The development of biological products has experienced continuous growth over the past three decades. The expiration of patent protection for many biological medicines has led to the development of biosimilars in many countries around the world. This paper reviews the literature on biosimilar drugs and covers their therapeutic status, clinical trials, approved biosimilars, and regulatory guidelines in Japan, South Korea, and Malaysia. The literature suggests that biosimilars are comparable but not identical to the reference product. They are not a generic version of an innovative product and do not ensure therapeutic equivalence. Biosimilars present more challenges than conventional generics and their marketing approval is also much more complicated. Guidelines for biosimilars were published in Japan in July 2009 by the Ministry of Health, Labour and Welfare (MHLW), in South Korea in March 2009 by the Ministry of Food and Drug Safety (MFDS), and in Malaysia in July 2008 by the National Pharmaceutical Control Bureau (NPCB). Since its beginnings, the biopharmaceutical industry  has been constantly evolving in order to meet the new therapeutic needs of society. This evolution has generally been driven by strong investment in research and development, which has allowed it to be recognized as a continuously growing industry, based on innovative products with high margins and returns. However, this vision is far from representing the current situation of the industry, which is subject to strong government pressure and erosion of prices of their products, as a result of the growth of the generic drug industry and its immersion in a highly competitive environment in all therapeutic areas, with no single company having a dominant role in the market . This siOf these products, more than 55% are products of biological and not chemical origin, opening up a great opportunity for new players in the development of biosimilars, with lower production costs and shorter development time (five to eight years) than an original medicine because of not having to follow the protocols of an unprecedented biological molecule. It is expected that biosimilars will be created in a fast-growing area of the biopharmaceutical industry and that they will become a viable alternative to compete with generic products.a compound with a high degree of similarity to their biological compound pioneer or innovator, but with the possibility of presenting small differences in components of clinically inactive molecule.” However, a biosimilar product may not differ significantly in terms of the degree of purity, potency, and safety of the product being administered to the patient [To better understand the earliest references to the biopharmaceutical industry, it is very important to define the different industries that might be involved in one way or another in the development of biosimilars: the pharmaceutical industry, the biopharmaceutical industry, and, of course, the biosimilar industry. The terms usually used in science and industry concerning these industries or sectors are mixed depending on the country or region. However, we can globally define the pharmaceutical industry as one that is related to the research and process development and production, as well as marketing and/or distribution, of pharmaceuticals of chemical origin  for therapeutic, prophylactic, and diagnostic purposes. The term referring to the biopharmaceutical industry involves the research and process development and production, including their marketing and/or distribution, of drugs of biological origin (large molecules) for therapeutic, prophylactic, and diagnostic uses . Finally patient .Large multinational firms and the Chief Research Officers (CROs) of their partners are already developing the business of biopharmaceuticals as an alternative way for obtaining profitability. Thus, from the already tested biological molecules (known as blockbusters), whose patents have expired or are on the verge of doing so, they are giving a “second life” to such molecules, including some with new therapeutic applications, but, as The United States, Europe, and Japan are the regions that invest the most in research and development of biological products. Therefore, they are expected to become the most attractive markets for the development of biosimilars. Sackman and Kuchenreuther  estimateWhile the biosimilars market has been dominated at this early stage by Europe and the United States, it is slowly emerging in countries with already installed biopharmaceutical infrastructure and companies. However, it is essential to consider some aspects in these countries, such as regulations, guidelines for products that fit the local market, development of therapeutic areas, economic margins that can be obtained from manufacturing , access to the necessary infrastructure, and potential strategic alliances. By addressing these issues, hopefully in the near future, the development of biosimilars can be converted into an appropriate economic model for countries that are emerging in these technologies. In this context, this paper presents an overview, evolution, and regulations assessment, while it also discusses the beginnings and development of biosimilars in Japan, South Korea, and Malaysia. biosimilars, development of biosimilars, biopharmaceutical companies, non-patent biologics, clinical trial, regulatory biosimilars, follow-on biologics, generic, molecule, biomedicine, data-marketing exclusivity, evolution, developing trials, and therapeutic.In order to assess the current status of biosimilars in the countries of interest, an information search strategy was designed, based on secondary sources such as government documents, official statistics, technical reports, review articles, and international journals, without language restriction that allowed establishing a regulatory framework and a diagnosis of the development of biosimilars. The keywords used in the search to process information includeInformation search was also conducted through the brand names and active components of each currently marketed biosimilar. A search of the websites of World Health Organization (WHO), the Food and Drug Administration of the United States (FDA), the European Medicines Agency (EMA), the Ministry of Health, Labour and Welfare (MHLW) of Japan, the Ministry of Food and Drug Safety (MFDS) of South Korea, and the National Pharmaceutical Control Bureau (NPCB) of Malaysia and overall regulatory authorities also was conducted for legislative decisions, guidance, and evaluation for approved biosimilars. A search for information on the main companies developing biosimilars in the countries of interest was also performed, allowing us to have an appreciation of the history of the biopharmaceutical industry and the changes it had undergone for the development of these new drugs.The Japanese pharmaceutical market is the second most important one in the world after the United States, with sales of over US $143 billion in 2014 , represeThe biopharmaceutical market in Japan is of great importance to the world. However, most of the products sold there are of foreign origin but manufactured locally under license. Moreover, as Of the nine most important biological drugs sold in Japan , only one  is of Japanese origin, which demonstrates the low local impact of research and development on these types of products.Standards for Quality Assurance of Drugs, Quasidrugs, Cosmetics, and Medical Devices. They are up to ministerial standards on good clinical practice and quality assurance of drugs.Regulations for Buildings and Facilities for Pharmacies and So On. Regulations are established on the monitoring of the physical facilities that manufacture and distribute drugs.Standards for Manufacturing Control and Quality Control of Drugs and Quasidrugs. They regulate the field of good manufacturing practices.There is also the Pharmaceuticals and Medical Devices Agency (PMDA), working together with the MHLW. The PMDA conducts scientific reviews of marketing authorization applications of pharmaceuticals and medical devices and monitoring of their postmarketing safety. It is also responsible for providing relief compensation for sufferers from adverse drug reaction and infections by pharmaceuticals or biological products. The PMDA's Office of Biologicals provides consultations concerning clinical trials of new drugs and medical devices and handles biotechnology medicines, including biosimilars [The Ministry of Health, Labour and Welfare (MHLW) is the regulatory body in Japan, responsible for the scientific evaluation of medicines developed by pharmaceutical companies to be used in Japan and for making decisions on approval of drugs, including biologicals. It consists of three main areas :Standarsimilars .equivalent and homogenous to the reference biological product in terms of efficacy, quality and safety.” This guide also exposes basic requirements necessary to grant the approval of a new biosimilar product to be marketed in Japan. The following requirements must be met [It should be established that the manufacturing process for the biosimilar is highly consistent.The biosimilar should be fully characterized, using analytical methods.The dosage form and route of administration of the biosimilar product should be the same as those of the reference product.Long-term, real-time, real-condition stability studies should follow the ICH Q5C guideline .A comparison of quality attributes between the biosimilar and the reference product should be conducted.Nonclinical studies  that can ensure the safety for administration to humans should be performed and completed prior to initiation of clinical studies.Clinical studies are required whenever the data from quality characterization and nonclinical studies is insufficient to demonstrate comparability with the reference product. Clinical studies should be designed based on the data from quality characterization, nonclinical studies, and comparability studies.The process for approval of a biosimilar in Japan begins when the owner of the drug  submits the marketing application, with the requirements listed above, to the MHLW. The application is then passed on to the PMDA, where it follows two necessary but different pipelines. The first is in Conformity Audit Office, which verifies compliance with good clinical and laboratory practices. At this stage, it is confirmed that the information provided by the owner is real. A visit to the premises where the product is manufactured and where clinical studies were conducted is also performed [These guidelines are based on the existing processes in Europe and were published by the MHLW in March 2009. Biosimilar drugs are considered as those that are “t be met :It shoulerformed . The secIn order to obtain the marketing authorization, it is necessary to have had people of Japanese origin included in one of the efficacy and pharmacokinetic studies. If clinical data do not include any people of Japanese ethnicity, it is mandatory to show the similarity between a biosimilar candidate and the reference product according to the International Conference on Harmonization Guidelines . The purWhile biosimilars cannot be protected by patents, because they have expired, there are regulations to ensure a period of exclusivity in marketing, so that their return is guaranteed. Therefore, research and development should be encouraged by these new types of products. In Japan, this information exclusivity lasts six years, while in the United States it lasts four years and in Europe eight years .It is also noted that, in the case of the United States, there is a distinction between exclusive data and exclusivity in marketing, ensuring a more extensive commercial level to the manufacturer's laboratory biosimilar protection, regardless of any other research and development laboratories conduct to create the original biosimilar. A particular feature of biosimilar approval in the United States is that there are two levels of approval: the biosimilar drug and the biosimilar “Interchangeable Drug” .Since the guide for the development of biosimilars in Japan in 2009 was approved, the sale of seven of these types of products has been authorized, the latest of them being insulin glargine BS in January 2015.Like most pharmaceuticals and biopharmaceuticals, biosimilars require mostly, as shown in Recently, Lupin Pharmaceuticals, of India, entered into a strategic joint venture with the Japanese-based pharmaceutical company Yoshindo and created a new entity, YL Biologics (YLB). This new company will be responsible for conducting clinical development of certain biosimilars and obtaining marketing authorization in Japan. Its main line of research will be monoclonal antibodies (mAbs) and it expects its first product to be a biosimilar of “Enbrel,” which is marketed in Japan by Takeda Pharmaceutical.One way to analyze the future development of biosimilars is through clinical trials. As of September 2015 , 124 worAccording to the public database of the United States , at presBelow is an outline of the five biosimilars and their area of use of the trials foreclosed to Japan. Carboplatin, Paclitaxel, and Gemcitabine Hydrochloride with or without Bevacizumab after Surgery in Treating Patients with Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer. Conditions: clear cell adenocarcinoma; Fallopian tube clear cell adenocarcinoma; Fallopian tube endometrioid adenocarcinoma; Fallopian tube mucinous adenocarcinoma; Fallopian tube serous adenocarcinoma; malignant ovarian mixed epithelial tumor; mucinous adenocarcinoma; ovarian Brenner tumor; ovarian clear cell adenocarcinofibroma; ovarian endometrioid adenocarcinoma; ovarian serous adenocarcinoma; primary peritoneal serous adenocarcinoma; recurrent Fallopian tube carcinoma; recurrent ovarian carcinoma; recurrent primary peritoneal carcinoma; undifferentiated carcinoma; undifferentiated Fallopian tube carcinoma; and undifferentiated ovarian carcinoma. Interventions: biological: Bevacizumab (biosimilar); drug: Carboplatin; drug: Docetaxel; drug: Gemcitabine Hydrochloride; other: laboratory biomarker analysis; drug: Paclitaxel; other: quality-of-life assessment. Responsibility and sponsor: National Cancer Institute (NCI). Listed country: Japan, USA, and South Korea.(i) Carboplatin and Paclitaxel with or without Bevacizumab in Treating Patients with Stage III or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer. Conditions: Fallopian tube clear cell adenocarcinoma; Fallopian tube endometrioid adenocarcinoma; Fallopian tube mucinous adenocarcinoma; Fallopian tube serous adenocarcinoma; Fallopian tube transitional cell carcinoma; malignant ovarian mixed epithelial tumor; ovarian Brenner tumor; ovarian clear cell adenocarcinoma; ovarian endometrioid adenocarcinoma; ovarian mucinous adenocarcinoma; ovarian serous adenocarcinoma; ovarian transitional cell carcinoma; primary peritoneal serous adenocarcinoma; Stage IIIA Fallopian tube cancer; Stage IIIA ovarian cancer; Stage IIIA primary peritoneal cancer; Stage IIIB Fallopian tube cancer; Stage IIIB ovarian cancer; Stage IIIB primary peritoneal cancer; Stage IIIC Fallopian tube cancer; Stage IIIC ovarian cancer; Stage IIIC primary peritoneal cancer; Stage IV Fallopian tube cancer; Stage IV ovarian cancer; Stage IV primary peritoneal cancer; undifferentiated Fallopian tube carcinoma; and undifferentiated ovarian carcinoma. Interventions: biological: Bevacizumab; drug: Carboplatin; other: laboratory biomarker analysis; drug: Paclitaxel; other: Placebo; other: quality-of-life assessment. Responsibility and sponsor: National Cancer Institute (NCI). Listed country: Japan, United States, Canada, and South Korea.(ii) Comparison of CHS-0214 to Enbrel (Etanercept) in Patients with Rheumatoid Arthritis (RA). Conditions: rheumatoid arthritis. Interventions: drug: etanercept; drug: CHS-0214. Responsibility and sponsor: Coherus Biosciences, Inc. Collaboration: Daiichi Sankyo Co., Ltd. Listed country: Japan, United States, Belarus, France, Germany, Hungary, Israel, Poland, Russian Federation, South Africa, Spain, and United Kingdom.(iii) GP2013 in the Treatment of Patients with Previously Untreated, Advanced Stage Follicular Lymphoma. Conditions: follicular lymphoma. Interventions: biological: GP2013; biological: Rituximab. Responsibility and sponsor: Sandoz. Collaboration: Novartis Pharmaceuticals. Listed country: Japan, Argentina, Australia, Austria, Brazil, Bulgaria, Colombia, France, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Malaysia, Netherlands, Peru, Poland, Portugal, Romania, Russian Federation, South Africa, Spain, Ukraine, and United Kingdom.(iv) GP2013 in Japanese Patients with CD20 Positive Low Tumor Burden Indolent B-Cell Non-Hodgkin's Lymphoma. Conditions: indolent B-cell non-Hodgkin's lymphoma. Intervention: drug: GP2013. Responsibility and sponsor: Sandoz. Collaboration: Novartis Pharmaceuticals. Listed country: Japan.(v)South Korea has been considered as one of the “tiger economies” as a result of the growth experienced by its exports during the second half of the 20th century. There is social health insurance in place since 1977, covering the entire population since 1989, but the country faces a significant challenge due to the aging of the population and the increasing health expenditure [In 2015, the pharmaceutical industry in South Korea became the tenth largest in the world. However, generic production has historically dominated the sector and little attention has been paid to products that are more innovative or require R&D, such as biologicals that need strong investments and involve high risk in their development. This situation has gradually changed over time, through adjustments introduced by successive governments in the country, starting by increasing health coverage in the population and launching institutional initiatives with a high degree of transparency. The aim was to make it attractive for multinational pharmaceutical companies to set up operations in South Korea by allowing good competitive prices, among other things. The public policies implemented in South Korea regarding expenses related to drugs were divided into two different funds. The first one corresponded to a security fund, while the second is related to the Health Care System Reform Act of 2000 or Separation of Prescribing and Dispensing (SPD) of drugs. Furthermore, different pricing policies were established in order to avoid a disproportionate increase in prices to patients caused by the SPD.The changes made to the intellectual property rights (IPR) law that also contributed to the “modernization” of the pharmaceutical industry in South Korea were due to its improved protection of patent rights for innovative products. In addition, the Free Trade Agreement (FTA) signed with the United States, Europe, and India gave a significant degree of security to the industry, allowing greater foreign investment.2 plant to manufacture biosimilars in the popular Songdo International Business District of South Korea. The company is currently conducting Phase II clinical trials of DA-6034  for the treatment of dry eyes and also is in the Phase III of DA-3031  for the treatment of chemotherapy-induced neutropenia in cancer patients. In 2015, Dong-A Pharmaceuticals sold its products to over 40 countries in Europe, Latin America, and Asia [The leading pharmaceutical company in South Korea is Dong-A Pharmaceuticals founded in 1932. In order to grow and reach revenues of nearly US $1 billion, the company established strategic alliances with firms such as Bayer and Meiji, which helped to expand its market and venture into R&D of high-impact biologics. Hence, the company has invested heavily in the development and manufacturing of biosimilars, working with the Incheon Free Economic Zone to build a 142,200 mbiological product that is comparable to an already marketed reference product in terms of quality, safety and efficacy” [The regulatory body for the approval of medicines in South Korea is the Ministry of Food and Drug Safety (MFDS), which is responsible for scientifically evaluating drugs developed by pharmaceutical companies in Korea. The legislation for biosimilars and the guideline for evaluating biosimilars were established by the same agency in July 2009. According to this guideline, a biosimilar in South Korea is defined as a “fficacy” . In addiThe MFDS guideline is harmonized with the World Health Organization guidelines and with the European Union guidelines in its scope and data requirements for authorization. The guideline, therefore, requires a demonstration of similarity and a comprehensive characterization and comparison at the quality level to enable a reduction in the nonclinical and clinical data required for authorization. The regulatory decision is then based on a comprehensive evaluation of quality, safety, and efficacy of data .Comparability exercise data, including extensive side-by-side characterization, physicochemical properties, biological activity, and immunochemical properties between the biosimilar and the reference product, should be collected.Comparative nonclinical studies should be designed to detect significant differences between biosimilar and reference products:in vitro study (receptor binding study and cell proliferation assays);in vivo study ;toxicity study .Comparative clinical trials are required on the following:pharmacokinetic aspects provide insight into how the drug moves in the body, since it is absorbed, distributed, and biotransformed until eliminated from the body. Moreover, the pharmacodynamics aspects will depend on the pharmacokinetic processes . Similarly, these pharmacokinetic and pharmacodynamics aspects allow understanding the types of interactions between different drugs, which allow changes in the actions of drugs and their effects on the body;clinical efficacy and safety trials: experimental systematic study is done both in patients and in healthy subjects to evaluate the efficacy and/or safety of one or more therapeutic, diagnostic, or other trials, and to know the effects on the human organism (pharmacodynamics) and/or absorption, distribution, metabolism, and excretion (pharmacokinetics);if applicable, confirmatory pharmacokinetic and pharmacodynamic studies can be used;equivalence design is recommended and equivalence margins should be prespecified and justified;safety data from a sufficient number of patients and study duration should be provided to compare the nature, severity, and frequency of adverse reactions (including immunogenicity study).For the approval of a biosimilar in South Korea, it is sufficient to demonstrate the similarity in safety and efficacy between the biosimilar and the reference product, in a particular clinical indication. If this is done correctly, the biosimilar authorization for another clinical indication can be obtained. The extrapolation of clinical indications of a biosimilar product is allowed for indications where the postmarketing surveillance period of the reference product has expired and if all of the following conditions are fulfilled [Sensitive clinical models to detect potential differences are used.Clinical relevant mechanism of action and involved receptor are the same in different indications.Safety and immunogenicity have been sufficiently characterized.In general, the South Korean pharmaceutical companies are stronger in developing generics than in developing more innovative pharmaceutical products. However, in recent years, they have several strategies that have been devised to encourage change. The South Korean government's current investment in the development of biosimilars reached around 35% of the total R&D costs in 2013, while its investment in chemical drug development accounted for just 12%. Another incentive was the creation of a biomedical background of US $80 million in 2009 to encourage the entry of new local companies to the global biopharmaceutical market [The authorization process for marketing a biosimilar in South Korea begins with the submission of a dossier by the owner of the product  to the MFDS offices. This file must have the following complete documentation :Comparabulfilled :Sensitivl market .Since the guide for biosimilars was published in July 2009, in South Korea, five biosimilars have been approved for marketing; the last one was Brenzys, in September 2015, as Enbrel (etanercept) is the best-selling biological drug in South Korea, with sales exceeding US $4.7 billion in 2014, representing a lucrative market for the development of biosimilars. The patents on Enbrel expire in the United States in November 2028, after Amgen was granted a new patent, while in Europe they expired in August 2015. The approval of Brenzys in South Korea represents the first product approval under Merck's collaboration with Samsung Bioepis, which is a joint venture between the biologics division of South Korean-based multinational Samsung and a United States biotechnology company, Biogen Idec. Samsung Bioepis also announced in January 2015 that it had submitted its etanercept biosimilar candidate, SB4, to the European Medicines Agency (EMA) for approval in the European Union .Celltrion received approval for Remsima in South Korea in July 2012. Further permits followed later on from the European Union, in 2013, and other countries. By obtaining authorization for marketing a biosimilar outside of South Korea, Celltrion became the first laboratory in exporting South Korean biopharmaceutical monoclonal antibodies (mAbs) to international markets, showing a new way to enter the global market for biosimilars . This isAs discussed in the previous section, to date (September 2015), 124 clinical trials in biosimilars have been or are being conducted globally, of which six (4.83%) are being carried out in South Korea. The details of the clinical trials carried out in South Korea are presented below . Carboplatin, Paclitaxel, and Gemcitabine Hydrochloride with or without Bevacizumab after Surgery in Treating Patients with Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer. Conditions: clear cell adenocarcinoma; Fallopian tube clear cell adenocarcinoma; Fallopian tube endometrioid adenocarcinoma; Fallopian tube mucinous adenocarcinoma; Fallopian tube serous adenocarcinoma; malignant ovarian mixed epithelial tumor; mucinous adenocarcinoma; ovarian Brenner tumor; ovarian clear cell adenocarcinofibroma; ovarian endometrioid adenocarcinoma; ovarian serous adenocarcinoma; primary peritoneal serous adenocarcinoma; recurrent Fallopian tube carcinoma; recurrent ovarian carcinoma; recurrent primary peritoneal carcinoma; undifferentiated carcinoma; undifferentiated Fallopian tube carcinoma; and undifferentiated ovarian carcinoma. Interventions: biological: Bevacizumab; drug: Carboplatin; drug: Docetaxel; drug: Gemcitabine Hydrochloride; other: laboratory biomarker analysis; drug: Paclitaxel; other: quality-of-life assessment. Responsibility and sponsor: National Cancer Institute (NCI). Listed country: Japan, USA, and South Korea.(i) Carboplatin and Paclitaxel with or without Bevacizumab in Treating Patients with Stage III or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer. Conditions: Fallopian tube clear cell adenocarcinoma; Fallopian tube endometrioid adenocarcinoma; Fallopian tube mucinous adenocarcinoma; Fallopian tube serous adenocarcinoma; Fallopian tube transitional cell carcinoma; malignant ovarian mixed epithelial tumor; ovarian Brenner tumor; ovarian clear cell adenocarcinoma; ovarian endometrioid adenocarcinoma; ovarian mucinous adenocarcinoma ovarian serous adenocarcinoma; ovarian transitional cell carcinoma; primary peritoneal serous adenocarcinoma; Stage IIIA Fallopian tube cancer; Stage IIIA ovarian cancer; Stage IIIA primary peritoneal cancer; Stage IIIB Fallopian tube cancer; Stage IIIB ovarian cancer; Stage IIIB primary peritoneal cancer; Stage IIIC Fallopian tube cancer; Stage IIIC ovarian cancer; Stage IIIC primary peritoneal cancer; Stage IV Fallopian tube cancer; Stage IV ovarian cancer; Stage IV primary peritoneal cancer; undifferentiated Fallopian tube carcinoma; and undifferentiated ovarian carcinoma. Interventions: biological: Bevacizumab; drug: Carboplatin; other: laboratory biomarker analysis; drug: Paclitaxel; other: Placebo; other: quality-of-life assessment. Responsibility and sponsor: National Cancer Institute (NCI). Listed country: Japan, United States, Canada, and South Korea.(ii) Paclitaxel and Carboplatin with or without Bevacizumab in Treating Patients with Stage II, Stage III, or Stage IV Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer. Conditions: malignant ovarian mixed epithelial tumor; ovarian Brenner tumor; ovarian clear cell cystadenocarcinoma; ovarian endometrioid adenocarcinoma; ovarian mucinous cystadenocarcinoma; ovarian serous cystadenocarcinoma; Stage IIA Fallopian tube cancer; Stage IIA ovarian cancer; Stage IIB Fallopian tube cancer; Stage IIB ovarian cancer; Stage IIC Fallopian tube cancer; Stage IIC ovarian cancer; Stage IIIA Fallopian tube cancer; Stage IIIA ovarian cancer; Stage IIIA primary peritoneal cancer; Stage IIIB Fallopian tube cancer; Stage IIIB ovarian cancer; Stage IIIB primary peritoneal cancer; Stage IIIC Fallopian tube cancer; Stage IIIC ovarian cancer; Stage IIIC primary peritoneal cancer; Stage IV Fallopian tube cancer; Stage IV ovarian cancer; Stage IV primary peritoneal cancer; and undifferentiated ovarian carcinoma. Interventions: biological: Bevacizumab; drug: Carboplatin; procedure: computed tomography; drug: Paclitaxel; procedure: therapeutic conventional surgery. Responsibility and sponsor: National Cancer Institute (NCI). Listed country: United States, Canada, and South Korea.(iii) Radiation Therapy with or without Trastuzumab in Treating Women with Ductal Carcinoma In Situ Who Have Undergone Lumpectomy. Conditions: ductal breast carcinoma in situ; HER2/Neu positive. Interventions: other: laboratory biomarker analysis; biological: trastuzumab; radiation: whole breast irradiation. Responsibility and sponsor: National Cancer Institute (NCI). Listed country: United States, Canada, South Korea, and Puerto Rico.(iv) An Extension Study to Demonstrate the Equivalence of Long-Term Efficacy and Safety of CT-P13 in Patients with Ankylosing Spondylitis Who Were Treated with Infliximab (Remicade or CT-P13) in Study CT-P13 1.1. Conditions: ankylosing spondylitis. Interventions: biological: infliximab. Responsibility and sponsor: Celltrion. Listed country: South Korea.(v) Demonstrating the Equivalence of CT-P10 to MabThera with respect to the Pharmacokinetic Profile in Patients with Rheumatoid Arthritis. Conditions: rheumatoid arthritis. Interventions: biological: Rituximab. Responsibility and sponsor: Celltrion. Listed country: South Korea.(vi)The demand for quality health has been considered crucial by the Malaysian government and its population, and living conditions in this country are improving on a yearly basis. The Malaysian health system has evolved greatly in recent decades and has been listed by the World Health Organization (WHO) as having a universal healthcare system. Malaysia currently invests 7.25% of the Gross Domestic Product (GDP) of the country in health.prescription medicines,over-the-counter (OTC) products,traditional medicines,health/food supplements.An update by the Malaysian Investment Development Authority (MIDA) [The pharmaceutical industry is one of the sectors that the Malaysian government has prioritized for its promotion and development. Pharmaceuticals in this country are divided into four broad categories:y (MIDA)  shows thAmong the major local companies are Pharmaniaga Manufacturing Berhad, Hovid Berhad, CCM Pharmaceuticals Division , and Kotra Pharma (M) Sdn Bhd. Some of the foreign-owned companies with manufacturing presence in the country include Y.S.P. Industries (M) Sdn Bhd (Taiwan), Sterling Drug (M) Sdn Bhd (the manufacturing arm of GlaxoSmithKline from the United Kingdom), Ranbaxy (M) Sdn Bhd (India), Xepa-Soul Pattinson (M) Sdn Bhd (Singapore), and SM Pharmaceuticals Sdn Bhd (India).The large MNCs—such as Pfizer, Schering Plough, Novartis, Eli Lilly, and AstraZeneca—are mainly licensed importers. Their products, mostly branded drugs, are distributed by locally incorporated companies.Biosimilars are expected to have a comparable, if not greater, impact on the biopharmaceutical industry than that of generics. Malaysia offers a more competitive cost option to investors due to its enabling environment. A large number of first-generation biopharmaceutical products are nearing maturity and major biopharmaceutical companies are likely to move these out to countries that offer a good value preposition, like Malaysia .Currently, in Malaysia, local and foreign players are already engaged in activities like the production of active pharmaceutical ingredients (APIs) and applications for good manufacturing practice (cGMP) compliant services at the United States Food and Drug Administration (FDA) and Europe, the Middle East and Africa (EMEA) focusing on monoclonal antibodies and recombinant proteins. Malaysia has also developed specialized parks to cater to the needs of specific industries, which are technology-intensive and research-intensive. Examples of these parks are the Technology Park Malaysia in Bukit Jalil, Kuala Lumpur, and the Kulim Hi-Tech Park in the northern state of Kedah. These parks comprise state-of-the-art buildings with specific functions and a fully integrated high-technology park. Other specialized parks developed by the Malaysian government agencies are the following: Bio-XCell Malaysia, Penang Science Park, Kulim Hi-Tech Park (KHTP), and techpark@enstek .Malaysia has been concerned with developing a powerful system of intellectual property protection, in accordance with international standards, akin to protect inventions and foreign and local investors.World Intellectual Property Organization (WIPO), 1967;Paris Convention for the Protection of Industrial Property, 1883;Berne Convention for the Protection of Literary and Artistic Works, 1886;Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement, 1994.Malaysia is a party to the following treaties:The Ministry of Health of Malaysia, through the National Pharmaceutical Control Bureau (NPCB), is the national authority that assures the quality of medicines in the country. The NPCB is responsible for ensuring that all pharmaceutical and biopharmaceutical products developed and commercialized in the country meet the standards of quality, safety, and efficacy as required by law .Unlike other countries that have been studied in this work, there is no elaboration of an exclusive guideline for biosimilars, only an addition to the law previously created for biological drugs (Drug Registration Guidance Document (DRGD)), as a subcategory of biological products. This implies that in order to obtain approval for a biosimilar it must meet all of the quality, safety, and efficiency requirements for any product of biological origin. No distinction is made between a new biological product and the one that has been marketed for many years and is now based in the development of a biosimilar.administrative information;product quality data ;product safety data ;clinical data, demonstrating clinical efficacy and capacity to meet therapeutic claims, through clinical studies.The process for registering a biosimilar begins with an online submission to the NPCB by the legal representative of the new product. With this, the office generates an appointment for the representative to present all of the information necessary to meet the approval requirements set forth, such as analytical methods and quality validation documentation. With this information, the NPCB consults with experts, usually external, such as academics, clinical advisors, and health and biological experts. Together, they produce an evaluation report that is sent to the Drug Control Authority (DCA) of NPCB, which defines whether or not the biological product can be approved to be marketed in Malaysia [The requirements for the registration of biologics/biopharmaceuticals are guided by the ASEAN Common Technical Dossier (ACTD) and the Drug Registration Guidance Document (DRGD). The requirements areMalaysia .Since the biosimilar guideline was published in July 2008, in Malaysia, five biosimilars have been approved for marketing. The latest was Insugen, in January 2014, as All biosimilars that have been approved so far are of a relatively small size and reduced complexity. But they must not be confused with generic molecules that are even smaller and simpler. While they all originate from a reference, biological products have been marketed in Malaysia for several years and with higher sales volumes. It is also striking that none of them is developed by local biopharmaceutical companies or at least with their collaboration.Nevertheless, apparently, this would be changing as Viropro, Inc., and Oncobiologics, Inc., signed a collaboration agreement for the development of biosimilars. Under this agreement, Viropro will have the rights to manufacture six monoclonal antibody products being developed by Oncobiologics for commercialization in more than 70 emerging market countries (excluding China). Viropro will have exclusive commercialization rights to the six biosimilars for Malaysia. In addition, the companies will comanage Viropro's Penang, Malaysia, Alpha Biologics biomanufacturing subsidiary. The six biosimilars are versions of Humira, Rituxan, Avastin, Herceptin, Erbitux, and one other nondisclosed biotherapeutic .Of the 124 clinical trials being carried out in biosimilars in the world, only two of them (1.6%) are being conducted in Malaysia . Analyzi Study of RTXM83 plus CHOP Chemotherapy versus a Rituximab plus CHOP Therapy in Patients with Non-Hodgkin's Lymphoma. Conditions: diffuse large B-cell lymphoma. Interventions: biological: RTXM83. Responsibility and sponsor: mAbxience SA. Collaborations: Pisa Farmacética; Laboratorios de Productos Éticos CEISA; Laboratorio Elea SACIF y A; Tecnoquímicas; Innogene Kalbiotech Pte. Ltd.; and Libbs Farmacêutica Ltda. Listed country: Malaysia, Argentina, Brazil, Colombia, India, Indonesia, Mexico, Paraguay, Philippines, South Africa, and Thailand.(i) GP2013 in the Treatment of Patients with Previously Untreated, Advanced Stage Follicular Lymphoma. Conditions: follicular lymphoma. Interventions: biological: GP2013; biological: Rituximab. Responsibility and sponsor: Sandoz. Collaborations: Novartis Pharmaceuticals. Listed country: Malaysia, Argentina, Australia, Austria, Brazil, Bulgaria, Colombia, France, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Japan, Netherlands, Peru, Poland, Portugal, Romania, Russian Federation, South Africa, Spain, Ukraine, and United Kingdom.(ii)Much of the biopharmaceutical industry is betting towards a future in biosimilars, giving a second life to biological molecules that are reaching the end of their period of intellectual property protection and, at the same time, a means to increase their profitability in the medium term, which new biological molecules tend to lack. The production and marketing of biosimilars involve lower risks and costs. In addition, it is considered that the biosimilar industry in 2015 covers globally only 1% of the total production of biological molecules because patents have only recently begun to expire, so that a promising future is announced for the next decade.The East and Southeast Asian countries discussed in this paper are highly developed in relation to the institutional and technological environment, although, interestingly, they show some delay in the effective implementation of clinical trials in their own countries and, consequently, in the development of biosimilars. This is reflected in their participation in various clinical trials of biosimilars around the world, which are actually only 124. Of these, Japan is involved in only five and contributes to 4%, while South Korea owns six clinical trials, with a contribution of 4.83% and, finally, Malaysia falls behind with only two trials and 1.6% of the total contribution. This does not mean that companies in these countries do not develop clinical trials in other countries or in their own research departments. There is evidence that the South Korean company Celltrion, for example, develops up to eight clinical trials in other countries. Perhaps the associated costs and regulations involve a major setback and make them more profitable in countries with less regulatory restrictions, as in the case of emerging countries.There is a cost advantage for the producer of a biosimilar, but the original owner of the biological molecule should not be forgotten, since the company continues to produce and market its product and should have a competitive advantage and comparative processes and marketing channels, taking advantage of this “inertia” provided by the production and marketing of the product for over 20 years. However, we would expect a strategic shift of these firms, perhaps through a reduction in their prices in order to remain competitive.Biosimilars are excellent news, not only for biopharmaceuticals, but also for patients due to the reduction of costs and prices up to 36% in comparison to the original drug. The great boom of biosimilars is to come in the next few decades, but there is still a need to unify criteria and regulations globally in order for their success to be full and widespread.


The use of antibiotics in food-producing animals has significantly increased animal health by lowering mortality and the incidence of diseases. Antibiotics also have largely contributed to increase productivity of farms. However, antibiotic usage in general and relevance of non-therapeutic antibiotics (growth promoters) in feed need to be reevaluated especially because bacterial pathogens of humans and animals have developed and shared a variety of antibiotic resistance mechanisms that can easily be spread within microbial communities. In Canada, poultry production involves more than 2600 regulated chicken producers who have access to several antibiotics approved as feed additives for poultry. Feed recipes and mixtures vary greatly geographically and from one farm to another, making links between use of a specific antibiotic feed additive and production yields or selection of specific antibiotic-resistant bacteria difficult to establish. Many on-farm studies have revealed the widespread presence of antibiotic-resistant bacteria in broiler chickens. While some reports linked the presence of antibiotic-resistant organisms to the use of feed supplemented with antibiotics, no recent studies could clearly demonstrate the benefit of antimicrobial growth promoters on performance and production yields. With modern biosecurity and hygienic practices, there is a genuine concern that intensive utilization of antibiotics or use of antimicrobial growth promoters in feed might no longer be useful. Public pressure and concerns about food and environmental safety  have driven researchers to actively look for alternatives to antibiotics. Some of the alternatives include pre- and probiotics, organic acids and essential oils. We will describe here the properties of some bioactive molecules, like those found in cranberry, which have shown interesting polyvalent antibacterial and immuno-stimulatory activities. Since the discovery of penicillin by Fleming in 1928, several antibiotics which can be classified based on their molecular targets in bacteria  have been marketed for the treatment of infectious diseases both in animals and humans. The agents used in the treatment of animals and humans often belong to the same classes of antibiotics having similar modes of action and bacterial cell targets. This interface brings a variety of problems and worries. Bacteria developing resistance to these drugs in animals may be transmitted to humans or spread their mechanisms of resistance, which may eventually be found in human pathogens. Such a situation may lead to the loss of therapeutic efficacy in both veterinary and human medicine.Streptomyces aureofaciens containing chlortetracycline residues showed improved performances . For example, antibiotics such as ceftiofur , bacitracin (polypeptide) and virginiamycin (streptogramin) are used in poultry production to respectively prevent and control infections (respiratory diseases and necrotic enteritis) and to improve food conversion and body-weight gain. The use of antibiotics as growth promoters was adopted in the 1940s when animals fed dried mycelia of The poultry industry has grown and improved in recent years due to the continuous integration of various disciplines for production such as poultry health, nutrition, breeding, husbandry, and knowledge of poultry products  has undeniably reduced treatment options and therapeutic efficacy in human medicine. However, the relative responsibility of selective pressures occasioned by human medicine, veterinary or agricultural practices is still unclear. Furthermore, metagenomic studies have established some links between resistance mechanisms found in microorganisms from the environment and the clinic  have been transmitted from cows or pigs to humans and could cause diseases  of the United Nations, the world chicken production was estimated at 71,851,372 tons in 2005, up 3% from the previous year . In the same year, Canada produced 1.02 billion kilograms of chicken (eviscerated weight), 60% of which was produced in the provinces of Quebec and Ontario. Canadian domestic consumption was 30 kilograms per person and retail purchases accounted for approximately 634 million kilograms representing 62% of Canada's total consumption. Canada exported over 5.9 million chicks to 13 countries; a commercial value estimated at over $14.5 million in 2012. The United States was the largest market (91%). Other countries included Mexico, Japan, the Philippines, and China (http://www.agr.gc.ca/poultry/index_eng.htm).Poultry production is an important industry in Canada. In 2012, the value of Canadian chicken products was estimated at $2.4 billion, involving 2645 regulated chicken producers and a large number of businesses associated with chicken farming Clostridium perfringens, the etiological cause of necrotic enteritis which is one of the main disease concerns for poultry producers worldwide , polypeptides (bacitracin), ionophores , β-lactams (penicillin), streptogramins (virginiamycin), and tetracyclines (chlortetracycline) are used in broiler production for growth promotion and prevention of infectious diseases Table . For broEscherichia coli  or into eggs (0.08–0.20 mg) as a prophylactic measure in Canada to prevent the yolk-sac infection , a costly disease caused by In Canada as well as in several countries, various combinations of antimicrobial agents are used in feed depending on birds' ages, formulation and mixtures and such recipes greatly vary geographically and from one farm to another. Hence, despite the intuitive link between antibiotic usage in poultry and the emergence of antibiotic resistant bacteria, variations in antimicrobial usage make links between the use of specific feed additives and the selection of specific antibiotic resistant bacteria difficult to establish  revealed that in the salinomycin-treated birds there was an increased abundance of the cell wall and capsule, iron acquisition, motility and β-lactamase gene categories while a decrease of multidrug efflux pump EGTs was detected  and oxytetracycline (2.5 ppm) that could explain the improvement of feed efficiency in broilers from days 0 to 21  indicating that virginiamycin modifies the composition of the chicken intestinal microbiota  in Canadian poultry  either alone or in combination with other resistance genes were reported in chickens  reported a possible association between ceftiofur-resistant E. coli can colonize and persist in the broiler gut. Of 256 E. coli isolates analyzed using DNA-microarray, 88% possessed at least one antimicrobial resistance gene with 42% showing multiple resistance genes , macrolides , tetracycline , streptogramins (satG_vatE8), bacitracin (bcrR), and lincosamide (linB) were detected in corresponding resistant E. faecium and E. faecalis strains , tetracycline (tet), sulfonamide (sulI or sulII), aminoglycoside [ant(3″)-Ia (aadA)] and phenicol resistance (floR) genes and class 1 integrons were reported in E. coli isolated from broilers  and the bacitracin resistance gene bcrA in enterococci isolated from broiler chickens . Some of these isolates were multi-resistant to bacitracin, ciprofloxacin, erythromycin, tylosin, flavomycin, streptomycin, kanamycin, lincomycin, quinupristin-dalfopristin, and tetracycline Table . In CanaPoultry litter, a mixture of materials including bedding, feces and feathers, is a valuable soil amendment that is rich in nutrients and can improve soil physical, chemical, and biological properties for agricultural crops , tetracycline (tetAB) and streptomycin (strAB) have been reported to survive for several months in soil following late summer litter application , lincomycin (linA), erythromycin (ermB), and β-lactams (blaZ) were isolated from air inside and outside broiler production facilities  are of special concern in poultry barns and slaughterhouses, where the high number of chickens handled in these facilities leads to the presence of substantial concentrations of bacteria and other microorganisms in air .Antibiotic resistance has become a worldwide threat to public health. For example in the United States of America (USA), according to a recent report from the Centers for Disease Control and Prevention (CDC), at least 2 million people become infected with “antibiotic resistant bacteria” among which at least 23,000 people die each year as a direct result of these infections CDC, . The USAConcerns for safe food and effective medical antibiotics have pressured authorities for elimination of antibiotics as growth promoters as well as those of medical importance in animal production. Despite incomplete data, there were sufficient genuine and reasonable arguments for implementing such regulations in the European Union and similar policies and recommendations in North America were made based on the precautionary principle. For example, the CDC supports the strategy of the FDA to promote the judicious use of antibiotics that are important in treating humans. In Canada, there is a variety of efforts that follow this trend  have driven researchers to actively look for alternative approaches that could eliminate or decrease the use of antibiotics while maintaining production yields and low mortality in poultry production. As discussed in previous sections, the biological basis for antibiotic effects on animal growth efficiency is most likely derived from effects on the intestinal microbiota, which in turn may reduce opportunistic subclinical infections, reduce the host response to the gut microflora, decrease competition for nutrients, and improve nutrient digestibility consequent to a reduction in some microbial fermentation by-products , are indigenous to wetlands of central and eastern North America  in uropathogenic E. coli  and phenolic acids that could possibly act as iron chelators. In view of these results, cranberry extracts could be used to perturb bacterial iron homeostasis and improve nutritional immunity in the gut  from fresh fruits also produced a cranberry fraction (FC111) modulating the same marker genes as demonstrated by qPCR. S. aureus cell surface disruption by cranberry is also supported by work from Wu et al.  and daptomycin  and some of our own cranberry extracts yielded stronger growth inhibition effects against Gram positive pathogens such as u et al.  and by cu et al. . Besidesaction FC11 modulaListeria spp. are important foodborne pathogens that can be associated with various foods including fresh and frozen meat and poultry. Cranberry fraction FC111 also showed bactericidal effects as well as antibiofilm formation activities against Listeria monocytogenes  is one of the major immuno-suppressive viruses affecting broilers. This virus is highly contagious and represents a major economic threat in poultry production worldwide  and foodborne pathogens such as non-typhoid Salmonella associated with poultry are some of the examples among others. It is imperative to determine the exact sources and ecology of these resistant bacteria in order to develop strategies to stop their spread. It is also urgent to develop alternatives to antimicrobial growth promoters that will not compromise livestock and poultry health as well as the actual industry productivity. Canadian studies in this area identified some promising sources of alternatives to antibiotics which have been discussed here.Antibiotics are important tools for the treatment of old and emerging infectious diseases. Their efficacy for this purpose should be preserved as it is now well documented that their abusive and inappropriate use in humans, livestock and poultry selects for antibiotic resistant bacteria, compromising thus their therapeutic efficacy. One of questionable practices in animal agriculture is the use of non-therapeutic antimicrobials for growth promotion. Even if this practice was determinant in the past, its advantage in current modern agriculture including poultry production needs to be re-evaluated because of the actual prevalence of antibiotic resistant bacteria in livestock and poultry and their products worldwide. The presence of multi-drug resistant commensal bacteria (The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Though it has been a focus of the country’s public health surveillance systems since the 1950s, schistosomiasis represents an ongoing public health challenge in China. Parallel, schistosomiasis-specific surveillance systems have been essential to China’s decades-long campaign to reduce the prevalence of the disease, and have contributed to the successful elimination in five of China’s twelve historically endemic provinces, and to the achievement of morbidity and transmission control in the other seven. More recently, an ambitious goal of achieving nation-wide transmission interruption by 2020 has been proposed. This paper details how schistosomiasis surveillance systems have been structured and restructured within China’s evolving public health system, and how parallel surveillance activities have provided an information system that has been integral to the characterization of, response to, and control of the disease. With the ongoing threat of re-emergence of schistosomiasis in areas previously considered to have achieved transmission control, a critical examination of China’s current surveillance capabilities is needed to direct future investments in health information systems and to enable improved coordination between systems in support of ongoing control. Lessons drawn from China’s experience are applied to the current global movement to reduce the burden of helminthiases, where surveillance capacity based on improved diagnostics is urgently needed. Schistosomiasis poses a major public health threat in many tropical and sub-tropical countries—the disease is endemic to 78 countries worldwide and, in 2011, at least 243 million people were infected and needed treatment, 6). Theroutine surveillance, national surveys, sentinel surveillance and the national infectious disease reporting system (NIDRS). These systems serve distinct, but complementary purposes. The routine surveillance system (termed ‘routine surveys’ in some literature), was initiated in the 1950s. The other three schistosomiasis surveillance systems created in the late 1980s were strengthened considerably in 1992 when the Chinese government received a long-term World Bank loan aimed at improving schistosomiasis morbidity control. The loan resulted in significant investment in schistosomiasis research[national and routine surveillance systems[China’s multiple, evolving surveillance systems for schistosomiasis have been integral to the country’s decades-long campaign to reduce the prevalence of the disease. Chinese surveillance for schistosomiasis began in the middle of the 20th century after the founding of the People’s Republic, with identification of endemic areas through both hospital-based reporting and limited epidemiological surveys. Currently, there are four parallel surveillance systems specific to schistosomiasis  provide a means to evaluate the transmission potential of a given setting, and the particular role played by non-human reservoirs.Schistosoma japonicum-specific immunoglobulin G standardized enzyme-linked immunosorbent assay (ELISA) and the indirect hemagglutination assay (IHA). Diagnostic immunological test kits have historically been subsidized by the national government, which has contributed to their widespread use. From a practical standpoint, immunologic methods are desirable as they require only a blood sample from a finger or ear-stick. Immunoassays generally have high sensitivity, but low specificity, due in part to the inability of the assay to distinguish between past and current infections[Detection of schistosomiasis infections in humans in China is typically accomplished by immunologic or coprologic assays. Immunologic assays commonly used in China include fections. The immSchistosoma eggs in standardized 41.7 mg smears and calculate eggs per gram (EPG) of the original sample, providing a widely accepted proxy measure of infection intensity[China relies on the Kato-Katz technique as the primary coprologic schistosomiasis diagnostic, following guidance of the World Health Organization. The metntensity. The assntensity, 14.Another common coprologic assay is the miracidium hatch test, which detects the presence of viable schistosome eggs in stool by inducing miracidia to hatch in an aqueous solution. Typically performed in county-level anti-schistosomiasis stations, 30 g stool samples are strained through a 200 μm nylon mesh to concentrate schistosome eggs and remove small particles. The enmeshed material is then suspended in an aqueous solution, and placed in a lit, temperature-controlled environment where the sample is examined at two, five and eight hours for the presence of miracidia using low magnification.S. japonicum in the bovine population serves as a complement to human surveillance, as bovines are a key non-human reservoir of S. japonicum in China. Thus detection of infections in bovines offers a means of monitoring the role of non-human hosts in introducing or sustaining transmission, particularly in agricultural settings where bovines are abundant[Detection of abundant. To testabundant.Oncomelania hupensis have long played an important role in China’s surveillance for schistosomiasis. Snail density surveys consist of collecting and counting snails from historical or newly identified snail habitat. Specimens are drawn from a consistent kuang-sized (0.11 m2) sampling frame at random or equal interval points along streams, irrigation canals, fields, and lakes in endemic and some formerly endemic areas[S. japonicum infections in snails is very low , and thw  in each province, which designed and managed surveillance and control programs, as well as units targeting specific infections. For schistosomiasis, county-level anti-schistosomiasis stations were established under the supervision of OEDs and were responsible for carrying out surveys on humans and the snail intermediate host, control activities and health education. These stations established the necessary infrastructure and recording procedures for documenting infection and treatment statuses, disease progression of patients, and distribution and abundance of the intermediate host of the pathogen, and hence played a central role in the first standardized schistosomiasis surveillance activities[In 1956, a massive nationwide schistosomiasis control campaign was launched, which bore the slogan "Schistosomiasis has to be eliminated" and was subsequently memorialized by Chairman Mao Zedong’s poem "Farewell to the God of Plague" in which he mourned the advance of the disease and championed its subsequent retreat, 22. Medt doctors, 24. At tivities.st century[In the late 1970s, reforms to China’s health systems led to the dismantling of the cooperative health system in place of a market-based system, and by 1985, barefoot doctors either became village doctors who worked on a fee-for-service basis, or they shifted to other professions. This su century, 27.In 2002, the National Center for Disease Control and Prevention and Control (China CDC) was established from the former Chinese Academy of Preventive Medicine. With thSurveillance was spotty and inconsistent in the years following the founding of People’s Republic of China, and not until 1989 did robust schistosomiasis surveillance programs emerge. A massiCoincident with this massive transformation of China’s public health institutions, a large World Bank loan that supported schistosomiasis control programs was ending, and its completion in 2001 resulted in a significant loss of funding for schistosomiasis surveillance. Surveillance and control efforts decreased, contributing to the re-emergence of schistosomiasis in several locations where it had previously been controlled, 33. In routine surveys, national surveys, sentinel surveys and NIDRS—and we describe how each surveillance system was impacted by changes in China’s health systems following the SARS epidemic in 2004.In the following sections, we describe the purpose, sampling approach, and diagnostics used in each of the four schistosomiasis surveillance systems—Routine schistosomiasis surveys involve periodic infection screening in every endemic village in the seven endemic provinces. Staff at county-level anti-schistosomiasis stations have historically conducted these screenings in collaboration with local village governments and hospitals[Routine surveys generate data used by the Ministry of Health to evaluate control measures, and provide information used by provincial-level schistosomiasis control steering committees to determine which counties have satisfied the official criteria for transmission control  for anti-schistosomiasis stations, which were folded into annual control performance reviews for the stations. To improve reliability of these surveys, a real-time, internet-based reporting system was established in 2011 to file, store and manage routine survey data[With the substantial increase in central government support for schistosomiasis control since 2004, local avey data, and quaRoutine surveys in a given endemic county are typically conducted over the course of two, three or more years depending on the level of endemicity in—and the control status of—the county. For counties that have achieved transmission control (Table sentinel schistosomiasis surveillance system (see below), routine surveys are not conducted and the necessary information is shared from the sentinel system.l Table , all vilroutine surveillance involves intermediate host surveys in the spring followed by surveys of the human population in the fall, at the end of the transmission season. The target human sample is >90% of residents between the ages of 6 and 65 years old[routine survey efforts, but these are the responsibility of the local animal husbandry department and the degree of coordination between the veterinary and public health efforts is highly variable[routine survey screening, public health workers will seek them out in their homes and request their participation.In a given village, variable. All resroutine surveys are standardized by the Ministry of Health to improve consistency between counties and provinces, though variations have been noted. In Sichuan Province, for example, different diagnostics have been used between counties, some carrying out serologic exams only, some serologic followed by stool exams and some stool exams only. Thus, there are limitations when directly comparing routine survey data between counties.Sampling and screening protocols for routine surveys are unique to schistosomiasis, providing spatial and temporal data on infection patterns that are generally unavailable for other parasitic diseases. The surveys are very resource-intensive, and thus they have not been adopted, for instance, for soil-transmitted helminths (STHs). A sentinel STH system exists and resembles routine schistosomiasis surveys with less exhaustive sampling. The standardized training of county-level staff that carry out routine survey screenings—and the infrastructure developed to support them—have provided ongoing quantitative data on the distribution of cases at fine spatial scales[In China, l scales. These dnational schistosomiasis survey with the purpose of estimating the prevalence of the disease in each endemic province. The resulting information served as an important baseline dataset for the World Bank loan for schistosomiasis control (see Introduction), and the 1989 data were subsequently compared with the 1995 national survey in an economic valuation of the loan-financed programs[National surveys are large, periodic cross-sectional studies that generate estimates of prevalence among humans and domestic animals across endemic settings. They are carried out every 6–9 years in China, and their primary outcomes and other characteristics are summarized in Table In 1989, China carried out the first programs. Nationanational schistosomiasis survey in 2004 included considerable technical improvements over previous surveys, such as an additional sampling stratum targeting low intensity infection areas; use of ultrasonography to screen a small number of subjects tested for schistosome-induced fibrosis; use of a subset of surveyed villages to assess the sensitivity of the Kato-Katz test as performed by Chinese technicians[national survey included all formerly endemic areas that had achieved infection control and transmission control  province, (2) environment/ecotype, and (3) estimated local prevalence based on the most recent routine survey data ; and eco-epidemiological zone . Sentinel system screening has been conducted by Kato-Katz since 1989, and the IHA test was added in 2000, with patients found positive by IHA confirmed with the Kato-Katz exam. If acute or advanced cases are found, epidemiological investigations are conducted to collect more detailed information about each case.The number of sentinel sites sustained by the system is based on the level of funding provided by the central government, and provinces with higher prevalence and infection intensity are allotted more resources (and thus sites). To select sites, national and provincial level OEDs consider two factors: variation in infection intensity  was established in the 1950s[NIDRS has historically involved a vertical reporting structure where hospitals reported the aggregated number of cases monthly by post to the county health department, who in turn report aggregate cases to the prefecture, then to the province, and finally to the central government. The information is used by Chinese public health officials to understand national patterns of infectious disease transmission, and to develop appropriate prevention and control programs[The National infectious disease reporting system , but not for assessing infection prevalence. What is more, diagnosis of a reported case is coded in the NIDRS as using either a clinical or a laboratory diagnostic, without further differentiation such as between stool and serologic exams[NIDRS system are listed in Table Cases of schistosomiasis diagnosed in clinics or hospitals are reported directly to the  by NIDRS. Becauseic exams. The priNIDRS revealed several limitations of surveillance capacity in China[NIDRS varied within and between provinces, limiting the generation and transmission of electronic case reports[NIDRS have been reported by county-level hospitals, in part because diagnostic capabilities are poorer at township-level hospitals, and diagnostic capabilities for parasitic diseases are sometimes entirely absent at private clinics and village healthcare centers[Schistosomiasis diagnostic and clinical capabilities, and therefore reporting capacity, differ considerably across China, and the transition to the internet-based in China. The ava reports. Hospita reports. Other c centers.NIDRS covers 39 infectious diseases in three classes based on their public health importance ; changes in the epidemiology of schistosomiasis; changes in available technologies for diagnosis and treatment; and majroutine surveys, sentinel surveys and national surveys have been published and used to develop control strategies and monitor progress towards achieving elimination. More recently, there has been an effort to expand the use of these data beyond endemic disease control. Routine surveillance data, for instance, has been used to provide evidence of re-emerging schistosomiasis in Sichuan Province in areas that had previously achieved local control[national and NIDRS surveillance data from all provinces to estimate the incidence, prevalence and disease burden of schistosomiasis, as well as malaria, hookworm and other water, sanitation, and hygiene-associated infections[national and NIDRS data were used to estimate the future burden of these infections under climate change[Throughout these major transitions, China has made remarkable progress towards controlling schistosomiasis. The country’s evolving, parallel surveillance systems have each played a distinct role in characterizing the dynamic state of schistosomiasis transmission across diverse regions of the country. Thus far, the systems and the information they provide have been used independently; numerous reports, based on  control. Surveilfections. The anae change. While thow a country can maximize the value of multiple, distinctive information sources to inform public health campaigns and investments. This in an area where future research is needed both in China and elsewhere. Furthermore, as many provinces move towards schistosomiasis elimination and case detection becomes ever more challenging and expensive, it will be even more important to determine how the data, sampling approaches, and detection methods these systems provide can be used to optimize the performance of surveillance efforts. Successful schistosomiasis elimination will require the ability to efficiently and accurately identify the few remaining infected individuals and non-human reservoirs among large uninfected populations. This will be complicated by decreased diagnostic sensitivity owing to reduced infection intensity, testing fatigue among residents as a result of long-standing repeated examinations, and ever-increasing health care costs associated with diagnosis. To be successful, China’s surveillance system must be prepared to modify sampling methods, reporting approaches and diagnostics in response to new scientific and technological advances and changing schistosomiasis infection patterns. Recent attempts to establish diagnostic standards through the systematic evaluation of an array of immunological assays[The overlapping nature of these systems, both spatially and temporally, provides a unique opportunity to explore l assays and new l assays, 57. Carexisting surveillance systems in achieving specific surveillance endpoints, such as a characterization of spatial and temporal variability in cases. While considerable effort has been devoted to evaluating surveillance systems from a functional standpoint[For China, research and innovations needed to succeed in continuing control and elimination of schistosomiasis include the development of diagnostic tools with higher sensitivity for the detection of human infections, and new ways of assessing human susceptibility to infection. In addition, effective ways to deploy recently developed tools for detecting the infectious stage of schistosomes (cercariae) in the natural environment, 58, 59 andpoint–66 —asseandpoint, record andpoint, 69 and andpoint–72 —few Globally, there is a major movement underway to reduce the burden of helminthiases. The priorities for the global control and elimination of schistosomiasis, along with STHs, were articulated by the WHO in 2013. The sursentinel systems offer a model for deploying targeted surveillance resources and monitoring control progress over time. Similar to China’s provincial surveys, which borrow from standardized national survey protocols, province-level schistosomiasis mapping of all endemic districts has recently begun in a few countries (e.g. Ethiopia), and is rapidly scaling up for other neglected tropical diseases such as trachoma, with the benefit of funds provided by the UK Department for International Development and The Bill & Melinda Gates Foundation[routine survey data. Crucially, this system provides a model for electronic data collection even in the absence of a sophisticated NIDRS capacity. As many low-resource countries aspire for control and even elimination of schistosomiasis, understanding the synergy of parallel systems will prove cost-effective both by reducing unnecessary redundancy in data collection and in maximizing programming dollars. The systems described in China have distinct utility, but how these systems may be translated to other areas of schistosomiasis endemicity is not yet known and must be explored. Looking forward, targeted surveillance capacity is needed to understand and respond to the transmission consequences of rapid environmental, social, and technological changes, such as the construction of dams and changes in agricultural practices, that can result in an upsurge in schistosomiasis cases[sentinel system offers a model for deploying targeted surveillance capacity in regions undergoing such changes[Given the current efforts to roll-out preventative chemotherapy, there will be a need to identify areas where disease burden is declining and mass-treatment efforts can be transitioned to targeted treatment and monitoring, as well as areas where disease burden is not declining, where more broad control efforts are needed. Throughout Africa, where over 90% of schistosomiasis cases occur, the capundation. These eis cases, 80–82.  changes.Optimal surveillance of schistosomiasis and other neglected tropical diseases must evolve with changing programmatic needs and technical advances. Currently, real-time electronic surveillance is limited by lack of broadband internet infrastructure in many rural schistosomiasis-endemic areas. However, mobile disease reporting technologies offer new opportunities in areas where traditional means of communication are limited, and may


The spatial distribution of species, functional traits and phylogenetic relationships at both the regional and local scales provide complementary approaches to study patterns of biodiversity and help to untangle the mechanisms driving community assembly. Few studies have simultaneously considered the taxonomic (TBD), functional (FBD) and phylogenetic (PBD) facets of beta diversity. Here we analyze the associations between TBD, FBD, and PBD with the biome  and land use, and investigate whether TBD, FBD and PBD were correlated. In the study design we considered two widely used indicator taxa (birds and ants) from two contrasting biomes  and land uses (tree plantations and cropfields) in the southern Neotropics. Non-metric multidimensional scaling showed that taxonomic, functional and phylogenetic distances were associated to biome and land use; study sites grouped into four groups on the bi-dimensional space , and that was consistent across beta diversity facets and taxa. Mantel and PERMANOVA tests showed that TBD, FBD and PBD were positively correlated for both bird and ant assemblages; in general, partial correlations were also significant. Some of the functional traits considered here were conserved along phylogeny. Our results will contribute to the development of sound land use planning and beta diversity conservation. A major goal in ecological research is to explain patterns of biological diversity in natural and anthropogenic environments. Traditional approaches from the purely taxonomic viewpoint recognized three spatial components of diversity: local and regional species diversity  and species turnover (beta diversity). However, since the beginning of the XXI century studies started to focus on the spatial distribution of both species functional traits and phylogenetic relationships , and morCommunity ecologists increasingly recognize that a trait-based approach may be more meaningful than the species richness or composition to understand species responses to the environment . The divet al. [et al. [Beta diversity is a central concept in theoretical ecology, conservation biology, and ecosystem management . While tet al.  showed t [et al.  found thAnthropogenic pressure on terrestrial ecosystems has been accelerated in the last decades, associated to an increase on human incomes and population growth . Human aClimate acts as a regional filter that sorts species distribution according to each species range of tolerance to the various environmental factors, a process of assemblage formation known as species sorting at the metacommunity scale ,28; togeTo study the turnover between biological assemblages, we tested the multivariate response of community composition to biome and land use, based on the taxonomic, functional and phylogenetic similarities between sites located in different regions and human land uses in the southern Neotropics. We selected two conservation priority biomes  with contrasting climates and vegetation structure, and two extended land uses  with contrasting vegetation structure. In each biome, we selected five study sites per land use, for a total of 10 sites per biome. Birds and ants were used as independent biological models to consider community responses of different organisms. Field study did not involve endangered or protected species, and no birds were collected.The two selected biomes were the semideciduous subtropical Atlantic forest and the Pampean grassland  in southern South America ; they arIn both Forest and Grassland, we selected five soybean cropfields and five stands of mature eucalypt plantations (from here on cropfields and tree plantations). Within each biome, sampling sites were located at an average distance of 16 km in Grassland and 10 km in Forest. Sampling sites with the same land use  within each region were located at an average distance of 11 km in Grassland and 9 km in Forest . When saBird surveys and ant collections were conducted in December 2007 in Forest and during January 2008 in Grassland, determined by soybean phenology. Birds were surveyed by establishing 10 observation points (200-m apart to avoid sub-sample overlap) in the 20 study sites. At each observation point, we recorded all birds seen or heard within a 100 m radius and five minutes observation period, on a single visit during the breeding season . SurveysAnts were sampled during 28 consecutive days in each study site, by using 10 pitfall traps  located et al. [et al. [We selected functional traits related to the recorded species life-history, based on literature studying functional diversity or responses to habitat replacement by birds – 45 and et al.  and Stot [et al.  and four [et al.  and Fern [et al.   statistically  and visually (NMDS) explore the independent influence of biome and land use on patterns of taxonomic, functional and phylogenetic beta diversities ; 2) explore the individual ant and bird species contributing mostly to differentiate land uses within and between biomes (SIMPER); and 3) examine the associations among the different facets of diversity  and the existence of phylogenetic signal in trait data (D-Statistic).The three beta diversity facets were estimated using the appropriate distance measure between sites. To estimate TBD between land uses (cropfields and tree plantations) and biomes (Forest and Grassland) we first built an incidence matrix (sites x species) for each of birds and ants, in which species presence/absence was recorded for each study site; then we calculated the 1-Sorensen index as a measure of taxonomic dissimilarity. To estimate FBD and PBD for both birds and ants, we first built phenotypic dendrograms and phylogenetic ultrametric trees and then calculated the 1-Sorf and 1-PhyloSor indices using PICANTE . Sorf anbladj algorithm  matrix (species x species), used to calculate the 1-Sorf index, was built using the selected species functional traits as variables . All trahylocom, ), which hylocom,  and antshylocom, –73 compihylocom, .After estimating TBD, FBD and PBD we tested for significant associations between taxonomic, functional and phylogenetic distance matrices with biome and land use. To do that, we first visually explored site ordination based on taxonomic, functional and phylogenetic distances between assemblages in the Euclidean space, by performing non-metric multidimensional scaling (NMDS). First and second axes were plotted to evaluate whether site ordination was associated with biome or land use. Then, we performed permutational multivariate analysis of variance (PERMANOVA)  that canTo analyze the association between the three beta diversity facets, we performed correlations between pairs of distances matrices   to test A high correlation between 1-Sorf and 1-Phylosor is a strong indicator of phylogenetic signal in trait data . Thus, tWe recorded a total of 638 individual birds representing 49 species . For theTaxonomic, functional and phylogenetic distances between bird and ant assemblages were associated to biome and land-use in the NMDS . Study sFor both bird and ant assemblages, PERMANOVA and single effects tests confirmed that site taxonomic, functional and phylogenetic composition was associated to both land use and biome . PERMANOMantel tests showed that TBD, FBD and PBD were positively correlated for both bird and ant assemblages . PartialAmong bird traits, carnivorous, frugivorous-granivorous and insectivorous diet types, migratory-status, body-size, and high and low foraging-strata were conserved along the phylogeny . Ant traStudying simultaneously major regional (i.e. biome determined by climate) and local (i.e. habitat type determined by human land use) factors driving species distribution contributes to a unified view of community dynamics . As expeResults obtained from PERMANOVA, PERMDISP and the NMDS exploration indicated that the biome on which human activities developed had a significant influence on the capability of species to exploit different types of human-created habitats. Our studied biomes have different species pools over which soybean cropfields and eucalypt plantations imposed the additional environmental filter, which likely leaded to the differential taxonomic, functional and phylogenetic assemblages. Furthermore, human-created habitats may be more or less similar (or preserve more or less elements) to the biome in which the habitat is located. For example, eucalypt plantations were structurally more similar to forests than to grasslands; and soybean cropfields were more similar to grasslands than to forests. Thus, the set of traits phylogenetically distributed allows species to use soybean cropfields and eucalypt plantations differently depending on whether the human activity is developed in the Pampas Grassland or the Atlantic Forest. In a previous study we demonstrated that soybean cropfields supported a higher proportion of native bird species in Grassland than in Forest, where similarity in vegetation structure between the native and human-created habitat was greater; the opposite occurred in tree plantations that supported more native species in Forest than in Grasslands .Results from PERMANOVA and PERMDISP indicated that both biome and land use were associated with taxonomic, functional and phylogenetic turnovers in bird and ant assemblages. Thus, land uses and biomes seemed to promote assemblage differentiation not only in species identities but in traits and lineages that occurred in anthropogenic habitats. Moreover, we showed evidence that TBD, FBD and PBD were positively associated to each other, and that most of the studied traits were conserved along bird and ant phylogenies. Results obtained by the partial Mantel tests indicated that in bird assemblages, species and trait compositions were not completely phylogenetically structured, and that other traits (not considered here) caused species and phylogenetic composition associations. However, the association between taxonomic and functional distances in ant communities was completely explained by the phylogenetic information considered. Moreover, the association between functional and phylogenetic distance in bird communities was completely explained by the taxonomic distance. Overall, those results suggest that taxonomic, functional and phylogenetic distances between assemblages were related to changes in phylogenetically conserved traits along each regional species pool. That is, lineages bearing traits which favored colonization and survival in soybean cropfields or eucalypt plantations differed between biomes, which is the pattern expected when communities were assembled by environmental filtering of independent lineages ,21.Bird TBD was associated (to some extent) with FBD beyond any phylogenetic structure of the communities. On the one hand, as mentioned before, that result is extremely dependent on the selected traits and consistent with traits that were not phylogenetically conserved. In fact, the inclusion of additional or alternative relevant traits could even reverse our findings if there is a phylogenetic signal in them. The result is also dependent on the obtained phylogenetic tree, because different phylogenetic considerations may lead to different trees and derive in a different result. On the other hand, it is possible that a “specific  component”  explained species turnovers beyond any phylogenetic relationship. As expected, both birds and ants were sensitive to human alterations of the habitat such as changing vegetation structure ,96–99. FFinally, we used an integrated approach to study community differentiation considering three complementary facets  of beta diversity. We accounted for regional (biome) and local (land use) factors that proved to influence turnover. To emphasize the relevance of the approach, we used conservation priority biomes and extended human-created habitats as the regional and local factors, respectively, influencing assemblage composition. In countries where economy depends on human activities that require large areas , our results contribute to the development of sound land use planning and beta diversity conservation. For example, our results should be useful to help selecting the most appropriate ecoregion to develop agriculture and forestry in Argentina. We hope our work will serve to encourage the use of a more complete approach to the study of beta diversity and its application in conservation biology.S1 Fig(DOC)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOC)Click here for additional data file.