[Problems and thoughts in clinical safety evaluation of traditional Chinese medicine].

Amid the modernization and internationalization of traditional Chinese medicine(TCM), the safety of TCM has attracted much attention. At the moment, the government, scientific research teams, and pharmaceutical enterprises have made great efforts to explore methods and techniques for clinical safety evaluation of TCM. Although considerable achievements have been made, there are still many problems, such as the non-standard terms of adverse reactions of TCM, unclear evaluation indicators, unreasonable judgment methods, lack of evaluation models, out-of-date evaluation standards, and unsound reporting systems. Therefore, it is urgent to further deepen the research mode and method of clinical safety evaluation of TCM. Based on the current national requirements for the life-cycle management of drugs, this study focused on the problems in the five dimensions of clinical safety evaluation of TCM, including normative terms, evaluation modes, judgment methods, evaluation standards, and reporting systems, and proposed suggestions on the development of a life-cycle clinical safety evaluation method that conformed to the characteristics of TCM, hoping to provide a reference for future research.

Nanomaterial Drug Products: Manufacturing and Analytical Perspectives.

The increasing use of nanotechnology, including nanoparticles, in the preparation of drug products requires both manufacturing and analytical considerations in order to establish the quality metrics suitable for performance and risk assessment. A range of different nanoparticle systems exists including (but not limited to) nano-drugs, nano-additives, and nano-carriers. These systems generally require more complex production and characterization strategies than conventional pharmaceutical dosage forms. The advantage of using nanoparticle systems in pharmaceutical science is that the effective and desired function of the material can be designed through modern manufacturing processes. This paper offers a systematic nomenclature which allows for greater understanding of the drug product under evaluation based on available data from other nanoparticle reports. Analytical considerations of nano-drugs, nano-additives, and nano-carriers and the way in which they are measured are directly connected to quality control. Ultimately, the objective is to consider the entire nano-drug, nano-additive, and nano-carrier product life cycle with respect to its manufacture, use, and eventual fate. The tools and approaches to address the needs of these products exist; it should be the task of the pharmaceutical scientists and those in related disciplines to increase their understanding of nanomedicine and its novel products.

Development of paediatric medicines: concepts and principles.

The term "off-label use of drugs in children" is common to current medical practice. A look into the historical context helps to elucidate the framework for the use of medicines in children. Proper drug labels are relatively new in history. They emerged half a century ago when U.S. legislation forced manufacturers to prove the safety and efficacy of drugs by adequate clinical trials. Today pharmaceutical progress is so obvious and well established that the discrepancy between its benefit for adults as compared to children started to be perceived by champions in different institutions. There is an increased understanding of the child's physiology during developmental growth, of the maturation of enzyme systems, of the pharmacokinetics and pharmacodynamics and of the differences in disease processes. The involved institutions include legislators, government, regulatory authorities, academic scientists, pharmaceutical companies, the WHO, to name just the most prominent ones, but there are many more. Driving forces for the improvement of medicines for children include societal priorities, the involvement of science, the mission of regulatory authorities the role of clinical pharmacologists, paediatricians, and the characteristics of our market-driven economy with its chaotic, contradictory and lively elements. We do not live in an ideal world, but there is progress, and children are likely to benefit from it.

Taking immunogenicity assessment of therapeutic proteins to the next level.

Therapeutic proteins provide innovative and effective therapies for numerous diseases. However, some of these products are associated with unwanted immunogenicity that may lead to clinical consequences such as reduced or loss of efficacy, altered pharmacokinetics (PK), general immune and hypersensitivity reactions, and neutralisation of the natural counterpart (e.g. the physiological hormone). Regulatory guidance on immunogenicity assessment needs to take into consideration a great diversity of products, indications and patient populations as well as constantly advancing manufacturing technologies. Such guidance needs to be sufficiently specific while, at the same time, allowing interactive discussion and adjusted benefit-risk weighing of each product on a case-by-case basis, e.g. for a unique treatment of a life threatening disease acceptable treatment risks may differ considerably from the ones in case of less serious disease. This theme was the focus of the international conference "Taking immunogenicity assessment of therapeutic proteins to the next level", held at the Paul-Ehrlich-Institut in Langen, Germany, on the 10-11. June 2010. The objectives of the conference were to highlight how the field could move from that of a mere description of risk factors to a system of risk assessment and mitigation, as well as an understanding of the impact of unwanted immunogenicity on the overall benefit/risk consideration for a medicinal product. More than 150 experts from industry, academia and regulatory authorities worldwide discussed the phenomenon of undesired immunogenicity from different perspectives. The conference focussed on issues relevant to three areas: (1) new European guidelines that are currently the subject of discussion; (2) testing strategies for immunogenicity assessment; and (3) scientific progress on the product-related factors that may contribute to the development of pathogenesis of immunogenicity, in particular in the field of protein aggregation and post-translational modifications. This report provides an overview of issues, insights, and conclusions that were discussed and achieved during the meeting.

Open access chemical and clinical probes to support drug discovery.

Drug discovery resources in academia and industry are not used efficiently, to the detriment of industry and society. Duplication could be reduced, and productivity could be increased, by performing basic biology and clinical proofs of concept within open access industry-academia partnerships. Chemical biologists could play a central role in this effort.

How to improve pharmacoeconomic data generalisability between different countries.

Pharmacoeconomics arises out of a response to the increasing need for accountability of healthcare money in an international environment, when escalating healthcare costs exert an unsustainable burden on the healthcare system. At present, it is difficult to convince any decision makers, whether at the national or institutional level, to list any new drugs into a formulary for subsidy purpose without providing some sort of 'cost-effectiveness' data. This paper discusses the need for having a consensus on what would make pharmacoeconomic data universally acceptable and deals with the issue of improving pharmacoeconomic data generalisability between different countries.

Canadian drug regulatory framework.

The role of regulatory drug submission evaluators in Canada is to critically assess both the data submitted and the sponsor's interpretation of the data in order to reach an evidence-, and context-based recommendation as to the potential benefits and potential harms (i.e., risks) associated with taking the drug under the proposed conditions of use. The purpose of this document is to outline the regulatory framework in which this assessment occurs, including: defining what "authorization to market a drug in Canada" means, in terms of the role of the sponsor, the responsibility of Health Canada in applying the Food and Drugs Act prior to and after marketing authorization, and the distinction between regulatory authorization versus physician authorization; highlighting organizational, process and legal factors within Health Canada related to authorization of clinical trials and authorization to market a drug; considerations during the review process, such as regulatory and scientific issues related to the drug, patient populations and trial designs; application of international guidelines, and decisions from other jurisdictions; regulatory realities regarding drug authorization, including the requirement for wording in the Product Monograph to accurately reflect the information currently available on the safe and effective use of a drug, and that hypothesis-confirming studies are essential to regulatory endorsement; current issues related to the review of therapies for dementia, such as assessing preventative treatments, and therapies that have symptomatic versus disease-modifying effects, statistical issues regarding missing data, and trial design issues.

Challenges in drug development for muscle disease: a stakeholders' meeting.

Current treatment benefits for patients with muscle disease are limited, but progress in legislative and scientific initiatives have set the stage for the development of new therapies. The MD-CARE Act (Public Law 107-84), which allocates federal resources to muscular dystrophy, was approved by Congress and signed into law by the President of the United States in 2001. This has shifted the emphasis toward translational research. To facilitate a push toward therapy for muscle disorders, the Muscular Dystrophy Association (MDA) sponsored a meeting with representatives from industry, the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and other government agencies and academia. Each contributed in different ways. The FDA helped define the necessary data to support investigational new drug (IND) applications including the design of proof-of-principle studies, outcome measures for clinical trials, and the pathway for developing surrogate measures for fast-tracking promising new drugs. The NIH, other government agencies, and the MDA described potential funding sources for translational research. Industry delineated a complementary role with academia, and academic investigators elucidated the current strengths and weaknesses of available clinical endpoints. The meeting provided a format for communication for diverse disciplines that usually have no common meeting ground, helping to lay the foundation for bringing products to market in a timely fashion.

Complementary new approaches enable repositioning of failed drug candidates.

Until recently, safe drug candidates that failed in clinical trials were shelved as drug developers channelled resources to the next candidates in the pipeline. In the past few years, new technologies, improved genomic information and high-throughput methods have made it possible to quickly and economically re-examine advanced drug candidates for therapeutic activity against other diseases. This development arrives at an opportune time, as pharmaceutical companies strive to fill sparse late-stage pipelines at the same time as keeping costs down. Specialised companies are emerging with new methods and a fresh point of view to assist pharmaceutical developers in turning failed drug candidates from one therapeutic area into successful treatments in another. This editorial introduces a series of papers to be published in Expert Opinion on Investigational Drugs, discussing discontinued drugs from 2005.

Are development times for pharmaceuticals increasing or decreasing?

This study examines trends in drug development times. Longer clinical trial times have been described as one factor leading to higher drug prices. Previous reports on development times have been based on proprietary data. We examined trends in development times for 168 drugs with data collected from publicly available sources. The median clinical trial and regulatory review periods for drugs approved between 1992 and 2002 were 5.1 and 1.2 years, respectively. Clinical trial periods have not increased during this time frame, and regulatory review periods have decreased. Therefore, it is unlikely that longer clinical trial times are contributing to rising prescription drug prices.

[Drug evaluation: new requirements and perspectives]. / La valutazione del farmaco: nuove esigenze e prospettive.

Lately the European and international regulatory Agencies, responsible for the evaluation of drugs, have not been capable to implement regulatory processes guiding clinical practice efficiently. The sudden withdrawal of innovative drugs, the incapacity of assuring independence, the not controlled trend of pharmaceutical expenditure are signals of the failure of a system which should respond to the mandate of public health and market regulation. Some intrinsic limits of present regulatory systems arise because regulatory Agencies approve medicinal products on the basis of minimum standards of efficacy or owing to fast registration procedures which do not allow to assure the real efficacy and safety of the product approved. Non-inferiority and equivalence trials, short duration studies conducted on small populations (not representing the real setting of utilization in clinical practice) are often considered sufficient for drug registration. Moreover, Agencies often lack data on the safety of approved products and based on post-marketing surveillance and monitoring plans which can assure the real profile of drug safety. Owing to the institution of the Italian Medicines Agency (AIFA), Italy has lately approached European standards of regulation and proposed a new original regulatory approach attempting to go beyond some of the main limitations described above. The main points the model is based on are: promotion of use appropriateness through the analysis of experiences occurring in the area; promotion of independent drug research in order to collect data reliable and useful for drug regulation; publication and distribution of independent information on drug utilization for health professionals. The Italian approach tries to bring regulatory provisions close to clinical practice by promoting a correct and rational use of drugs and developing new areas of intervention for research, vigilance and information.