Barriers and enablers to introducing comprehensive patient blood management in the hospital

Patient Blood Management (PBM) is a patient-focused multidisciplinary and comprehensive concept that is designed to ensure the optimal, appropriate and safe use of blood and blood products, resulting in better outcome and safety for the recipients. The World Health Organization, in May 2010, adopted a resolution in favour of PBM, on the availability, safety and quality of blood products and their safe and rational use. However, several factors may enhance or hamper this process including health care personnel, available techniques and technologies, devices, standards, guidelines and documentation, quality systems as well as coordination, monitoring and evaluation. The implications in developing countries may have other peculiarities.     

Current risk assessment approaches for environmental and food and feed safety assessment

Foundational activities at the international level underlie current risk and safety assessment approaches for genetically engineered/modified organisms (GEOs/GMOs). Early risk assessment considerations beginning with the OECD ‘Blue Book’ established risk/safety assessment as the characterization of the organism and its environmental release; establishment and persistence in the environment; and human and ecological effects, analyzed in principle through existing methods. Important in this context was recognition that GEOs/GMOs as a class did not represent new risks relative to products of traditional plant breeding and that any incremental risk would need to be established on a stepwise case-by-case comparative basis with existing crops and derived-foods as the baseline. Accordingly, concepts of familiarity and substantial equivalence were advanced by OECD and WHO as ways to establish a risk analysis baseline for determining whether and to what extent risk/safety assessment was needed. Regulatory implementations of this paradigm have skewed to increasingly complex portfolios of studies rather than adhering to analysis which is formulated to fit the risk/safety questions relevant to a given case. Plants produced through genome editing technology will benefit from risk analysis that implements sound problem formulation to guide the need for and nature of risk/safety assessments.

     

How safe is blood,really?

Blood is safer than it has ever been, however the progression of transfusion from dangerous intervention to reliable supportive care been non-linear. Disparities resulting from geography, economy, and social class persist. Some risks are known, others are unknown but predictable, and still others may be totally unpredictable. Among the known risks are infectious and immunologic events that can be calculated per unit of blood transfused. These risks vary by component. Among the unknown risks are the potential for emerging pathogens transmitted by blood and for processing or storage lesions to result in short or long-term toxicity. National registries provide some reassurance that transfusion may not affect mortality significantly beyond the first few weeks after administration. Nevertheless, transmission of novel pathogens, repeated allogeneic stimulation, and infusion of cytokines or chemokines may have unrecognized consequences. Blood safety can be effected dramatically with small investment in developing countries. In the developed world, technologies such as pathogen inactivation, antigen camouflage, component substitutes, or cell expansion promise relatively small advances in safety at substantial cost. No strategy guarantees zero-risk.     

Evaluation of similar biotherapeutic products (SBPs): scientific principles and their implementation

The availability of biotherapeutic products to patients has a major impact on the success in treating many life-threatening and chronic diseases. These products are often derived by recombinant DNA technology and are expensive for the majority of patients who need them most. Increasing numbers of patents/data protection are now expiring and biologicals "similar" to the originators (innovative products) are coming to the market. This process is seen as a mechanism for increasing the access to biotherapeutic products which are very much needed for the treatment of chronic diseases worldwide. The emergence of Similar Biological Products (SBPs) has created numerous challenges in developing, licensing, and using these important products. From a public health perspective, the overall expectation is that similar products will be available at an affordable price and will increase patients' access to the therapy. In response to the requests for assistance in defining regulatory requirements for SBPs, the WHO Expert Committee on Biological Standardization (ECBS) adopted the new WHO Guidelines for evaluation of SBPs in October 2009. This article provides a brief account of the WHO initiative to assist its member states to establish national requirements for the regulatory oversight of SBPs. The aim of the article is to inform its readers of the current status of WHO Guidelines on the evaluation of similar biotherapeutic products and of the plan to strengthen national regulatory requirements to assure quality, safety and efficacy of similar biotherapeutic products at the global level.     

Material & equipment,procurement & maintenance: Impact on blood safety

Blood Transfusion Safety is dependent on effectively organised and managed blood services, which have adequate financial resources, skilled manpower, appropriate infrastructure and quality management systems in place.80% of the world's population has access to 20% of the supply blood products, of which little is consistently safe.HIV highlighted the importance of blood safety. The lack of effective blood services in low human development index (LHDI), developing countries, has lead to international funding and capacity building for more than three decades. The initial strategies focused on providing HIV testing reagents to prevention transmission, however this only addresses one part of blood safety.Blood safety is not only dependent on preventing HIV transmission. In many populations there are other infectious agents, which have a higher prevalence. Ensuring the correct blood is provided to the patient depends on: well managed services with effective leadership and adequate budgets; capacity building and retention of skilled experienced staff; availability of laboratory equipment, correctly maintained; blood cold chain systems; procedures for tendering, purchasing and ensuring an unbroken supply of reagents and consumables; and quality management systems.Barriers for simplified effective tendering, procurement and contracting require urgent attention and coordination of all funding organisations to ensure an unbroken supply of reagents.     

Regulatory affairs and biotechnology in Europe. I. Introduction into good regulatory practice

The high cost and risks associated with the research and development of new drugs demand an alert as well as realistic legislative policy at both national and international levels. Registration of a new drug required before a marketing license is granted, is important for all branches of the pharmaceutical industry but is crucial for success in the innovative biotechnological sector. Innovation as such is no guarantee to be profitable. Increasing government demands have introduced uncertainty on whether new products will secure registration and have led to a disproportionate increase in the economical risks for innovative industry. Preparation and submission of an application for registration should be undertaken seriously and professionally since it has significantly more consequences than simply obtaining a marketing licence. It will influence marketing strategies and results. It is proposed--since dealing with regulatory affairs can be considered as an essential specialism--to apply a Quality Assurance approach. Activities in this context should comply with the same performance standards as developed for GMP, GLP and GCP leading to Good Regulatory Practice (GRP). By acknowledging regulatory affairs as a quality assurance means one can define a set of standard procedures within an organization to ensure that decisions are made on current and future regulations. In such a setup regulatory affairs becomes a marketing tool. This paper illustrates the complex problems found in registration activities. It underlines the necessity of introducing a GRP-approach of performance resulting in substantive evidence of regulatory efficacy.     

WHO informal consultation on regulatory evaluation of therapeutic biological medicinal products held at WHO Headquarters, Geneva, 19-20 April 2007.

This report reflects the discussion and conclusions of an informal consultation held on 19-20 April 2007 at the World Health Organization concerning the regulatory evaluation of therapeutic biological medicinal products. The objectives of this meeting were to discuss the current status of so-called "similar" biological medicinal products (biosimilars) and to review regulatory pathways and challenges in evaluating the quality, safety and efficacy of these products. Biosimilars are products that are subject to licensing with a reduced data package due to a proven 'similarity' to the licensed reference product. The meeting was attended by experts in biotherapeutics from regulatory agencies, industry and academia representing 16 countries worldwide. Dr. Elwyn Griffiths (Canada) acted as Chairman and Dr. James Robertson (UK) was the Rapporteur. The meeting strongly focused on the usage of biosimilars and the current regulatory situation in many different countries. The application of International Nonproprietary Names (INN) to biosimilars, their potential immunogenicity, and WHO international standards and reference materials were also discussed, alongside presentations from the innovator and generic manufacturing industries. The consultation recognized the importance of the terminology as well as a definition of biosimilars for future considerations of these products. However, achieving a global consensus on the terminology for these new challenging products was not attempted at the Consultation, and it was decided that a future WHO working group should act on this issue as a next step. For purposes of this meeting report only, the term 'biosimilars' is temporarily used to refer to this category of products. It became clear that biotherapeutics authorized on the basis of a reduced data package are available and being used in some countries, with more appearing on the market. The existence of divergent approaches to the regulatory oversight of biosimilars in different countries revealed a need for defining regulatory expectations for these products at the global level. While many countries are following the guideline developed within the EU for quality aspects, discrepancies remain regarding the non-clinical and clinical studies of these products. The Consultation recommended that the WHO should develop a guideline in this area in order to provide a framework for the development of regulatory pathways for these products worldwide. For this purpose, agreement on the scope, definition and terminology of these products was deemed necessary. The interchangeability and substitution of products were also flagged as areas in need of harmonization. A WHO working group should be established to develop a guideline that would promote global consensus on the regulation of biosimilars, assist in their registration and enhance the availability of safe and effective biosimilar products worldwide.     

Regulatory affairs and biotechnology in Europe

The high cost and risks associated with the research and development of new drugs demand an alert as well as realistic legislative policy at both national and international levels. Registration of a new drug required before a marketing licence is granted, is important for all branches of the pharmaceutical industry but is crucial for success in the innovative biotechnological sector.Innovation as such is no guarantee to be profitable. Increasing government demands have introduced uncertainty on whether new products will secure registration and have led to a disproportionate increase in the economical risks for innovative industry. Preparation and submission of an application for registration should be undertaken seriously and professionally since it has significantly more consequences than simply obtaining a marketing licence. It will influence marketing strategies and results. It is proposed — since dealing with regulatory affairs can be considered as an essential specialism — to apply a Quality Assurance approach. Activities in this context should comply with the same performance standards as developed for GMP, GLP and GCP leading to Good Regulatory Practice (GRP).By acknowledging regulatory affairs as a quality assurance means one can define a set of standard procedures within an organization to ensure that decisions are made on current and future regulations. In such a setup regulatory affairs becomes a marketing tool.This paper illustrates the complex problems found in registration activities. It underlines the necessity of introducing a GRP-approach of performance resulting in substantive evidence of regulatory efficacy.     

Clinical use of blood,blood components and blood products.

The goal of modern transfusion therapy is to provide appropriate replacement therapy with blood components as opposed to whole blood for patients with specific hematologic deficiencies. A prerequisite of component therapy is, therefore, correct identification of the deficiency. Appropriate use of components avoids many of the hazards associated with the use of whole blood, and at the same time makes maximal use of this valuable resource. Blood components separated from whole blood soon after collection and appropriately stored can, in combination, provide all the factors present in fresh whole blood. Red cell concentrates prepared from multiple packs have a hematocrit of approximately 70%. They may be stored for up to 3 weeks at 4 degrees C and are recommended for most situations requiring red cell transfusions. Platelet concentrates, which can be stored for up to 72 hours at 22 degrees C, may be used for thrombocytopenic patients. Fresh frozen plasma, stored plasma, cryoprecipitated factor VIII, factor VIII concentrate and factor IX complex concentrate are available for the proper treatment of patients with hemorrhagic disorders due to coagulation factor deficiencies. Similarly, albumin and immune serum globulin are available for their oncotic and antibody properties respectively. Thus, the availability and appropriate use of the various blood products allows not only optimal transfusion therapy for each patient, but also fuller utilization of national blood resources.     

Stability evaluation of vaccines: WHO approach

The stability of vaccines has a major impact on the success of immunization programmes worldwide. In line with this, clear definition of the stability characteristics of a vaccine is of critical importance. One of the concerns at country level is whether vaccines will remain potent on its way from the manufacturer, through the distribution channels, to the final users and vaccine recipients. In response to the requests for assistance in defining stability profile of vaccines, the Expert Committee on Biological Standardization (ECBS) in October 2006 agreed that new WHO guidelines be established on stability evaluation of vaccines (http://www.who.int/biologicals/publications/trs/areas/vaccines/stability/en/index.html). This document applies to all vaccines against infectious diseases. The aim of this guideline is to provide the scientific basis and guiding principles for evaluation of vaccine stability for the purpose of clinical trial approval, licensing, and post-licensure monitoring. As part of its initiative to promote use of vaccines of assured quality, WHO emphasizes the role of National Regulatory Authorities (NRAs) and National Control Laboratories (NCLs) in overall vaccine evaluation, including stability assessment. While recognizing that manufacturers are responsible for the quality of the vaccines they produce, compliance with vaccine quality specifications is part of regulatory oversight. This article provides basic information about WHO international standards as well as key definitions and principles for stability evaluation of vaccines that are elaborated in detail in the above mentioned guidance document.     

基层医院输血科工作现状及改进

输血是现代医学中重要的抢救、治疗手段,临床输血是一门极其复杂的学科。血液及其制品的管理是一项科学的系统工程,是保证血液质量、提高医疗用血效率、促进输血事业和科研技术水平不断发展的关键。输血科是医院的重要部门,具体负责临床用血的技术指导和技术实施,确保贮血、配发血和其他科学、合理用血措施的执行,其基本目的是将血液及成分安全、有效、合理而便宜的输注给需要的病人并取得疗效。输血科如何履行好职能,保证临床输血安全、科学、合理、有效,已成为当前基层医院首先需要解决的问题。本文就基层医院输血科的工作状况进行了分析,并提出完善规章制度,严格执行操作,更新输血观念,科学合理用血,开展业务新技术,保证输血有效性等相应整改措施,在实际运行中取得可喜的成绩。     

Role of regulatory agencies

In this paper the authors discuss the role of regulation in assuring blood safety. After an overview of the subject by a leading expert, examples are provided of regulatory systems for blood transfusion services in several countries and regions. Additionally, the perspective of WHO is given on the essential role of national regulatory authorities in assuring the quality of national blood programmes.Collectively, the sections of this paper afford an opportunity for readers to make comparisons among different regulatory frameworks and to "benchmark" among the existing systems. Despite many differences in approach, a clear pattern emerges of worldwide efforts to strengthen blood regulatory systems.     

The Legal Regime Governing Sea Transport of Ultrahazardous Radioactive Materials

Although the international community has taken some steps to address the risks created by the movements of ultrahazardous radioactive cargoes, important gaps still exist in the legal regime governing these activities. An apparent consensus has been reached at the International Maritime Organization (IMO) to make the Code for the Safe Carriage of Irradiated Nuclear Fuel, Plutonium, and High-Level Radioactive Wastes in Flasks Aboard Ships (the INF Code) mandatory and to seek some clarification of the standards governing shipboard safety. But still lacking are agreements regarding salvage responsibilities, liability of shippers for damages, revision of transport cask safety standards to meet maritime accident conditions, obligations to consult regarding the best routes and to provide advance notification to concerned coastal states, the preparation of environmental assessments, and contingency planning to handle shore emergencies and salvage responsibilities. Until agreements are reached on these important matters, the shipment of these extremely dangerous or "ultrahazardous" materials will continue to violate fundamental norms of international law and comity because they place coastal nations that receive no benefit from the shipments at grave risk of environmental disaster without any legal protections. Because the shipments of ultrahazardous radioactive cargoes are increasing, it is highly advisable for concerned nations to negotiate regional protocols delineating the legal regime that applies to these maritime transports. A draft model protocol is attached at the end of this article which may provide guidance on this effort. It is also appropriate for concerned nations to consider bringing a claim against the shipping nations under the dispute resolution mechanisms established by the 1982 United Nations Law of the Sea Convention. Such a claim would be based on the failure of the shipping nations to comply with their obligations under the convention to prepare and distribute environmental impact assessments, consult with affected nations, prepare emergency contingency plans, and agree to an effective liability regime in the event of an accident. Because of the grave potential risks created by these shipments and because of the failure of the shippers to meet their obligations to protect coastal nations from these risks, coastal nations may be justified under international law to take unilateral or regional action to block future shipments.     

Quality Control of Fungal and Viral Biocontrol Agents - Assurance of Product Performance

An essential feature of the production of all microbial control agents is an effective quality control system. Well-defined product specifications with accompanying quality control procedures help to maximize product performance, ensure product safety, standardize manufacturing costs and reduce the risks of supply failure, thus building user confidence. A production system that does not have a quality control system is one whose output is uncontrolled and a lack of thorough quality feedback can result in batches of product with variable concentrations of active agent. This results in products with variable performance leading to control failures by users and serious loss of user confidence. Strict quality control procedures are not only essential for product consistency, but also for safety. Where quality control is inadequate, microbial contamination of the final product is inevitable. In most of such cases this will merely lead to a loss of efficacy due to dilution of the active ingredient by competing microorganisms, but also the potential of producing human pathogens must be ruled out. Recognition of contaminants and quantification of the degree of contamination are therefore important in determining any possible risk to human health. Many low technology production systems in use around the world have minimal or no quality control procedures. This is unacceptable and can damage the reputation of microbial control in addition to possibly posing health risks to those that produce or are exposed to the product. Two case studies from developing countries, are used to illustrate how the lack of quality control procedures can lead to the production of low viability, highly contaminated products with low or negligible concentrations of the active ingredient. However, it is also demonstrated that low technology production systems in developing countries can produce high quality products, provided appropriate quality control procedures are firmly implemented. It must be recognized that quality control procedures can be more complex and technologically demanding than the production procedures themselves, but it is largely on the effectiveness of these control procedures that the long-term acceptability of fungal and viral products depends. This paper details the quality control procedures considered necessary in the mass production of fungi and viruses for use as biocontrol agents, and attempts to suggest reasonable standards that can be achieved by all producers.     

Advancing environmental risk assessment for transgenic biofeedstock crops

Transgenic modification of plants is a key enabling technology for developing sustainable biofeedstocks for biofuels production. Regulatory decisions and the wider acceptance and development of transgenic biofeedstock crops are considered from the context of science-based risk assessment. The risk assessment paradigm for transgenic biofeedstock crops is fundamentally no different from that of current generation transgenic crops, except that the focus of the assessment must consider the unique attributes of a given biofeedstock crop and its environmental release. For currently envisioned biofeedstock crops, particular emphasis in risk assessment will be given to characterization of altered metabolic profiles and their implications relative to non-target environmental effects and food safety; weediness and invasiveness when plants are modified for abiotic stress tolerance or are domesticated; and aggregate risk when plants are platforms for multi-product production. Robust risk assessments for transgenic biofeedstock crops are case-specific, initiated through problem formulation, and use tiered approaches for risk characterization.     

Bioequivalence of generic aerosol bronchodilators: what are the issues?

I have attempted to address some critical issues relating to the introduction of generic aerosol bronchodilators in Canada. I approached Genpharm to obtain information on the data submitted to the HPB, including the number of subjects involved, but the company refused to divulge this information because it was concerned about the use of such information by its competitors. In addition to the in-vitro testing conducted by the HPB, should a single pharmacodynamic study be sufficient to demonstrate the safety and efficacy of a drug that serves such a critical role in the prevention of serious illness and possibly death? If so, what will constitute the minimum requirements for the design of such a study? In general, what should be the minimum standards required for safety, efficacy and bioequivalence of aerosol bronchodilators? The next phase rests with the provincial governments. What criteria will they use to determine whether a generic aerosol bronchodilator will be considered bioequivalent? It is essential that the criteria for bioequivalence be developed by experts, and ideally those criteria should be agreed upon and accepted by federal and provincial regulatory bodies before a product is given the status of bioequivalence. Unless such a step is taken it will be difficult to have confidence that products can be considered interchangeable. The issue of interchangeability of aerosol bronchodilators demands immediate attention. Regulatory agencies are caught between those groups with vested interests on both sides. Since patients will either benefit or suffer as a consequence of regulatory decisions, action must be taken to ensure that the best decisions are made. Scientists, clinicians and government officials should convene as soon as possible to formulate a satisfactory approach to this problem of interchangeability. The medical and pharmaceutical professions need reliable information, and patients should not be denied less expensive generic drugs if it can be determined that they are comparable to the innovator''s product.     

The WHO network of collaborating centres on standardization and regulatory evaluation of vaccines

WHO Collaborating Centres (CCs) form part of an international collaborative network set up by WHO in support of its mandated programme at the country, intercountry, regional, interregional and global levels, as appropriate. As part of its mandate in the area of biologicals, WHO has broadened the scope of its work and has expanded the range of activities devoted to the establishment of international standards for vaccines. In line with global immunization goals, the need for standards for evaluation of quality, safety and efficacy of new vaccines, as well as those that have been in use for a long time, has significantly increased. Furthermore, complex issues related to new production methodologies, more sophisticated techniques for characterization and laboratory testing, and for nonclinical and clinical evaluation of vaccines have raised a number of regulatory challenges for WHO when requested to assist its Member States. In this context, CCs in the area of standardization of vaccines and biotherapeutics (excluding blood products) have provided technical assistance and have broadened the scope of their work over time. In the area of standardization and regulatory evaluation of vaccines, WHO currently has six CCs as well as one candidate centre for which the designation process has been initiated and a further three candidate centres with great potential. The purpose of the meeting held on 24–26 April 2012 was to improve understanding of WHO's priorities in setting standards, to facilitate their implementation, and to increase transparency of the roles and responsibilities of CCs. The meeting was also an excellent opportunity to explore possibilities for improving collaboration between WHO and CCs, as well as among CCs themselves by working as a CC network. All CCs expressed a wish for increased interaction, information-sharing, collaboration and other ways of working together that may lead to cross-fertilization between the CCs. Synergy was recognized as a significant mechanism for leveraging existing resources in responding to global public health challenges and in addressing WHO's priorities. Agreement was reached for operating as a network of CCs.     

Coding and traceability for cells,tissues and organs for transplantation

Modern transplantation of cells, tissues and organs has been practiced within the last century achieving both life saving and enhancing results. Associated risks have been recognized including infectious disease transmission, malignancy, immune mediated disease and graft failure. This has resulted in establishment of government regulation, professional standard setting and establishment of vigilance and surveillance systems for early detection and prevention and to improve patient safety. The increased transportation of grafts across national boundaries has made traceability difficult and sometimes impossible. Experience during the first Gulf War with miss-identification of blood units coming from multiple countries without standardized coding and labeling has led international organizations to develop standardized nomenclature and coding for blood. Following this example, cell therapy and tissue transplant practitioners have also moved to standardization of coding systems. Establishment of an international coding system has progressed rapidly and implementation for blood has demonstrated multiple advantages. WHO has held two global consultations on human cells and tissues for transplantation, which recognized the global circulation of cells and tissues and growing commercialization and the need for means of coding to identify tissues and cells used in transplantation, are essential for full traceability. There is currently a wide diversity in the identification and coding of tissue and cell products. For tissues, with a few exceptions, product terminology has not been standardized even at the national level. Progress has been made in blood and cell therapies with a slow and steady trend towards implementation of the international code ISBT 128. Across all fields, there are now 3,700 licensed facilities in 66 countries. Efforts are necessary to encourage the introduction of a standardized international coding system for donation identification numbers, such as ISBT 128, for all donated biologic products.     

Towards a more open debate about values in decision-making on agricultural biotechnology

Regulatory decision-making over the use of products of new technology aims to be based on science-based risk assessment. In some jurisdictions, decision-making about the cultivation of genetically modified (GM) plants is blocked supposedly because of scientific uncertainty about risks to the environment. However, disagreement about the acceptability of risks is primarily a dispute over normative values, which is not resolvable through natural sciences. Natural sciences may improve the quality and relevance of the scientific information used to support environmental risk assessments and make scientific uncertainties explicit, but offer little to resolve differences about values. Decisions about cultivating GM plants will thus not necessarily be eased by performing more research to reduce scientific uncertainty in environmental risk assessments, but by clarifying the debate over values. We suggest several approaches to reveal values in decision-making: (1) clarifying policy objectives; (2) determining what constitutes environmental harm; (3) making explicit the factual and normative premises on which risk assessments are based; (4) better demarcating environmental risk assessment studies from ecological research; (5) weighing the potential for environmental benefits (i.e., opportunities) as well as the potential for environmental harms (i.e., risks); and (6) expanding participation in the risk governance of GM plants. Recognising and openly debating differences about values will not remove controversy about the cultivation of GM plants. However, by revealing what is truly in dispute, debates about values will clarify decision-making criteria.