药物临床试验机构资格认定工作的实践与体会

虽然药品临床试验管理规范(GCP)已实施多年,但药物临床试验与临床医疗在专业技术和政策法规等方面要求的迥异,仍然是申报药物临床试验机构资格认定和已获资格的医疗机构亟待正确认识的重要问题。本刊曹彩编委从事多年的GCP管理经验,特邀请她从药物临床试验的法律法规及其相关管理要求的角度谈一些工作体会,以帮助研究者认识了解药物临床试验的风险性和严格执行GCP相关法律法规的必要性。研究者对GCP等相关法律法规和规范的认识与理解,是步入药物临床试验专业准入的重要知识储备,而研究者即使有良好的专业技能还不够,GCP更强调临床试验需符合道德规范和法定程序。     

Klinische Forschung an Kindern

Zusammenfassung Kranke Kinder haben ein Recht auf Behandlungsverfahren, deren Nutzen und Risiken systematisch und wissenschaftlich korrekt untersucht worden sind. Neue, europaweit gültige Gesetze ermöglichen erstmals valide kontrollierte und randomisierte klinische Arzneimittelprüfungen im Kindesalter. Die dazu gehörigen Durchführungsbestimmungen bedingen allerdings einen sehr hohen formalen Aufwand. Dies gilt gleichermaßen für industrielle und akademische klinische Forschung, da die strengen Richtlinien der guten klinischen Praxis (good clinical practice, GCP) ausdrücklich für alle Studien gelten. Angesichts der zeitlichen Belastung des Personals in der Patientenversorgung erscheint die Durchführung klinischer Prüfungen fast nicht mehr machbar. Dennoch stellt die aktuelle Situation eine Chance für die nichtkommerzielle pädiatrische Forschung in Deutschland dar. An immer mehr Standorten formieren sich Zentren, die über Fachkompetenz sowie die personellen und technischen Ressourcen verfügen, um die GCP-Anforderungen an eine klinische Prüfung zu erfüllen. Ein Ziel des Arzneimitteländerungsgesetzes, die evidenzbasierte Arzneimitteltherapie auch dem pädiatrischen Patienten zur Verfügung zu stellen, kann so durchaus näher rücken.     

Good clinical practice: a nuisance,a help or a necessity for clinical pharmacology?

This article reviews the impact of good clinical practice (GCP) on clinical pharmacology with particular reference to the new European Union Clinical Trial Directive. The Directive will be applied to both commercial and noncommercial studies on medicinal products for human use. The Directive requires that GCP should be used in all clinical trials except noninterventional studies. GCP is likely to follow the International Conference on Harmonization GCP guidelines in many aspects. GCP will enforce tighter guidelines on ethical aspects of a clinical study. Higher standards will be required in terms of comprehensive documentation for the clinical protocol, record keeping, training, and facilities including computers. Quality assurance and inspections will ensure that these standards are achieved. The additional requirements of GCP are discussed and any advantage to the study subject. The impact of the new Directive within the Research Governance Framework of the UK Department of Health is reviewed.     

2-MPPA,a selective glutamate carboxypeptidase II inhibitor,attenuates morphine tolerance but not dependence in C57/Bl mice

Rationale and objectives We have recently reported that conditioned morphine reward and tolerance to its antinociceptive effect, but not expression of morphine dependence, were attenuated by 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a prototypic inhibitor of glutamate carboxipeptidase II (GCP II), which is an enzyme responsible for the supply of glutamate. In the present study, we investigated in more detail the effects of GCP II inhibition on opioid dependence and tolerance to its antinociceptive effect in C57/Bl mice using a novel GCP II inhibitor.Results The treatment with 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA; 60 but not 10 or 30 mg/kg) prevented the development of morphine tolerance without affecting acute morphine antinociception. 2-MPPA at 30 and 60 mg/kg did not prevent the development of dependence induced by 10 and 30 mg/kg of morphine. The study on opioid withdrawal syndrome, i.e., expression of opioid dependence, demonstrated that 2-MPPA potentiated jumping behavior and teeth chattering but attenuated chewing and ptosis. None of these opioid withdrawal signs were affected by 2-MPPA in morphine nondependent mice. Pretreatment with the mGluR II antagonist LY341495 (1 mg/kg) reversed the 2-MPPA-induced increase or decrease in opioid withdrawal signs in morphine-dependent mice. 2-MPPA (60 mg/kg) administered for 7 days with morphine did not affect brain concentration of this opiate.Conclusions The present findings suggest complex effects of GCP II inhibition on morphine dependence and tolerance and imply a role of mGluR II in the actions of 2-MPPA.     

Safety and Efficacy of Edoxaban,an Oral Factor Xa Inhibitor,Versus Enoxaparin for Thromboprophylaxis After Total Knee Arthroplasty: The STARS E-3 Trial

Introduction

This phase 3 trial compared the safety and efficacy of edoxaban, an oral direct factor Xa inhibitor, with enoxaparin sodium (enoxaparin) for thromboprophylaxis after total knee arthroplasty (TKA) in patients in Japan and Taiwan.

Materials and methods

In this randomized, double-blind, double-dummy study, patients received oral edoxaban 30 mg once daily beginning 6 to 24 hours postsurgery or enoxaparin 2000 IU (equivalent to 20 mg) subcutaneously twice daily beginning 24 to 36 hours postsurgery for 11 to 14 days. The primary efficacy endpoint was the composite of symptomatic pulmonary embolism and symptomatic and asymptomatic deep vein thrombosis. Safety endpoints included the incidence of major bleeding, clinically relevant non-major (CRNM) bleeding, major bleeding or CRNM bleeding, all bleeding events, adverse events, and adverse drug reactions.

Results

Of 716 patients enrolled, 360 and 356 were randomized to receive edoxaban or enoxaparin, respectively. The primary efficacy outcome occurred in 22/299 (7.4%) and 41/295 (13.9%) patients in the edoxaban and enoxaparin groups, respectively (relative risk reduction = 46.8%), indicating non-inferiority (P < 0.001) and superiority (P = 0.010) of edoxaban versus enoxaparin. In the edoxaban and enoxaparin groups, major bleeding occurred in 4/354 (1.1%) versus 1/349 (0.3%) patients (P = 0.373); major or CRNM bleeding occurred in 22/354 (6.2%) versus 13/349 (3.7%) patients (P = 0.129), respectively.

Conclusions

Edoxaban 30 mg once daily was more effective for thromboprophylaxis than subcutaneous enoxaparin 2000 IU twice daily following TKA and demonstrated a similar incidence of bleeding events.     

Effect of reduced dose schedules and intramuscular injection of anthrax vaccine adsorbed on immunological response and safety profile: A randomized trial

Objective

We evaluated an alternative administration route, reduced schedule priming series, and increased intervals between booster doses for anthrax vaccine adsorbed (AVA). AVA's originally licensed schedule was 6 subcutaneous (SQ) priming injections administered at months (m) 0, 0.5, 1, 6, 12 and 18 with annual boosters; a simpler schedule is desired.

Methods

Through a multicenter randomized, double blind, non-inferiority Phase IV human clinical trial, the originally licensed schedule was compared to four alternative and two placebo schedules. 8-SQ group participants received 6 SQ injections with m30 and m42 “annual” boosters; participants in the 8-IM group received intramuscular (IM) injections according to the same schedule. Reduced schedule groups (7-IM, 5-IM, 4-IM) received IM injections at m0, m1, m6; at least one of the m0.5, m12, m18, m30 vaccine doses were replaced with saline. All reduced schedule groups received a m42 booster. Post-injection blood draws were taken two to four weeks following injection. Non-inferiority of the alternative schedules was compared to the 8-SQ group at m2, m7, and m43. Reactogenicity outcomes were proportions of injection site and systemic adverse events (AEs).

Results

The 8-IM group's m2 response was non-inferior to the 8-SQ group for the three primary endpoints of anti-protective antigen IgG geometric mean concentration (GMC), geometric mean titer, and proportion of responders with a 4-fold rise in titer. At m7 anti-PA IgG GMCs for the three reduced dosage groups were non-inferior to the 8-SQ group GMCs. At m43, 8-IM, 5-IM, and 4-IM group GMCs were superior to the 8-SQ group. Solicited injection site AEs occurred at lower proportions in the IM group compared to SQ. Route of administration did not influence the occurrence of systemic AEs. A 3 dose IM priming schedule with doses administered at m0, m1, and m6 elicited long term immunological responses and robust immunological memory that was efficiently stimulated by a single booster vaccination at 42 months.

Conclusions

A priming series of 3 intramuscular doses administered at m0, m1, and m6 with a triennial booster was non-inferior to more complex schedules for achieving antibody response.     

Two decades of hepatitis B vaccination in mentally retarded patients: effectiveness, antibody persistence and duration of immune memory

Introduction

Institutionalized mentally retarded subjects are well-known to be at-risk for HBV infection. We studied the persistence of vaccine-induced anti-HBs antibodies and the robustness of the HBsAg-specific immune memory in this population, 18–20 years after the first vaccine dose.

Materials and methods

Non-immune residents of 4 institutions were immunized in 1984–1986. In 2004, 207 subjects were bled to determine humoral and cellular immune memory. Immune response to a booster dose was evaluated in subjects with anti-HBs level <100 IU/L.

Results

Four subjects showed anti-HBc seroconversion, without clinical implications. Pre-booster anti-HBs levels <100 IU/L were found in 45 subjects (22%); 34/39 (87%) responded with a rapid and high anti-HBs titer to the booster dose. Robust T and B cell memory was present pre- and post-booster.

Discussion and conclusion

Overall results confirm that hepatitis B vaccines are highly effective and immunogenic, and confer long-term persistence of antibodies and immune memory in an at-risk population.     

浅谈医院药物临床试验质量控制体系的建设

目的 介绍本院执行《药物临床试验质量管理规范》（GCP）的工作经验,探讨医院药物临床试验质量控制体系的建设.方法 总结了药物临床试验在知情同意、试验的实施及实验室检查方面存在的问题.介绍了本院以GCP为指导原则,完善制度和标准操作规程、建立“三级质控”工作模式、强化GCP培训、加强机构内部的沟通协调、着力提升新药临床试验质量的具体做法和经验.结果与结论 新药必须在人体进行临床试验才能最终确定药物的有效性和安全性.医院药物临床试验机构建立完善的临床试验质量控制体系,有利于为公众筛选安全、有效的药物,推动医药卫生事业的进步与发展.     

Integrated risk assessment of a hydroxyapatite-protein-composite for use in oral care products: a weight-of-evidence case study

Risk assessment of cosmetic ingredients represents a regulatory standard requirement in Europe and other regions. An integrated approach was designed to assess the safety of HPC, a particulate composite of hydroxyapatite and protein (gelatin) for use in oral care products, employing a weight-of-evidence assessment and considering specific physico-chemical properties and exposure conditions. An initial evaluation of the constituents suggested that their chemical nature does not represent a particular health hazard per se. Hydroxyapatite is the main component of teeth and bones in mammals; gelatin is used in food and assumed to be safe once a BSE/TSE risk has been excluded. In vitro screening tests were chosen to further evaluate the biocompatibility: Hen's egg test-chorioallantoic membrane (HET-CAM) to assess irritating effects towards mucous membranes; MTT cytotoxicity test with 3T3 fibroblasts; human corneal epithelial models to investigate inflammatory mediators and cytotoxicity; macrophage assays to measure cytotoxicity, inflammatory mediators and oxidative stress. Together with results from clinical studies, exposure estimates and analyses of kinetic properties, the presented information provides sound evidence to support the safe use of HPC. This is an example of a risk assessment for cosmetic use of small particles without the need for additional animal studies.