The November 1995 revised Australian guidelines for the economic evaluation of pharmaceuticals

In November 1995, the revised Australian Guidelines for the Economic Evaluation of Pharmaceuticals ('the Guidelines') were published. The new document is to be seen as a measured bureaucratic response to the perceived shortcomings of the August 1992 document. The new document sets substantially more demanding and more rigorous evidentiary standards in the reporting of randomised clinical trials and in the justification of the selected evaluation methodology. It also introduces the requirement for a trial- or efficacy-based preliminary economic evaluation, and it recognises the need, under certain circumstances, to model economic evaluations. Although this document has an immediate appeal to those coming to pharmacoeconomic evaluations from a clinical perspective, the approach taken is unlikely to appeal either to economists (the Guidelines continue to discourage cost-benefit analysis) or to health system evaluators working in a competitive delivery environment (such as the US). The Guidelines, in a US environment, would be seen as not only unreasonable in their evidentiary demands and in the task imposed on evaluators, but limited in their failure to take an explicit modeling or system approach to therapy intervention evaluations.     

The emerging government requirement for economic evaluation of pharmaceuticals

With the advent of government guidelines for the provision of cost-effectiveness data, economic evidence has been elevated to a status similar to that of evidence of efficacy and safety, which is required before licensing of pharmaceutical products. Whilst the precise nature of government requirements is likely to vary from place to place, they pose a number of practical problems for pharmaceutical companies, in the funding of studies and in the need to modify the clinical trials programme to facilitate economic data collection. Economic evaluation requirements have been viewed by various parties as a basis for pricing and reimbursement, as a form of cost containment and as a way of securing more value for money in the healthcare system. It is unlikely that economic evidence could ever form the sole basis for setting price, since both industry and government often seek to introduce other factors into the price negotiations. Requirements for economic evidence may also be an inefficient form of cost containment, compared with other methods such as budgetary caps. These offer some potential as a way of securing more value for money, but they should be applied equally across all health technologies. In the future there needs to be much more clarity of purpose in government guidelines, and methodological standards for economic analysis need to be refined.     

Recommended structure for reporting economic evaluation on pharmaceuticals in Belgium

Pharmacoeconomic evaluations become more important for the reimbursement of pharmaceuticals, and will be obligatory for new pharmaceutical drugs for which an added therapeutic value is claimed and a price premium is proposed by the manufacturer. Therefore, it is important to guide purchasers and providers of pharmaceutical care in their efforts related to the evaluation process. Standard Report Format can support the quality, transparency and exhaustiveness of the data submitted. A multidisciplinary task force developed a Standard Report Format for pharmacoeconomic evaluations in Belgium.     

Proposal for international guidelines for reproductive and developmental toxicity testing for pharmaceuticals.

1. A Workshop was organized by the Centre for Medicines Research in London, 13th-15th May 1991 to discuss the current situation concerning tests for reproductive and developmental toxicity required for new drug development, and whether a unified series of guidelines could be developed which would satisfy Regulatory Authorities and Scientists worldwide. 2. The international group of experts invited to participate in this meeting reached a consensus regarding the desirability of developing new and flexible guidelines. An approach was proposed based on the state of the art of scientific knowledge in the field of reproductive and developmental toxicology coupled with the minimum use of experimental animals, and taking into consideration the European proposal for a new guideline which has been open for discussion since 1989. 3. Although time did not permit detailed discussion of all study designs, several which are considered to provide acceptable tests for reproductive and developmental toxicity of new therapeutic candidates have been proposed for further discussion. These include the possibility of considerable reduction in duration and size of studies, and numbers of animals used where there is an indication that a low hazard potential exists. 4. Whichever of the combinations are ultimately used in the premarketing assessment, it is most important that the investigators justify in detail the rationale underlying the choice of studies undertaken. This should take into account the specific properties of the drug molecule and its proposed clinical use. 5. This paper reflects the discussions which took place at the Workshop and its publication has been agreed to by the participants. It is intended that it could be used as the basis for discussions of a harmonized approach to reproductive and developmental toxicity testing of pharmaceuticals. As such, it will be made available to regulatory agencies, trade associations and other appropriate groups for their consideration and acceptance, modification or scientific augmentation.     

Canadian water quality guidelines for tebuthiuron

A review of the scientific literature was conducted on the environmental toxicology, chemistry, fate, and effects of the herbicide tebuthiuron on a variety of water uses in Canada. These uses include raw water for the drinking water supply, freshwater and marine life, crop irrigation and livestock watering, recreational water quality and aesthetics, and industrial water supplies. This information was critically evaluated and used to derive water quality guidelines for the protection of these major uses of water in Canada (see Table A on next page). © 1997 by John Wiley & Sons, Inc. Environ Toxicol Water Qual 12: 61–95, 1997     

Canadian water quality guidelines for linuron

The environmental chemistry, fate, and toxicology of the herbicide, linuron, is reviewed. Linuron is a phenylurea herbicide used for selective control of annual weeds in fruit and field crops and noncrop areas. Linuron is soluble in water which suggests that it may leach readily through soils. Its log K_oc for soil is 2.83, which indicates a moderate adsorption potential and a moderate mobility. Its half-life is less than 4 weeks in water and approximately 2 months in soil. The primary mode of degradation is microbial. In regions of intensive agriculture, linuron concentrations up to 1100 and 2800 μg L⁻¹ have been detected in Canadian surface waters and ground waters, respectively. Duckweed (Lemna minor), the most sensitive freshwater species for which data were available, had a 5-d lowest-observed-effect level of 70 μg L⁻¹ for growth inhibition. The most sensitive crop species was the tomato (Lycopersicum esculentum) with a LOEAR of 0.018 kg ha⁻¹ for reduced fresh weight. Canadian Water Quality Guidelines (CWQG) specify levels of contaminants that should not be exceeded in order to protect and sustain the major beneficial uses of water in Canada. For linuron, sufficient toxicity data were available to derive an interim CWQG of 7 μg L⁻¹ for the protection of freshwater life, a full CWQG of 0.071 μg L⁻¹ for irrigation water to protect cereals, tame hays, and pasture, and an interim CWQG of 3.3 μg L⁻¹ for irrigation water to protect other crops. © 1998 John Wiley & Sons, Inc. Environ Toxicol Water Qual 13 : 1–41, 1998     

Canadian water quality guidelines for deltamethrin

Canadian Water Quality Guidelines (CWQG) are numerical or narrative limits that protect designated water uses. Development of CWQG is based on review of deltamethrin's properties, uses, fate in the environment, ambient levels, accumulation in biota, and toxicity. Deltamethrin is a synthetic pyrethroid insecticide used against agricultural pests. Concentrations of deltamethrin in Canadian agricultural areas range between 10 and 1000 ng m⁻³ in air, 0.04 and 24.0 μg L⁻¹ in water, 3 and 5 ng g⁻¹ in sediments, 281 and 1375 ng g⁻¹ in plants, and 3.0 and 50.0 ng g⁻¹ in animals. In nature, deltamethrin can undergo volatilization, isomerization, and hydrolysis. Estimates of toxicity of deltamethrin to freshwater life range from 0.0001 μg L⁻¹ (48- and 96-h EC₀ for immobilization of Daphnia magna) to 1700 mg L⁻¹ (EC₅₀ for photoinhibition of Selanastrum capricornutum). Terrestrial life is affected by concentrations of deltamethrin ranging from 1.0 mg kg⁻¹ (retardation of fetus development in mice) to 5000 mg kg⁻¹ (LD₅₀ for a rat). A full guideline of 0.4 μg L⁻¹ is recommended for the protection of freshwater life. A full guideline of 2.5 μg L⁻¹ is recommended for water used for livestock production. There were insufficient data to derive guidelines for recreation, irrigation, and industrial applications. © 1998 John Wiley & Sons, Inc. Environ Toxicol Water Qual 13: 175–210, 1998     

Canadian water quality guidelines for chromium

Canadian Water Quality Guidelines (CWQG) are numerical or narrative limits that protect designated water uses. Development of CWQG is based on review of chromium's properties, uses, fate in the environment, ambient levels, accumulation in biota, and toxicity. Chromium's principal uses and entry into the environment include electroplating, production of paints and pigments, tanning, wood preservation, chromium chemicals production, metal smelting, and pulp and paper production. Concentrations of chromium in Canada range between 1 and 545,000 ng·m⁻³ in air, 0.001 and 0.165 mg·L⁻¹ in water, nondetectable and 31,000 mg·kg⁻¹ in sediments, 10 and 5000 mg·kg⁻¹ in soils, 0.006 and 18 mg·kg⁻¹ in plants, and 0.03 and 1.6 mg·kg⁻¹ in animals. In nature, trivalent chromium sorbs to various ligands and forms insoluble entities becoming unavailable for uptake by biota. Hexavalent chromium forms many soluble salts that can enter body membranes and induce a toxic response. Estimates of toxicity of hexavalent chromium to aquatic life range from 0.0006 mg·L⁻¹ (reduction in algal growth) to 1000 mg·L⁻¹ (decrease in rest time of Chironomus tentans). For trivalent chromium the toxicity ranges from 0.002 mg·L⁻¹ (reduction in filtering rate of Perna perna) to 937 mg·L⁻¹ (48-h LC₅₀ of Asellus aquaticus). Plants are affected by the concentrations of hexavalent chromium ranging from 0.16 mg·L⁻¹ (growth reduction in lettuce) to 75 mg·L⁻¹ (no effects in sweet orange). For trivalent chromium the toxicity ranges between 0.104 mg·L⁻¹ (reduction in root growth of oats) and 50 mg·L⁻¹ (stunted growth of corn and tomato). Terrestrial animals such as the beagle dog can be affected by concentrations exceeding 62.7 mg·L⁻¹ (Cr VI). Mice can tolerate 100 mg·L⁻¹ of hexavalent chromium. Trivalent chromium has adverse effects on rats and mice at 28.0 mg·L⁻¹. For freshwater life, guidelines of 0.001 (Cr VI; full) and 0.008 (Cr III; interim) mg·L⁻¹ are recommended. For marine life, guidelines of 0.001 (Cr VI; draft) and 0.05 (Cr III; interim) mg·L⁻¹ are recommended. Irrigation guidelines are set at 0.008 (Cr VI) and 0.005 (Cr III). A guideline of 0.05 mg·L⁻¹ is recommended for drinking and livestock waters. © 1997 by John Wiley & Sons, Inc. Environ Toxicol Water Qual 12: 123–183, 1997     

Harmonization of guidelines for toxicity testing of pharmaceuticals by 1992

In the past there has been considerable disagreement between various regulatory authorities regarding the type and design of animal tests that should be required before a new medicine can be used ethically and safely in the clinic. However, regulatory variations have largely been removed within politically and geographically similar regions (e.g., the U.S.A., the European Community, the Nordic countries) and there now appears to be a consensus regarding the value of harmonizing international requirements. In order to assist the process of harmonization, a detailed table of preclinical toxicity requirements in the U.S.A., Canada, Japan, and the European Community for each test (acute, subacute, chronic, carcinogenicity, mutagenicity, reproduction) has been compiled. This has been circulated to the relevant regulatory authorities to ensure that it accurately reflects current requirements. The major differences between authorities were found to be the duration of chronic, repeated-dose tests and the design of reproduction studies. International pharmaceutical companies were asked to complete a questionnaire, indicating how they design their preclinical testing program to comply with varying regulatory requirements. Most of the respondent companies indicated that chronic tests of longer than 6 months were conducted solely to comply with some regulatory requirements. Many companies repeat reproduction studies in order to comply with Japanese requirements. This emphasizes the need to harmonize these guidelines and discussions are currently underway to attempt to develop protocols acceptable to the FDA, the EC, and the Japanese Ministry of Health and Welfare.     

蛋白降解靶向嵌合体药物的非临床评价策略分析

蛋白降解靶向嵌合体(PROTAC)将靶向蛋白募集到E3泛素连接酶进行泛素化标记,然后通过泛素-蛋白酶体途径将其降解,从而将过表达和突变的致病蛋白清除。本文基于已有的文献报道,总结PROTAC药物研发进展,针对其存在的相对分子质量较大、生物利用度低、稳定性和血管穿透能力差等问题提出应对策略,并从药理药效、代谢和安全性评价等方面对该类药物的非临床评价研究需要考虑的问题进行分析,为制定PROTAC药物非临床评价研究方案提供参考。     

环孢素A与他克莫司应用于肝移植受者的药物经济学评价

目的评价环孢素A胶囊与他克莫司胶囊治疗肝移植受体排斥的经济性。方法选择在我院接受肝移植,并于2010年1月-2011年12月在门诊继续治疗的患者共60例,比较用药半年后的临床疗效、不良反应及用药成本,运用药物经济学的最小成本分析法对两种药物的经济效果进行评价。结果环孢素A胶囊组总有效率为78%,他克莫司胶囊组为86%,两组比较差异无统计学意义(P>0.05),环孢素A胶囊组的不良反应发生率较他克莫司胶囊组低。成本/效果比(C/E):环孢素A胶囊组为55.81,他克莫司胶囊组为46.19。结论与环孢素A胶囊比较,他克莫司胶囊用于肝移植受者更为经济有效。