Drug Safety Evaluation in China.

PURPOSE OF REVIEW: This review aimed to introduce the regulations management and current situations of drug safety evaluation in China. RECENT FINDINGS: The nationwide implementation of good laboratory practice and good clinical practice guarantees the quality of pre-marketing drug safety evaluation. In recent years, post-marketing drug safety monitoring is changing from passive mode to the combination of active and passive monitoring. A national adverse drug reaction monitoring sentinel alliance has been created to actively identify, report, and evaluate adverse reactions, with more than 1.4 million cases reported in 2017. But the quality of the reports is not optimal, with few reports from drug manufacturers, low rate of severe reports, and trend of lag reporting. Drug safety evaluation in China is transitioning from passive monitoring to a combination mode. Drug pharmacovigilance is a powerful tool for active monitoring, but participation by drug manufacturers would be essential to an effective drug safety evaluation system.

[Phytovigilance: A medical requirement and a legal obligation]. / La phytovigilance: impératif médical et obligation légale.

Phytovigilance consists in supervision of side effects and drug interactions consequential to use of herbal medicinal products, herbal food supplements, herbal cosmetics and/or medicinal plants. It includes thus pharmacovigilance applied to phytotherapy, nutrivigilance and cosmetovigilance but also addictovigilance in case of plants, which lead to drug addiction, and toxicovigilance in case of toxic plants. Becoming necessary owing to (acute or chronic) toxicity risks or to drug interactions risks (of pharmacocinetical or pharmacodynamical kind)--as far as it concerns interactions between several associated plants or between a plant and a chemical or biotechnological allopathic medicine--phytovigilance represents moreover a legal obligation. Pharmacovigilance--in case of herbal medicinal products--is indeed becoming mandatory according to title IX of the European directive 2001/83/EC, whereas nutrivigilance is imposed by the European Food Safety Agency (EFSA).

Adverse food-drug interactions.

Food supplements and herbal products are increasingly popular amongst consumers. This leads to increased risks of interactions between prescribed drugs and these products containing bioactive ingredients. From 1991 up to 2014, 55 cases of suspected adverse drug reactions due to concomitant intake of health-enhancing products and drugs were reported to Lareb, the Netherlands Pharmacovigilance Centre. An overview of these suspected interactions is presented and their potential mechanisms of action are described. Mainly during the metabolism of xenobiotics and due to the pharmacodynamics effects interactions seem to occur, which may result in adverse drug reactions. Where legislation is seen to distinct food and medicine, legislation concerning these different bioactive products is less clear-cut. This can only be resolved by increasing the molecular knowledge on bioactive substances and their potential interactions. Thereby potential interactions can be better understood and prevented on an individual level. By considering the dietary pattern and use of bioactive substances with prescribed medication, both health professionals and consumers will be increasingly aware of interactions and these interactive adverse effects can be prevented.

The Role of Adverse Event Reporting in the FDA Response to a Multistate Outbreak of Liver Disease Associated with a Dietary Supplement.

OBJECTIVE: Liver disease is a potential complication from using dietary supplements. This study investigated an outbreak of non-viral liver disease associated with the use of OxyELITE Pro(TM), a dietary supplement used for weight loss and/or muscle building. METHODS: Illness details were ascertained from MedWatch reports submitted to the U.S. Food and Drug Administration (FDA) describing consumers who ingested OxyELITE Pro alone or in combination with other dietary supplements. FDA's Forensic Chemistry Center analyzed samples of OxyELITE Pro. RESULTS: From February 2012 to February 2014, FDA received 114 reports of adverse events of all kinds involving consumers who ingested OxyELITE Pro. The onset of illness for the first report was December 2010 and for the last report was January 2014. Thirty-three states, two foreign nations, and Puerto Rico submitted reports. Fifty-five of the reports (48%) described liver disease in the absence of viral infection, gallbladder disease, autoimmune disease, or other known causes of liver damage. A total of 33 (60%) of these patients were hospitalized, and three underwent liver transplantation. In early 2013, OxyELITE Pro products entered the market with a formulation distinct from products sold previously. The new formulation replaced 1,3-dimethylamylamine with aegeline. However, the manufacturer failed to submit to FDA a required "new dietary ingredient" notice for the use of aegeline in OxyELITE Pro products. Laboratory analysis identified no drugs, poisons, pharmaceuticals, toxic metals, usnic acid, N-Nitroso-fenfluramine, pyrrolizidine alkaloids, aristocholic acid, or phenethylamines in the products. CONCLUSIONS: Vigilant surveillance is required for adverse events linked to the use of dietary supplements.

Regulatory causality evaluation methods applied in kava hepatotoxicity: are they appropriate?

Since 1998 liver injury has been assumed in some patients after the use of kava (Piper methysticum G. Forster) as an anxyolytic herbal extract, but the regulatory causality evaluation of these cases was a matter of international and scientific debate. This review critically analyzes the regulatory issues of causality assessments of patients with primarily suspected kava hepatotoxicity and suggests recommendations for minimizing regulatory risks when assessing causality in these and other related cases. The various regulatory causality approaches were based on liver unspecific assessments such as ad hoc evaluations, the WHO scale using the definitions of the WHO Collaborating Centre for International Drug Monitoring, and the Naranjo scale. Due to their liver unspecificity, however, these causality approaches are not suitable for assessing cases of primarily assumed liver related adverse reactions by drugs and herbs including kava. Major problems emerged trough the combination of regulatory inappropriate causality assessment methods with the poor data quality as presented by the regulatory agency when reassessment was done and the resulting data were heavily criticized worldwide within the scientific community. Conversely, causality of cases with primarily assumed kava hepatotoxicity is best assessed by structured, quantitative and liver specific causality algorithms such as the scale of the CIOMS (Council for International Organizations of Medical Sciences) or the main-test as its update. Future strategies should therefore focus on the implementation of structured, quantitative and liver specific causality assessment methods as regulatory standards to improve regulatory causality assessments for liver injury by drugs and herbs including kava.

Risk management in dermatology: an analysis of data available from several British-based reporting systems.

BACKGROUND: The elimination or reduction of risk is a prime requirement of all healthcare workers. The matter has come to the fore in dermatological practice recently with the widespread use of effective drugs that have significant side-effects (e.g. retinoids, cytotoxic drugs, biologics), the increase in skin surgery, especially for skin cancer, and the extensive use of phototherapies. OBJECTIVES: To examine the available database from different agencies to which adverse events may be reported over at least a 5-year time frame, categorize the risks, look forward to where as yet unidentified risks might exist, and draw conclusions to improve the safety of dermatological practice. This work came about through a request from the National Patient Safety Agency [to the Joint Specialty Committee of the British Association of Dermatologists (BAD) and Royal College of Physicians] for information on risks to patients receiving treatment or investigation for skin disease. METHODS: Organizations in the U.K. that receive information about adverse events, whether caused by drugs or procedures in dermatological treatments, were approached for information about reported events over a 5-year (or, in one case, 10-year) time frame up to 2009. Data were received from the National Patient Safety Agency, the Medicines and Healthcare Products Regulatory Agency, the National Health Service Litigation Authority, the Medical Protection Society and the Medical Defence Union. In addition, the results of a survey conducted in 2010 by the BAD of its members concerning potential critical incident reporting were included. The received information was analysed according to category of event and conclusions drawn about how best to manage the risks that were identified. RESULTS: Adverse events were divided into the following categories, listed in order of the number of reports received: drug side-effects (biologics and retinoids), phototherapy dosage, drug monitoring (including initial screening), pregnancy prevention programmes, skin cancer follow-up (including acting on reports), dermatopathological reporting and conduct of dermatological surgery (including management of complications, equipment problems, use of lasers, cosmetic procedures and cryotherapy). Critical incidents reported by BAD members often concerned follow-up failures, e.g. of patients receiving systemic drugs or of those with skin cancer. CONCLUSIONS: Several of the reported adverse events concern systemic failures. Recommendations for risk reduction include the following points: better systems for drug monitoring (including regularity of attendance, provision of sufficient follow-up appointments, acting on results and adequacy of pregnancy prevention programmes); staff training and record keeping for phototherapy; acting on skin cancer multidisciplinary team meeting outcomes (including provision of sufficient follow-up appointments); and adequate training of staff in dermatological surgery including cryotherapy. Regular monitoring of the occurrence of such reports is needed to ensure safe practice and to identify early areas of new risk.

Dietary supplement adverse event reports: review and analysis.

The Food and Drug Administration (FDA) works actively to ensure that all the dietary supplements currently in the market are safe for the public. Existing policies are often remodeled and new regulations are developed periodically. A recent change to supplement regulations includes the implementation of a system that allows consumers to contact the FDA or product manufacturer directly to report an adverse reaction as a result of dietary supplement consumption. FDA has employed an adverse event reporting (AER) system that is aimed to police postmarketing effects of dietary supplements.This article will shed light on the importance of tracking serious adverse events with respect to dietary supplements that have already been marketed. Using this data, dietary supplement companies will be able to take the necessary steps to ensure that their products remain safe for the public by removing problematic ingredients from their products and engaging in more effective labeling and product disclaimer practices.

[Research on foreign countries laws and regulations on surveillance and reporting of postmarketing drugs adverse reactions].

Following more and more new drugs are authorized into market, new, serious or unexpected adverse drug reactions appear frequently, which is a serious threat to people health and life. Through making laws and guidelines, governments of various countries aim to strengthen and standardize the surveillance and reporting of postmarketing drugs. The drugs management department of our country are doing related jobs positively, but there are some problems, such as drug risk-menagement is not emphasized well, and the management department lacks clarity on operating related regulations. This article tries to explore foreign countries' laws and regulations on the surveillance and reporting of postmarketing drugs, aiming to provide reference for our courtry.

Physicians' understanding of the regulation of dietary supplements.

BACKGROUND: After passage of the Dietary Supplement Health and Education Act, herbs and other supplements were allowed to be sold to the public without Food and Drug Administration (FDA) approval or premarket evaluation. Data suggest that many people are unaware of this lack of governmental oversight and may rely on their physicians for education in this arena. This study was designed to evaluate physicians' level of understanding of dietary supplement regulation and the adverse event reporting process and to determine whether an interactive online curriculum could aid in improving knowledge. METHODS: A multicenter online educational intervention was developed and administered to physicians at 15 internal medicine residency programs throughout the United States between March 1, 2006, and June 30, 2006. Pretest performance was used to measure baseline knowledge, while posttest performance compared with pretest performance measured the effectiveness of the educational intervention. RESULTS: A total of 335 physicians completed the module. Ninety percent of those completing the module were residents, while 10% were attending physicians. Baseline knowledge of dietary supplement regulatory issues was poor. The total average pretest score was only 59% (986/1675). The average score rose to 91% (1526/1675) after completion of the curriculum (P<.001). With regard to specific content areas, about one third of physicians were unaware that dietary supplements did not require FDA approval or submission of safety and efficacy data before being marketed. Similar percentages believed that there are regulations in place to ensure supplement quality. Most physicians were unaware that serious adverse events due to the use of supplements should be reported through the FDA MedWatch system. CONCLUSIONS: Physician knowledge of dietary supplement regulation and adverse event reporting is poor. An online didactic module may improve knowledge and potentially enhance patient-physician communication regarding the use of such products.

Safety assessment of newly marketed herbal medicines--methodological approach (Ginkgo biloba example in Bulgaria).

This study presents a proposal for the methodological approach for postmarketing safety profile assessment based on sales data and information for adverse drug reactions of newly introduced herbal medicinal products in the market. The study covers all herbal medicinal products containing dry extract of Ginkgo biloba leaves allowed for sale in Bulgaria. The methodological approach we create should be used for the establishment of the national herbal drugs policy complying with the recent European regulatory changes and specificity of the therapeutic practice in the country.

[Fundamental principles of clinical trials]. / Grundlagen der klinischen Arzneimittelprüfung.

Medical conduct relies on the efficacy and tolerability of a given pharmacotherapy. On the basis of an experimental comparison of different treatment options, a clinical trial provides the foundation for an evidence-based medicine that complies with state-of-the-art scientific practice. The quality of the data assessment determines the clinical relevance of the study results. Clinical trials are classified into Phases I-IV to ensure the development of an effective and safe pharmaceutical. The investigator is responsible for being experienced in the relevant area of expertise, for conducting the study according to the investigational plan, and for complying with ethical guidelines and drug safety.

[Harmonisation of regulatory requirements for clinical trials on medicinal products for human use in the Directive 2001/20/EC and complementary guidance. Implementation of the 12th Law Amending the German Drug Law]. / Angleichung der regulatorischen Anforderungen für die klinische Prüfung von Arzneimitteln am Menschen in der EU Die Richtlinie 2001/20/EG und die diese ergänzenden Verordnungen und Empfehlungen: die 12. Novelle zum AMG.

Directive 2001/20/EC of the European Parliament and the Council of 4 April 2001 aims to harmonise national regulations governing clinical trials of medicinal products for human use in the European Union. This aim is to be achieved by harmonising the legal regulations and administrative provisions in force in the Member States, especially with respect to the requirements for starting and conducting clinical trials, taking into account international ethical and scientific standards (Good Clinical Practice). The goal is to further improve the protection of participants in clinical trials and to promote clinical research within the European Union. In Germany, the necessary transposition into the national Drug Law has taken place in the form of the 12th Law Amending the Drug Law of 30 July 2004 as well as complementary implementation provisions. The amendments to the German Drug Law affect in particular the official authorisation procedure, the involvement of ethics committees as well as the conduct of clinical trials on minors. The Directive's requirements have been transposed into German law while maintaining the high level of protection for the participants in clinical trials which had already existed in German legislation.

[Special therapeutic guidelines from the viewpoint of BfArM (Federal Institute for Drug and Medical Products)]. / Besondere Therapierichtungen aus der Sicht des BfArM.

Homeopathic, anthroposophic and phytotherapeutic drugs are subject to the German Medicines Act of 1976 (AMG). The relevant EU regulations also refer to this group of medicinal products. Definitions and requirements for proof of adequate quality, efficacy and safety are set out by regulations under national law, as well as EU and WHO regulations. Homeopathic products may be registered without statement of indication. It has become possible in the meantime that medicinal products belonging to these particular schools of therapy and groups of substances are critically reviewed and assessed without being blamed for bias in the sense of discrimination against one of these therapies or exaggerated criticism. The term of "particular schools of therapy and groups of substances" is different from what is understood by "traditional" products according to article 109a AMG. "Traditional" products are subject to reduced requirements and their documentation need not fulfil the assessment criteria established for particular schools of therapy.

[Special therapeutic processes from the viewpoint of clinical pharmacology]. / Besondere Therapierichtungen aus der Sicht der Klinischen Pharmakologie.

Special therapies comprise homeopathic drugs, anthroposophic medicine and phytotherapy a heterogenous mixture, which consists partly on authorities (Hahnemann, Steiner) and partly describes the origin of the drug (herbal drugs). The field, therefore, is open to new additions (Chinese traditional medicine, American Indian drug therapy etc.). These drugs do not meet the requirements for safety and efficacy required for modern drugs and this is not required, because according to German lawyers this would be inadequate. We demonstrate examples where the health of patients has been severely damaged by this kind of medical therapies and point out that these problems continue. Reasons are presented, why the public has the right to demand proof of efficacy and safety of all drugs.