subcategory of products not subject to medical prescription was introduced in Portugal. This category of medicinal products promotes the accessibility to treatment, ensuring safety and efficacy, with benefits to public health. This article analyzed the medicines classified as medicinal products for human use not subject to medical prescription dispensed exclusively in pharmacy or equivalent in seven European countries, United Kingdom, Denmark, Sweden, Norway, Italy, Czech Republic and Portugal, and proposes a preliminary list of common international names/ medicines that possess the characteristics that justify their inclusion in Portugal, in this category. For the selection, common international names /medicines approved in the considered countries were selected if, in at least one of the countries considered, they are classified as medicinal products for human use not subject to medical prescription dispensed exclusively in pharmacy or equivalent, and/ or have the classification of medicinal products subject to medical prescription in Portugal and medicinal products not subject to medical prescription in one of the considered countries. The preliminary list obtained contains 271 different common international names / presentations. About 19% of the selected common international names do not have a valid marketing authorization in Portugal and the majority (42%) is classified in Portugal as medicinal products not subject to medical prescription, a lower percentage (35%) as medicinal products subject to medical prescription, and only 4% as medicinal products for human use not subject to medical prescription dispensed exclusively in pharmacy. Safety is one of the main aspects to be considered in the context of the reclassification of medicines regarding their supply to the public. The results obtained promote a reflection on the relevance of extending the availability of medicines with the classification of medicinal products for human use not subject to medical prescription dispensed exclusively in pharmacy in Portugal, which, due to their characteristics and indications, would benefit from an access without a medical prescription, ensuring the safety in its use.

1.10 - Medicinal Product Regulation: Portugal’s Framework

The prescription, supply and use of medicines should centre on their rational use, in order to foster patients’ interests and integrity, and promote public health and national economic sustainability. The pharmaceutical industry is one of the most tightly regulated sectors, and it is essential to know each country’s legislative framework in order to understand the regulation, approval, and marketing of medicinal products for human use. Portugal has played an important role in the European Union and European Economic Area as a Reference Member State (RMS). The aim is to describe the main statutes and procedures governing medicinal products for human use in Portugal, as well as the role of the country's National Medicines and Health Products Authority.

Negotiating prices of drugs for rare diseases.

Rare diseases are often serious, chronic and life-threatening. The European Union (EU) definition of a rare disease is one that affects fewer than 5 in 10 000 people. (1) At present, more than 6000 rare diseases are known; around 80% of them are genetic disorders and half of them occur during childhood. Grouped together, rare diseases affect 6-8% (or about 30 million people) out of the 508 million population of EU countries. (2) This roughly equals the estimated prevalence of diabetes in the World Health Organization European Region, which in 2013 was 6.8% of 658.7 million adults in the 20-79 year age group. (3) This illustrates the paradox of rarity: each disease is rare but collectively, rare diseases affect many people. (4) In 2009, responding to increasing concerns about the issue, the European Council published a recommendation (2009/C 151/02) on action in the field of rare diseases, recommending Member States to adopt and establish national plans for rare diseases by the end of 2013. (2) Rare diseases are associated with a high psychological burden for the patient but they can also have a major impact on a patient's family. (5) In addition to the health burden on patients, few of these diseases have an effective drug treatment available. This is because the drugs to treat rare diseases (called orphan drugs) are not commercially viable for pharmaceutical companies, due to the small number of patients per disease. To encourage pharmaceutical companies to develop and market orphan drugs, the European Parliament and the European Council published the regulation (EC) No 141/2000 on orphan medicinal products in 1999. (1) Orphan designation for a medicine is granted at the European level by the European Medicines Agency (EMA). Three criteria must be met, as stated in the regulation: (i) the medicine must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating; (ii) the prevalence of the condition in the European Union must be no more than 5 in 10 000 or it must be unlikely that the marketing of the medicine would generate sufficient returns to justify the investment needed for its development; and (iii) no satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorized, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition. (1) The application for orphan designation, which can be submitted by the sponsor of the medicinal product at any stage of drug development, is then examined within 90 days by the Committee for Orphan Medicinal Products of the EMA. When a medicine is granted orphan designation, several incentives are provided to the sponsor of a clinical trial, as stated in regulation (EC) No 141/2000. (1) These incentives include protocol assistance, scientific advice from EMA before the submission for marketing authorization and market exclusivity of 10 years once the medicine is marketed. This period of market exclusivity can be extended by two years for medicines that comply with an agreed investigation plan for medicines for paediatric care. Finally, depending on the status of the sponsor and the type of service required, reductions in fees to be paid for regulatory activities related to the evaluation of orphan medicinal products by EMA (e.g. protocol assistance, application for marketing authorization) can also be available for the sponsor. By the end of 2015, 89 different orphan medicinal products had received authorization to enter the market from the EMA's Committee for Medicinal Products for Human Use, and 123 other medicinal products intended for rare diseases but without the orphan designation in Europe also received the European marketing authorization. (6) In addition, an increasing number of applications for orphan designation are submitted to EMA each year (Fig. 1). (7) As a consequence, an increasing number of applications for a marketing authorization of an orphan medicinal product is observed each year. …

Medicinal Product Regulation: Portugal׳s Framework

PurposeThe pharmaceutical industry is one of the most tightly regulated sectors, and it is essential to know each country׳s legal framework to understand the regulation, approval, and marketing of medicinal products for human use. This article describes the main statutes and procedures governing medicinal products for human use in Portugal and the role of the country׳s National Medicines and Health Products Authority (Autoridade Nacional do Medicamento e Produtos de Saúde, I.P.; INFARMED). MethodsFrom the most recently available data, an update of requests and approvals concerning marketing authorizations, variations, pricing, and reimbursements is provided. Data were sourced from the INFARMED website, Infomed (database of medicinal products for human use), and periodic reports issued by national authorities. Organic laws, acts, and law decrees published in the government gazette (Diário da República) are cited and reproduced as required. FindingsIn 2015 Portugal ranked fifth in the European System of Medicines Evaluation in terms of the number of completed procedures as a reference member state. Approximately 80% of all approved drug applications in Portugal in 2015 were for generic drugs, mostly pertaining to the nervous system. In Portugal, INFARMED monitors drug quality, safety profile, and efficacy in all stages of the drug life cycle, ensuring patients’ safety. ImplicationsThe Portuguese market for medicinal products for human use has been appreciably changed by the advent of generic drugs. There is an increased trend for new request applications for biological and biotechnological substances.

European regulatory incentives for common drugs and the power of patents—working together towards innovation, against it or just getting lost in the middle?

The idea that patent owners should be granted early exclusionary rights conferring a broad scope of protection stems from the Prospect Theory elaborated by Edward Kitch. 1 Kitch advocated the early grant of patents targeted at the construction of broad patent portfolios in order to give the patent owner sufficient incentives to make further investments and ‘to maximize the value of the patent without fear that the fruits of the investment will produce unpatentable information appropriable by competitors’. 2 This approach would produce an increase in follow-on innovation and product development, tailored to the needs of society. Kitch’s arguments have attracted support and prompted the creation of ad hoc legislation. A prime example is the framework of regulatory incentives designed by the European Commission and disciplined by Directive 2000/83/EC on the Community code relating to medicinal products for human use, as amended. 3 This piece of legislation sought to stimulate innovation and timely patient access to medicines, preserving the stimulus for investments in research in the medical field.

Targeted supplementation design for improved production and quality of enveloped viral particles in insect cell-baculovirus expression system

The recent approval of vaccines and gene therapy products for human use produced in the Insect Cell-Baculovirus Expression Vector System (IC-BEVS) underlines the high potential and versatility of this platform. The interest in developing robust production processes emerges to cope with manufacturing pressure, as well as stringent product quality guidelines. Previously, we addressed the impact of the baculovirus infection on the physiology of insect host cell lines, identifying key cellular pathways enrolled in heterologous gene/protein expression. In the present work, this knowledge was applied to design tailored media supplementation schemes to boost IC-BEVS production yields and quality of enveloped viral particles: influenza VLPs (Inf-VLP) and baculovirus vectors (BV).The addition of reduced glutathione, antioxidants and polyamines increased the cell specific yields of baculovirus particles up to 3 fold. Cholesterol was identified as the most critical system booster, capable of improving 2.5 and 6-fold cell specific yields of BV and Inf-VLPs, respectively. Surprisingly, the combination of polyamines and cholesterol supplementation improved baculovirus stock quality, by preventing the accumulation of non-infectious particles during viral replication while selectively increasing infectious particles production. In addition, the specific yields of both enveloped viral particles, BVs and Inf-VLPs, were also increased.The correlation between supplement addition and systems productivity was extensively analyzed, providing a critical assessment on final product quantity and quality as drivers of bioprocess optimization efforts.

Legal responses to placebo-controlled trials in developing countries

ABSTRACTThe conduct of clinical trials involving placebo in developing countries in the presence of an existing effective treatment triggered an intense debate on the standard of care to be provided to those populations. Charges of exploitation of vulnerable groups and double standards have been raised by several scholars. In response to these concerns, the Declaration of Helsinki (DoH) was revised in 2000, 2008 and 2013, eventually endorsing the golden standard instead of the local standard of care. The European Union (EU) adopted a strategy on the Marketing Authorization of medicinal products tested in third countries, improved with Regulation 536/2014 on clinical trials on medicinal products for human use. Additional rules have been enacted by other international organizations (UNESCO, Council of Europe). The present paper has the aim of analyzing scope and content of existing international and regional standards on placebo.

Commercialisation of a natural material – wool: a bio-based PCM

Cold-chain temperature control is necessary to prevent damage to life-saving vaccines caused by heat exposure. However, keeping vaccines too cold is just as harmful, since freezing damages many vaccines. Protecting vaccines from freeze damage remains one of the most poorly addressed problems in vaccine management. Cold-chain practices tend to prioritise the protection of vaccines from heat damage, often at the risk of exposing them inadvertently to freezing temperatures. The maintenance of accurate and uniform temperatures is, therefore, of significant importance in improvements to global human healthcare. Exposure to heating or freezing conditions will weaken and subsequently break the hydrogen bonds holding the tertiary structure together, causing the vaccine to become ineffective. This paper demonstrates a design innovation process leading to the development of a high-performance, sustainable fibre material, with cradle-to-cradle credentials, that has transformed the market for passive insulated packaging used in the global distribution of temperature-sensitive pharmaceutical products for human use. The extensive scientific research on this natural ‘smart fibre’ has resulted in an insulated packaging material that substantially exceeds the temperature performance criteria required by European and US good distribution practice regulations for the distribution of medicines. This smart fibre is 100% pure sheep’s wool.

Benefit-risk reassessment of medicines: a retrospective analysis of all safety-related referral procedures in Europe during 2001-2012

The aim of this study was to determine the outcomes and timing within the product life cycle of all benefit-risk reassessment procedures for marketed products that were completed by the committee for medicinal product for human use during 2001-2012. A cohort of all referral procedures for benefit-risk reassessment (Article 20, Article 31, Article 36, Article 107 procedures) for which committee for medicinal product for human use issued an opinion between 1 January 2001 and 31 December 2012 was created. The European Medicines Agency website and the Dutch Medicines Evaluation Board website were used to collect all data. There were a total of 73 benefit-risk reassessments during the study period; 61 reassessments for a single product and 12 reassessments for multiple products or an entire product class. Nineteen reassessments resulted in the recommendation to remove the product from the market. On average, a benefit-risk reassessment was performed 18.7 years after the product was first marketed. Seventeen products were marketed 5 years or less when the reassessment procedure was completed; six of these products were subsequently removed from the market. The majority of all benefit-risk reassessments that were performed during the study period did not result in removing the product from the market, but rather, in confirming the positive benefit-risk of the product, conditional to changes to the product's marketing authorisation. About half of all products that were removed from the market during the 2000s had been marketed for more than 20 years. Copyright © 2016 John Wiley & Sons, Ltd.

Informed consent for clinical investigation in the critically ill patient. An introduction to the regulation 536/2014/EC on clinical investigation of medicinal products for human use, repealing Directive 2001/20/EC

The principle of patient information, awareness and documented consent for the participation in clinical trials is a cornerstone in the modern ethics of clinical research. However, this procedure is seldom applicable in the critically ill patient who becomes suddenly incapable of fully evaluating the risk vs benefit of the alternative therapeutic options. This issue becomes particularly problematic in those conditions where the benefit of any intervention is highly time-dependent, such as acute myocardial infarction, stroke, cardiac arrest, polytrauma and other similar conditions. The new directive 536/2014/EC defines the concept that in these cases the expert clinician and the Ethics Committees, based upon a rigorous study protocol, are in better conditions, as compared to patients' proxies and any legal representative, to take an appropriate decision. This decision should be later confirmed (deferred consent) by the patient, in case he returns competent, or by his proxies or legal tutor, in order to use experimental data. The new directive ends a long period of disparity among the Member States, some of which had taken unilateral decisions allowing the participation of incapable patients, whereas others, among which Italy, had a more conservative approach. Unfortunately, owing to technical and bureaucratic issues, the new regulation is unlikely to become active before the beginning of 2018.