Points to consider on the non-clinical safety evaluation of anticancer drugs

Since malignant tumors are life-threatening, the death rate from these diseases is high, and existing therapies have limited effectiveness, it is desired to provide new effective anticancer drugs to tumor patients sooner. However, there is no guideline regarding non-clinical safety studies on the development of anticancer drugs required for the first in human clinical trials and for the approval applications in Japan. Then, the Ministry of Health, Labour and Welfare (MHLW) established the collaboration group including regulatory, academic and industrial scientists to prepare the guideline on the non-clinical safety evaluation of anticancer drugs in 2004. As a guide for basic concept of non-clinical safety studies on anticancer drugs, the "Points to Consider" document was prepared by this group in 2007.     

Impact of the last 15 years: from PMDEC to PMDA --looking back at the first stage of the PMDEC

The Ministry of Health and Welfare (MHW) (renamed the Ministry of Health, Labour and Welfare [MHLW] in Jan. 2001) amended the Pharmaceutical Affairs Law, resulting in a fundamental reform of the review system for New Drug Applications, based on the 1996 report of the ad-hoc Committee for Drug Safety Ensuring Measures. One of the most important changes in the review system was the establishment of the Pharmaceuticals and Medical Devices Evaluation Center (PMDEC) on July 1, 1997 followed by the Pharmaceuticals and Medical Devices Agency (PMDA) in 2004. In five years, the drug approval system in Japan underwent a series of significant reforms, such as adopting new GCP based on the ICH/E6 (R1), changes relating to ethnic factors in the acceptability of foreign clinical data (ICH/E5 (R1)), and the establishment of a Common Technical Document (CTD) (ICH/M4). The addition of the PMDEC has greatly improved the speed of review for new drugs, especially oncology drugs and orphan drugs. We discuss the philosophy of PMDA in relation to the concept of regulatory science.     

Clinical and regulatory perspectives on general/safety pharmacology tests: Results of a pharmaceutical industry survey

General/safety pharmacology is an emerging discipline within the pharmaceutical industry in which unanticipated effects of new drug candidates on major organ function (i.e., secondary pharmacological effects) are critically assessed in a variety of animal models. A survey was conducted to obtain customer input on the role and strategies of this emerging discipline. Four surveys were distributed to each of 30 U.S. pharmaceutical companies. Two surveys went to individuals within the regulatory department, and two went to individuals within the clinical department of each company. All responses were returned anonymously to the survey authors. Sixty-six responses from at least 19 different companies were obtained. The responses from the clinical and regulatory departments were essentially the same and led to the following conclusions: (1) Major organ functions are monitored routinely in clinical trials to assess potential adverse drug effects; (2) major organ function studies are considered an essential part of non-clinical drug safety testing; (3) respiratory, gastrointestinal, autonomic, and endocrine evaluations are considered an important part of major organ function studies, whereas cardiovascular, renal and central nervous evaluations are considered essential; (4) non-clinical testing of these major organ functions should be conducted early in drug development, preferably before initiation of clinical trials; and (5) organ function investigations involving mechanisms of secondary pharmacological effects or drug interaction are considered an important part of general/safety pharmacology testing. © 1995 Wiley-Liss, Inc.     

The development and operation of a package inserts service system for electronic medical records

To promote the appropriate use of pharmaceuticals and to prevent side effects, physicians need package inserts on medicinal drugs as soon as possible. A medicinal drug information service system was established for electronic medical records to speed up and increase the efficiency of package insert communications within a medical institution. Development of this system facilitates access to package inserts by, for example, physicians. The time required to maintain files of package inserts was shortened, and the efficiency of the drug information service increased. As a source of package inserts for this system, package inserts using a standard generalized markup language (SGML) form were used, which are accessible to the public on the homepage of the Organization for Pharmaceutical Safety and Research (OPSR). This study found that a delay occurred in communicating revised package inserts from pharmaceutical companies to the OPSR. Therefore a pharmaceutical department page was set up as part of the homepage of the medical institution for electronic medical records to shorten the delay in the revision of package inserts posted on the medicinal drug information service homepage of the OPSR. The usefulness of this package insert service system for electronic medical records is clear. For more effective use of this system based on the OPSR homepage pharmaceutical companies have been requested to provide quicker updating of package inserts.     

Practical aspects of designing and conducting pharmacoeconomic studies in Japan

The advent of simultaneous global clinical trials and drug registration strategies has increased the demand for global pharmacoeconomic strategies. Outcomes researchers in pharmaceutical companies are faced with the challenge of assessing at a strategic level what pharmacoeconomic data are most useful in Japan and when, and then deciding at a tactical level what type of study designs are feasible. This paper is written mainly for the benefit of researchers working outside of Japan in the pharmaceutical/medical device industry or academia who are interested in conducting research in Japan.We reviewed the existing pharmacoeconomic literature in Japan, and found that the number of studies per year has been steadily increasing. The majority of studies have been cost-effectiveness and cost-consequence analyses. Typical data sources available in Japan are somewhat limited compared with other Western countries. However, charge data can be easily accessed through the national uniform reimbursement fee system and these data are particularly relevant for pharmaceutical pricing negotiations with the Ministry of Health, Labor and Welfare (MHLW). The present use of pharmacoeconomic data by pharmaceutical companies is mainly for pricing negotiations but recent reforms make certain types of data useful for marketing strategies too. The demand for pharmacoeconomic data may increase because of upcoming MHLW pharmaceutical pricing and/or recent health insurance system reforms.Economic evaluation of medical technologies in Japan, though lagging behind North America, Australia and Europe, has the potential to rapidly gather momentum as increasing cost-escalation worries contribute to a growing interest in pharmacoeconomic data.     

Non-clinical Post-Marketing Commitments for newly licenced pharmaceuticals

There are clear minimum requirements for non-clinical (toxicology) studies which are needed prior to human exposure to a potential new pharmaceutical and additional studies are needed in an ongoing manner to support clinical development and marketing [ICH, 2009. ICH M3(R2) Non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (CPMP/ICH/286/95). Adopted June 2009, effective December 2009.] The pharmaceutical industry is under increasing pressure to reduce costs and reduce, refine and replace the use of animals, as far as possible. Hence any increase in regulatory requirements for non-clinical safety data could have a significant impact both on the economic and ethical considerations of drug development. It is, therefore, of interest that further non-clinical studies are required by the Regulatory Authorities for a small but increasing proportion of drug product applications at the marketing approval/data review stage. These studies are known as Post-Marketing Commitments (PMCs).     

A problem-oriented approach to safety issues in drug development and beyond.

Human safety issues arise throughout the life cycle of pharmaceutical products and relevant information comes from a multitude of sources. Assessment and management of risks to humans requires a problem-based analysis to bring together relevant information regardless of source. The Safety Evaluation Plan (SEP) is a tool to support problem-oriented safety analysis. Safety issues are specified and the evaluation and management of each problem is based on a status summary that integrates the most current information from all relevant sources. The status summary is updated regularly during the course of clinical development to reflect the results of new studies and new clinical trials. In the postmarketing period, relevant postmarketing data is incorporated. Recent regulatory initiatives emphasise early identification of product safety risks so that appropriate risk-management measures can be instituted at the time of approval. A problem-oriented approach supports growing regulatory expectations regarding risk assessment and risk management. The problem-oriented approach facilitates early identification of safety issues and an evidence-based approach to their evaluation. Proactive management of safety problems leads to prompt assessment of risks and timely and appropriate steps aimed at risk reduction. The SEP provides a single global assessment for each safety issue. Regulatory submissions for pharmaceutical and biological products are organised by type of information. International Conference of Harmonisation documents covering clinical safety issues structure and analyse information separately by type, for example, adverse events, serious adverse events, laboratory data, vital signs, etc. A problem-oriented analysis would need to find a place in the regulatory process. A problem-oriented approach to safety cuts across typical structures in the pharmaceutical industry where different groups handle preclinical, clinical and postmarketing safety information. The SEP can improve communication within the company and externally. Nonetheless, supporting structures need to be adapted to support such an interdisciplinary process. Overall, the problem-oriented approach, supported by a SEP, contributes to realistic expectations and sustained credibility when dealing with safety issues.     

Perspectives on non-clinical safety evaluation of drug metabolites through the JSOT workshop

The prompt and appropriate safety assessment of drug metabolite(s) was mentioned in regulatory guidances such as an International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance, entitled "Guidance on Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals" (ICH M3(R2)) implemented in January 1 of 2011 in Japan, and has become a significant issue in the drug development. Upon release of ICH M3(R2) Step 4, a survey was conducted between March and April 2010 on the safety assessment of drug metabolites in 63 member companies of the Japan Pharmaceutical Manufacturers Association (JPMA). The Pharmacokinetics Team in the Non-Clinical Evaluation Expert Committee in JPMA conducted a questionnaire survey and compiled the results to comprehend how safety of drug metabolites are currently assessed at research-based pharmaceutical companies in Japan. The assessment of "Metabolites in Safety Testing" (MIST) can be divided into three stages based on the research purpose as follows: MIST 1 is a stage of estimating human drug metabolites and predicting their potential risks, MIST 2 is a stage of deciding the necessity for non-clinical safety studies, and MIST 3 is a stage of conducting non-clinical safety studies. In this paper, we propose typical approaches on safety assessment of metabolites that meet the purpose of each stage, considering the current level of scientific technology. Our proposals are based on the results from our survey and a symposium about the safety assessment of drug metabolites at the 37th annual meeting of the Japanese Society of Toxicology held in June 2010.     

2020年1—2月美国、欧盟和日本新批准药物概述

2020年1—2月,美国、欧盟和日本共批准47个新药,包括新分子实体、新有效成分、新生物制品、新增适应证及新剂型药物。对全球首次获得批准的新分子实体、新有效成分、新生物制品进行分析,重点介绍这些药物的临床研究结果和研发历史进程。     

Status of safety pharmacology in the pharmaceutical industry—1995

Safety pharmacology contributes to the pharmacological characterization, risk assessment, and registration of new drugs; however, safety pharmacology strategies and study designs for new drugs vary widely across the pharmaceutical industry. We surveyed 26 pharmaceutical companies for how and why they conduct safety pharmacology studies. All conduct/contract safety pharmacology studies; 19 have safety pharmacology units, seven do not; ten locate responsibility for safety pharmacology in development, 16 in discovery (or research). Total staff range from two to 16 full-time equivalents (fte)/unit. Most companies conduct evaluations of cardiovascular and CNS functions, less evaluate respiratory, gastrointestinal and renal functions; a few conduct a ligand-binding/activity panel as part of their pharmacological profiling. Resources to complete a company's standard safety pharmacology program are ～1–4 fte/compound. One-third of companies use a maximum tolerated dose (MTD) for safety pharmacology studies, two-thirds use multiples of pharmacological or therapeutic doses. Approximately half conduct safety pharmacology studies to Good Laboratory Practices (GLPs) and use the 1992 Japanese guidelines only as a guide or outline. Company clinicians are most often cited as the “primary customer” for whom Safety Pharmacology studies are done, followed by research and development scientists, and then regulatory authorities. The results suggest that most companies conduct safety pharmacology for its contribution to risk assessment and critical care management. © 1995 Wiley-Liss, Inc.     

The problem of post-marketing surveillance planning on drugs for infectious disease

In principle, a new drug is approved via the assessments of safety and efficacy by the Ministry of Health, Labor and Welfare (MHLW). After approval, conduct of post-marketing surveillance is requested by law in order to assess the safety and efficacy of the drug in a large number of patients. Before initiating a surveillance, submission to MHLW of a document on the plan of survey is necessary in the purpose of inspection if it includes any ethical or regulatory problem or not. Through the inspections of the plans submitted during the period of April 1998 and March 2000, many problems have been pointed out. In this report, the author introduces some of the concrete problems noted in the plans on drugs for infectious diseases and shows some of the guidance made by the authority how to improve them. It is expected that such practical analyses of cases may be useful for future planning of post-marketing surveillance on drugs for infectious diseases.     

Exploratory Safety Pharmacology: a new safety paradigm to de-risk drug candidates prior to selection for regulatory science investigations

The primary objective of Safety Pharmacology is to ensure the safety of medicines on physiological functions in order to protect humans against adverse drug reactions. Safety Pharmacology became a major non-clinical discipline in 2000 when the International Conference on Harmonization approved the S7A guideline. This regulatory document requires pharmaceutical companies to undertake Safety Pharmacology assessment under Good Laboratory Practice (GLP) in order to guarantee the absence of unmanageable risks on vital organ function for compounds to be tested on humans. These regulatory studies often reveal liabilities impacting on the smooth transition of drug candidates from the discovery phase into the clinical arena. However, if these safety issues were uncovered prior to regulatory science assessment, the chemistry of poorly safe molecules could be modified during the lead optimisation phase for preventing later occurring attrition accidents. This article proposes the establishment of a spin-off specialty of Regulatory Safety Pharmacology, for which the name ‘Exploratory Safety Pharmacology’ is proposed. The objective of this discipline would be to conduct early safety investigations on potential drug candidates by applying, outside the constraints of GLP, in silico, in vitro, ex vivo and in vivo platforms translating clinical liabilities into simple, fast and cost-effective screening assays. This approach should result in early hazard detection with rapid turnaround of the data, enabling medicinal chemists to mitigate the safety liabilities of new compounds in an iterative manner. Hence, the ultimate aim of Exploratory Safety Pharmacology activities is to transform Regulatory Safety Pharmacology investigations into risk-known exercises.     

Japan-Specific Key Regulatory Aspects for Development of New Biopharmaceutical Drug Products

Japan represents the third largest pharmaceutical market in the world. Developing a new biopharmaceutical drug product for the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. Understanding Japan-specific key regulatory requirements is essential to achieve successful approvals. Understanding the full context of Japan-specific regulatory requirements/expectations is challenging to global pharmaceutical companies due to differences in language and culture. This article summarizes key Japan-specific regulatory aspects/requirements/expectations applicable to new drug development, approval, and postapproval phases. Formulation excipients should meet Japan compendial requirements with respect to the type of excipient, excipient grade, and excipient concentration. Preclinical safety assessments needed to support clinical phases I, II, and III development are summarized. Japanese regulatory authorities have taken appropriate steps to consider foreign clinical data, thereby enabling accelerated drug development and approval in Japan. Other important topics summarized in this article include: Japan new drug application-specific bracketing strategies for critical and noncritical aspects of the manufacturing process, regulatory requirements related to stability studies, release specifications and testing methods, standard processes involved in pre and postapproval inspections, management of postapproval changes, and Japan regulatory authority's consultation services available to global pharmaceutical companies.     

A framework to assess the translation of safety pharmacology data to humans

This article outlines a strategy for collecting accurate data for the determination of the sensitivity, specificity and predictive value of safety pharmacology models. This entails performing a retrospective analysis on commonly used safety pharmacology endpoints and an objective assessment of new non-clinical models. Such assessments require a systematic quantitative analysis of safety pharmacology parameters as well as clinical Phase I adverse events. Once the sensitivity, specificity and predictive capacity of models have been determined, they can be aligned within specific phases of the drug discovery and development pipeline for maximal impact, or removed from the screening cascade altogether. Furthermore, data will contribute to evidence-based decision-making based on the knowledge of the model sensitivity and specificity. This strategy should therefore contribute to the reduction of candidate drug attrition and a more appropriate use of animals. More data are needed to increase the power of analysis and enable more accurate comparisons of models e.g. pharmacokinetic/phamacodynamic (PK/PD) relationships as well as non-clinical and clinical outcomes for determining concordance. This task requires the collaboration and agreement of pharmaceutical companies to share data anonymously on proprietary and candidate drugs.     

Drug evaluation and registration in Hungary

In Hungary, the actual drug evaluation and registration system reflects international standards and national traditions. The compulsory drug registration system that was established in 1933 was among the first in Europe. Laboratory control (since 1927), clinical trials (since 1951) and human clinical pharmaceutical experiments (since 1967) are prerequisites for new-drug approval. Applications should be sent to the National Institute of Pharmacy, which has the overall responsibility for the registration of pharmaceutical products. Applications are assessed on the basis of the drug's quality, safety, and efficacy. The procedure follows several steps: evaluation of chemical and pharmaceutical data by the staff of the National Institute of Pharmacy; evaluation of toxicologic and pharmacologic documentation with the help of the Committee on Drug Administration; after consultation with the Committee on Medical Research Ethics (mandatory in cases of original new drugs), authorized clinical pharmacologic investigations are conducted in the units of the Clinical Pharmacological Network, which are supervised by the National Center for Clinical Pharmacology; clinical trials; application for registration (scientific evaluation); and finally, application to the Ministry of Health for a marketing authorization. The process may be facilitated appreciably for preparations already registered in another country. Moreover, Hungary is an active member in the World Health Organization (WHO), Pharmaceutical Inspection Convention of the European Free Trade Association (EFTA PIC), the Council of Mutual Economic Assistance (COMECON), and other international pharmaceutical and clinical pharmaceutical collaborations.     

Utilisation of human pharmacology studies with biomarkers for new drug applications in Japan

OBJECTIVE: This study evaluated the utilisation of human pharmacology studies with biomarkers for either efficacy or safety estimation conducted for new drug applications (NDAs) submitted to the Japanese regulatory authority, the Ministry of Health, Labour and Welfare (MHLW). METHODS: A total of 50 new chemical entities (NCEs) posted on the Websites, which were approved from June 2000 to November 2001, were evaluated by investigating their approval information. The utilisation of human pharmacology studies with biomarkers was evaluated by focusing on the classification referred to biomarkers for either efficacy or safety estimation and timing of studies. RESULTS: The human pharmacology studies with biomarkers for either efficacy or safety estimation were conducted in 20 compounds classified by utilising measures of either efficacy (17 compounds) or safety (seven compounds). In 4 of 17 NCEs, some of the biomarkers in human pharmacology studies were similar to the clinical endpoints for efficacy assessment in therapeutic exploratory and/or therapeutic confirmatory studies. For safety assessment in therapeutic exploratory and/or therapeutic confirmatory studies, clinical endpoints rather than biomarkers in human pharmacology studies were used in all seven NCEs. The timing of each type of clinical study could only be obtained for 15 NCEs. Of these 15 NCEs, human pharmacology studies with biomarkers for either efficacy or safety estimation were conducted on six compounds. There were only two compounds for which human pharmacology studies with biomarkers for efficacy estimation were conducted before pivotal studies such as a therapeutic exploratory study or a bridging study. CONCLUSION: Our survey suggests that with Japanese NDAs, human pharmacology studies with biomarkers for either efficacy or safety estimation do not play a key role in accelerating drug development and maximising the knowledge gained from confirmatory trials. The relationship between a biomarker and a clinical endpoint should be investigated appropriately for accelerating drug development. We think that the utilisation of human pharmacology studies with biomarkers for either efficacy or safety estimation in the regulatory review process for NDAs should be encouraged with the advancements of drug evaluation research using an appropriate biomarker based on clinical pharmacology.     

Teratogenic potential of third-generation antiepileptic drugs: Current status and research needs

The aim of this review was to scrutinize the current literature available on teratogenic safety of third-generation antiepileptic drugs (TGAEDs) considering their clinical implications and to highlight for further research need in the interest of the diseased population in general and women with epilepsy in particular. For evaluation of the teratogenic potential of TGAEDs, this review summarized the existing information on controlled clinical trials conducted by the pharmaceutical companies, case reports, scholarly articles (prospective and retrospective studies), and experimental tests carried out so far. Firstly, clinical reports have reviewed on each drug followed by non-clinical studies reported hitherto. The Pub-Med and Google search engine was used to explore the relevant articles with pertinent keywords like pregnancy, epilepsy, seizures, women with epilepsy, antiepileptic or anticonvulsant drugs, first-second/new and third/ newest generation antiepileptic drugs, teratogenicity, teratological potential, birth defects, congenital anomalies, epilepsy and pregnancy registries, malformation surveillance program. The search was also carried out by the individual name of 20 third-generation AEDs. This review declared that although much research has been carried out on clinical and non-clinical implications for the assessment of the teratogenic potential of FGAEDs and SGAEDs, reports on the teratogenic safety of TGAEDs are still limited. It is concluded that there is an urgent need to exaggerate a large number of clinical intervention trials/reports and experimental studies to draw a definite conclusion for the teratogenic safety of TGAEDs. This is a pioneer attempt by our laboratory to review the teratogenic potential of third-generation antiepileptic drugs.     

Safety pharmacology in focus: new methods developed in the light of the ICH S7B guidance document

'Safety' continues to be a growth area in 'Pharmacology'. This issue of Journal of Pharmacological and Toxicological Methods is the third to be focused on methods development in the safety pharmacology area. The unusual nature of safety pharmacology mandates that methods development be done with, not only scientific validation, but also, adherence to the mandates of legislation to the forefront. This focused issue draws on a broad range of global safety pharmacology experts, many of whom operate in the industrial milieu. They have reviewed and updated current models, validated modifications, and have also introduced novel methodology important to the conduct of non-clinical safety pharmacology studies. The contributors were all active participants at the 5th Annual Safety Pharmacology Society (SPS) meeting held in Mannheim, Germany September 25-28, 2005. The publications presented here describe in vitro and in vivo pharmacological methods development that has been informed by the S7A regulatory guidance document for pre-clinical safety testing of drugs. While S7A describes the 'core battery' of methods used to characterize the safety pharmacology profile of a compound, the most recent news in Safety Pharmacology involves ratification of the related S7B safety guidance document. Unlike the past, S7B heralds a new era for the pharmaceutical industry since it now sets out how to address safety concerns of a new chemical entity (NCE) in relation to adverse actions on ventricular repolarization, a topic that has vexed industry and regulatory authorities for many years. Unsurprisingly there are many papers in the present issue that address this specific aspect of safety pharmacology. These include results from the Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) initiative, in which non-clinical in vitro (hERG and Purkinje fiber) and in vivo (QT dog study) assays were found to be useful in the determination of drug-induced QT prolongation risk, and thus provide better characterization of a biomarker for the potential risk in humans for development of the torsades de pointes syndrome. However, safety methods development does not begin and end with ventricular repolarization. This focused issue also describes the re-evaluation and validation of a primate CNS model for evaluating orthostatic hypotension, and outlines a simple and rapid rodent object recognition task model that can be used to assess the amnesic potential of an NCE. Reviews of respiratory safety studies as well as both in vitro and in vivo aspects of cardiovascular function are also described. There are also papers that describe the pharmacology of vehicles and solvents used to solubilize study drugs and the applicability of voltage-sensitive dyes to optically record cardiac action potentials from single myocytes. Thus, this issue of the Journal of Pharmacological and Toxicological Methods remains a primary resource for industrial and academic pharmacologists interested in better understanding non-clinical safety pharmacology methods.