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REGULATION AND GUIDELINE Guideline for Postmarketing Chinese Medicine Pharmacoeconomic Evaluation WANG Xin (王 昕)1,2, WANG Zhi-fei (王志飞)1, XIE Yan-ming (谢雁鸣)1, ZHANG Wen (张 雯)1, LIAO Xing (廖 星)1, and CHANG Yan-peng (常艳鹏)1, for the Specialty Committee of Evaluation of Postmarketing Chinese Medicines of World Federation of Chinese Medicine Societies ABSTRACT Pharmacoeconomics is an important part of the postmarketing Chinese medicine (CM) evaluation, and postmarketing pharmacoeconomic evaluation can reveal the clinical and market value of CM. The purpose of establishing the guideline for pharmacoeconomic evaluation is to make the evaluation process and results regarding Chinese patent medicines both scientific and fair. Every country's guidelines for pharmacoeconomic evaluation act as reference guidelines, we have already drawn up the guideline that takes into account the special characteristics of CM; and these are in preparation for the postmarketing CM pharmacoeconomic evaluation. KEYWORDS
postmarketing evaluation, Chinese medicine, pharmacoeconomics, guideline
With the rapid development of China's medical and health industry, along the orientation directed by Good Manufacturing Practice, more and more new products and new dosage forms of Chinese patent drugs have been introduced to the market, and the annual consumption of Chinese patent drugs have shown a significant growth. Diversified drugs provide more choices for both doctors and patients; however, the broadened variety of drugs exposed a more evident issue: many drugs are similar in terms of functions and indications. For this reason, it is necessary to make pharmacoeconomic evaluation, then those drugs with good efficacy but low/moderate cost can be identified. These are more in line with national policies of healthcare reforms, allowing patients to enjoy safe, effective and healthy healthcare services, and achieving the best therapy at the lowest cost. Pharmacoeconomic evaluation is one of the important means of evaluation of postmarketing Chinese medicines (CMs). It is also an extension of the evaluation of new CMs. The development of the guideline is one of the research tasks of "study on key technologies for evaluation of postmarketing CMs", a major national science and technology project for "major new medicine development" of the State Ministry of Science and Technology in 2009. This study accumulated a wealth of experiences in postmarketing CMs pharmacoeconomic evaluation, and eventually led to the development of the relevant guideline. Upon adoption by the experts committee, the guideline is to be studied, verified, supplemented
and applied in clinical institutions. Now, the guideline has become relatively sophisticated and a consensus has been achieved among experts and professionals. The guideline will provide technical support for the proper evaluation of postmarketing CMs, thus making the postmarketing CMs pharmacoeconomic evaluation more scientific, rational and operable.(1) Pharmacoeconomics is an emerging cross science aiming to address the issue of medical and medicinal resources arrangements. Its research and evaluation are conducted mainly from the the perspectives of society, patients, medical institutions and insurers. The range of cost and output to be measured varies with different research perspectives. Evaluation of pharmacoeconomics is of great importance in CMs pre-marketing review and postmarketing evaluation. To date, 33 countries and territories have had their relevant
©The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2014 Supported by the Research on Key Techniques of Reevaluation of Postmarketing Chinese Medicines, the Ministry of Science and Technology (No. 2009ZX09502-030), the Seventh-Science Foundation of China Academy of Chinese Medical Sciences (No. ZZ070817), and National Natural Science Foundation of China (General program, No. 81202776) 1. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing (100700), China; 2. Beijing Bionovo Medicine Development Co., Ltd., Beijing (100024), China Correspondence to: Prof. XIE Yan-ming, Tel: 86-10-64014411, E-mail: [email protected] DOI: 10.1007/s11655-014-1749-y
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authorities developing a total of 40 guidelines on pharmacoeconomics evaluation. These are used to direct and regulate pharmacoeconomics evaluation. In China, pharmacoeconomics research is a recently developed field, and in order to standardize the pharmacoeconomics research of the country, in 2011, China introduced "the Guide to Pharmacoeconomics Evaluation of China" (GPEC).(2) Compared with general Western medicines, CM has a higher patient tolerance, which is dependent on particular resources; there is unstability between different batches. These features result in unique challenges in the implementation of pharmacoeconomics evaluation of CM. The economic study of CM is still in its infancy, and there are difficulties to overcome in the study and in its implementation. Methods of economic evaluation for CM are still emerging. On the basis of GPEC, this article takes a lead to develop proposed guideline for postmarketing CM pharmacoeconomics evaluation from a technical perspective. It aims to regulate the design and practice of the programs of CM pharmacoeconomics evaluation, thus allowing for the evaluation to be made scientific and rational.
moreover, as it is time-consuming and strenuous, it is hard to be widely applied within a short time.(2)
Piggy-Back Combining pharmacoeconomics studies with drug clinical trials, and performing economics evaluation during drug clinical trial (phase Ⅳ) is a common method that medicine manufacturers use in the pharmacoeconomics study of new drugs. It features good credibility and internal validity, but it is low in external validity.(2)
Retrospective Cohort Design Much relevant data can be directly obtained, accordingly the cost is low, the research time is short, and it features good external validity. In a cohort design, it is necessary to control all possible confounding factors such as age, sex, severity of disease, and complications. As it is susceptible to selection bias, which must be identified and controlled.(2)
Mixed Method Design
The guideline applies to the pharmacoeconomics evaluation of CMs that have been already sold in the market, including Chinese patent drugs, Chinese crude drugs that have approval reference numbers, and other CM preparations serving as drugs.
Mixed method design is a comprehensive method integrating the above methods in one. In general, to further the adequate data of clinical effect obtained from prospective clinical trials or retrospective cohort designs, it is necessary to collect relevant cost data through retrospective/cross sectional investigations. Mixed method design is a method of pharmacoeconomics evaluation consuming less time and efforts than the other methods.(2)
Normative References
Cost
The guideline has referred to the following references which are essential for this document: the GPEC (revision 2011),(2) and guide to pharmacoeconomics evaluation of USA (revision 2009),(3) Netherland (revision 2006)(4) and Australia (revision 2007).(5)
Cost means the resources (labor, capital, materials, and time) consumed in prevention, diagnosis and treatment items. It consists of cost identification, cost measurement, discounting analysis, and uncertainty analysis. In terms of socialization, the cost of pharmacoeconomics evaluation comprises direct and indirect cost, each of which consists of medical costs and non-medical costs.(2)
Scope
Terms and Definitions The following terms and definitions are applied to the guideline.
Pragmatic Clinical Trial Pragmatic clinical trial is specially designed for pharmacoeconomics research. It is able to reflect the treatment effects under realistic conditions, with good external validity. However, due to the absence of external restrictions, poor subject compliance and many confounding factors, the internal validity is poor;
Direct medical costs comprise the costs directly related to treatment and interventions, e.g., prevention, diagnosis, treatment cost, etc. Direct non-medical costs related to treatment and interventions should also be input into the analysis, e.g., patients' travel costs, and nutrition costs. Indirect costs generally comprise the loss of productivity arising from the disease or death. These also need to be apportioned in the calculations.
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Intangible costs comprise financial loss through aches and pains arising from a particular disease, status or intervention. Incremental costs comprise extra costs of one medical intervention compared to another one.
Effectiveness In the pharmacoeconomics evaluation of CM, there is a priority to use effectiveness indicators in the study and its evaluation.(2) If only effect indicators under test conditions are available, it is recommended that the analysis should not be made until the estimated clinical effect indicators of the relevant models are worked out. If model estimate is infeasible, the clinical effect indicators can still be adopted in the evaluation, but the possible bias between ideal conditions and realistic conditions must be pointed out, and a sensitivity analysis should also be carried out. In order to improve the comparability between different intervention measures, pharmacoeconomics evaluation of CM should adopt final endpoints. If it is unfeasible to obtain final endpoints, it is also viable to adopt key intermediate endpoints to perform the analysis. In such a case, relevant references and the basis of the analysis must be provided to clarify the connections and relevance between final endpoints and intermediate endpoints.
Utility In the measurement of health utility, when the subject population are healthy people, it is recommended to use a generic utility scale.(2) If the subject population are people suffering from a disease, and the utility scale for such a disease is available, it is recommended to use the disease specific utility scale. When the subject group are people suffering a disease, but no utility scale for such a disease is available, it is recommended to use a generic utility scale. The measurement tools of health utility can be found in GPEC.
Benefit Direct benefit means the healthcare resources that the intervention measure saves. It is quite important that repetitive calculations are avoided when measuring direct benefits, to prevent the change of healthcare resources being stated in both cost and variables of health output at the same time.(2) Indirect benefits refer to the benefits from the reduction of loss on patients' health and time and the recovery of productivity after intervention measures
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that are carried out. Intangible benefits comprise the relief or avoidance of physical or mental pain as well as the comfort and joy brought by recovery after a certain intervention measure that is taken. As no income on money exchange is produced in the quantitization of the two benefits, it is to be measured in a correct way.
Cost Effectiveness Analysis The guideline depends on applying the restricted optimal method, i.e. maximized cost effect and minimized effect cost. The health results are represented in physical or natural units. The natural units are either various clinical indicators such as a reduction in blood pressure (in mm Hg), an improvement in a clinical scale scoring, or in clinical endpoints such as days of disability, number of lives saved and extension of lifespan. This is a widely applied method in pharmacoeconomics evaluation. When the clinical effects (e.g. efficacy and safety) of the drug as the research subject is the same with that of a comparison group, it is applicable to use cost-minimization analysis (CMA), namely, applicable to directly compare the costs.(2)
CMA It is also known as minimum cost analysis. It is a most cost-effective method of pharmacoeconomics evaluation, which is applicable when the results of two optional treatment programs are the same (in terms of efficacy and safety). In short, this method directly compares costs.(2)
Cost Utility Analysis Cost utility analysis (CUA) takes quality-adjusted life years (QALYs) as health output, to evaluate two or more optional medical interventions, it is a special form of cost-effectiveness analysis (CEA) effects represented by QALYs. QALYs take quality of life (QOL) and change of quantity into account, as it employs a single cost indicator (currency) and utility indicator (QALYs), it is suitable for comparison between different treatment drugs with different clinical resultant indicators.(2)
Cost Benefit Analysis Cost benefit analysis (CBA) e mp l oy s t he standards of Pareto improvement of benefit economics as the theoretical fundamentals. It is a method in which costs and results are translated into currency units, to perform economics evaluation on two or more optional medical interventions. However, because it is difficult to calculate the benefit accurately, this
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method is seldom used. Today, more common ways to estimate benefit are human capital approach (HCA) and willingness to pay (WTP).(6)
Discounting Discounting is the conversion of future costs and results into a present value.(2) In general, the discount rate is the market interest rate. It is recommended to use national one-year steering interest rates or the interest rate of national debt for discounting. For health output, it is recommended to perform discounting and sensitivity analysis using the same discount rate with that of cost.
Main Contents of Pharmacoeconomics Evaluation Objective and Perspective Postmarketing CM pharmacoeconomics evaluation aims to perform postmarketing CM CEA, to provide the most cost-effective drug therapy and intervention options, monitor adverse drug reaction (ADR), and optimize the configurations of drug resources. Pharmacoeconomics evaluation of CM can benefit the state, corporations, medical service providers (e.g. hospitals), third-party payers, and end consumers, respectively from the perspective of society, industry, medical service providers, insurers, and patients. The purpose and objective of evaluation may vary with the position and views of evaluators. Pharmacoeconomics evaluation of CM, from the perspective of society, aims to realize the optimum configurations and best utilization of drug resources of the whole society, and maximize improvements in the health of the whole population. Pharmacoeconomics evaluation of CM, from the perspective of the medical service providers and insurers, aims to understand how to achieve the highest income at the lowest cost, and to realize maximum benefits of their own. From the perspective of patients, the aim is to investigate how to realize the maximum improvement in personal health for the smallest personal financial burden. Researchers should identify their research perspective according to the research objective and reporting objective, and should always insist that the same research perspective is applied throughout the study. Once the research perspective is decided, a series of evaluation processes including research design, analysis method, cost and effectiveness estimates shall also be established.
Evaluated Drugs As most CM falls under the category of class A drugs for basic national medical insurance and workrelated insurance, which are generic medicines, their cost-effectiveness has been proven, so no evaluation needs to be carried out. For new drugs to be enlisted into the category of class B drugs for basic national medical insurance and work-related insurance, the pharmacoeconomics evaluation may be made to compare the incremental cost-effectiveness ratio between the new drugs and conventional drugs, thereby providing the basis for deciding whether a CM can be enlisted into the category of class B drugs of each province. No evaluation needs to be made for new drugs developed for acquired immune deficiency syndrome (AIDS), cancers, rare diseases, for diseases for which there are no current effective therapies, drugs for emergency incidents, drugs with insufficient or rare substitutes, drugs without prominent therapeutic advantages or cost advantages. However, the evaluation is to be made for drugs newly put on sale and with many substitutes. For those CMs with traditional efficacy, economics evaluation is to be made on key issues. In addition, the objects of the evaluation also include those CMs oriented to a disease for which both Chinese and Western therapy options are in place, or whose substitutes of different brands in the same species vary widely in quality, and there are a variety of drug forms available.
Design of Evaluation Design of pharmacoeconomics evaluation includes pragmatic clinical trials, piggy-back trials, retrospective cohort design, modeling method and mixed method design. (7) Pragmatic clinical trials of pharmacoeconomics is a common method used in pharmacoeconomics evaluation. It is also acceptable to perform Meta-analysis of secondary data, but it is essential to ensure the homogeneity of the research literature. (8) Diagnosis should be made through integrating disease with certifications.
Selection of Evaluation Indicators As CMs are medicines processed in specified formula and methods, they contain a variety of ingredients, able to produce multiple effects. Before making the evaluation, a set of observation indicators and judgment standards must be set in place. More
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than one indicator can be set for clinical effects, including primary/secondary efficacy, auxiliary efficacy, and ADR. The standards for efficacy evaluation should refer to domestic and international scoring standards. CM stresses comprehensive efficacy, and totally adjusts bodily functions, accordingly, the standards for efficacy evaluation is to be set depending on particular research objectives and which drugs are being compared. When a CM has multiple curative effects, the object of measurement and evaluation should be its primary efficacy. Further, biological and physiological indicators, clinical effect indicators and health indicators are to be used in the evaluation. The efficacy of CM should be evaluated in accordance with widely-accepted efficacy evaluation standards for the relevant disease.
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Description of Products, Description of Target Population and Financial Burden of Disease A survey should be carried out regarding the total cost of medicine undergoing pharmacoeconomics evaluation incurred for a specific disease, to make a macro study on the economic loss brought by the disease, thereby providing a basis for selecting preferred patients. To perform pharmacoeconomics evaluation on a product, the target population, inclusion standards and exclusion standards must be identified. To describe the target population, the type of subject is to be described in epidemiologic terms such as type and severity of disease, age, sex, socioeconomic characteristics, complications or other risk factors.
Clarifying the Clinical Orientation of Drugs The evaluation of clinical effect can be made either by means of integrating disease with certification or by means of a comprehensive evaluation. As a patient may suffer from more than one disease, they may need to take other medicines while the evaluated medicine is being administered. Therefore, synergistic or antagonistic effects may arise between the evaluated medicine and other medicine, this may adversely affect the judgment on the effect of the evaluated medicines. In such a case, a comparison can be made on the same patient before and after treatment with the evaluated medicine, or comparison can be made on the patients in pairs, so as to eliminate the impact of the combination therapy on the evaluated medicine. Basically, the therapy of CM does not use a single CM, but adopts combination therapy (hereinafter referred to as "basic therapy") in which one CM is used together with other ones or Western drugs. Therefore, there are three therapy options: the evaluated CM + basic therapy group, the conventional drugs for comparison + basic therapy group, and the basic therapy group. The efficacy of the three groups should be measured, then compare each of them with the basic therapy group, thereby learning the efficacy of the evaluated CM and the drugs for comparison. To judge the efficacy of a CM, in addition to normal physical and medical tests, the CM diagnosis before and after treatment should also be taken into account. Furthermore, a comparison should be made with the predicted CM diagnosis results under the above said theoretical assumptions, to make the evaluation as close as possible to the truth.
The scope of application of the drug is to be illustrated. If the scope is narrow, the restrictions are to be precisely pointed out; if the scope is wide, the indications are to be clearly defined. In addition, the combined use of drugs should also be taken into account in clinical application. As some CM is a multi-layer and multi-target medicine, complicated in ingredients, its indications are complicated and unclear in clinical settings. The clinical orientation is to be expressly defined in pharmacoeconomics evaluation; cost-output analysis should be performed over relevant indications. In order to identify clinical orientation, before pharmacoeconomics evaluation is made, relevant clinical surveys and analysis are to be made so as to clarify the clinical orientation of the drugs.
Selection of Drugs for Comparison Economic evaluation of CM is based on the comparison between different therapy methods; accordingly it is very important to select proper drugs for comparison. In principle, justice and equality must be observed in the selection of drugs for comparison. The comparison of drug is usually the standard therapy option and common therapy option, which could be medicine or non-medicine options. The standard comparison is the first choice of therapy whose effect has been proven in conventional medical treatment. The conventional drugs with similar indications should be selected as the drugs for comparison; if the drug is classified as a new therapy, the drugs with the closest indications will be chosen as the drug comparison. If for some disease there are
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still no effective medical measures or no intervention is recommended, placebo can be selected for comparison, but the clinical reasonability without medical intervention is to be ascertained.
Requirements for Evaluators They must have been well-trained, own relevant expertise, skills, experiences, know well the background and requirements of research, and have good ethics.
Cost Measurement In terms of socialization, the cost of pharmacoeconomics evaluation comprises direct costs and indirect costs, each of which consists of medical costs and non-medical costs, respectively. Costs are the product of the vector quantity and unit price of resources. The quantity of each resource is to be set out in natural units. The unit price of direct costs uses the market retail price.
culture), ADR risk, the percentage of clinical trial discontinuation due to ADR or treatment failure, are usually used to evaluate the effectiveness of medicine. In general, the observation for pharmacoeconomics evaluation on chronic disease lasts months even years, outcome indicators such as morbidity, recurrence rate, mortality, QOL, etc. can be measured. The utility and benefit indicators may also be used in the effectiveness measurement for pharmacoeconomics evaluation. Which indicator is to be adopted depends on the research objective, research perspective, research design, expected effect of drugs and the features of the disease. The effectiveness indicator can be used as the first choice in postmarketing CM pharmacoeconomics evaluation. If conditions permit, it is viable to translate the results of health measurement into the benefit indicators stated in currency units.
ADR Monitoring There are three methods for the calculation of indirect non-medical cost, i.e., HCA, WTP method and friction cost method. Among all, the most common method is HCA, which measures the socioeconomic loss arising from disease or death in annual average wages. (8) WTP capital means the highest amount that a patient is willing to pay for ensuring health or receiving a certain treatment or intervention; such data is obtained by questionnaires given to subjects. To use this method, the research assumptions, method of questioning, the scope of benefits measured, and language used in the questionnaire should be explained. As the responses of subjects are affected by the healthcare system and many other factors, this method requires further improvements. The basis for friction cost method is the loss of production brought by disease depending on the time that the manufacturer spent on the recovery of production. It is the cost spent in substitute of the subject. It is usually affected by the unemployment rate in the market; the period when productivity suffers loss is called the friction period.(9)
Effectiveness Measurement An effectiveness indicator is used in effectiveness measurement in pharmacoeconomics evaluation. Various substitute indicators, including biological or physiological measurements (e.g., blood pressure, blood glucose, blood lipids, hematological indicators, viral markers, and negative conversion of pathogen
It is hard to identify and foresee all safety issues of a drug; generally, we determine risk, type and features of ADR of the drug through large-scale, long-term clinical monitoring. The pharmacoeconomics evaluation should cover the economic loss caused by ADR as the cost analysis and risk benefit evaluation of ADR.
Discounting of Costs and Benefits Discounting refers to converting the future costs and results into a present value. In general, CM pharmacoeconomics evaluation takes a long time, once the research time is longer than one year, the cost and effectiveness must be discounted. In order to improve the comparability between research studies, it is essential for all research to adopt the same discounting rate. It is recommended to perform sensitivity analysis on the discounting.(9)
Treatment of Uncertainty Pharmacoeconomics evaluation of CM features strong predictability, that is to say, all the data used in CM pharmacoeconomics evaluation research is not the actual data collected from the application of the options in an actual population, but from the application of the options in samples. There are many factors influencing the values of cost and income data of the sample and an actual population. The change of these factors is more or less uncertain due to the effect of differences in research conditions and individual patient. Moreover,
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the dependence of the representativeness, veracity and reliability of the sample data on the scientificity and rationality of the design on pharmacoeconomics evaluation of CM could be included in these factors. All these impact may lead to bias between data of samples and data of actual populations. Therefore, the resulting deviation or errors of evaluation conclusion finally reveal the risk and loss for the patients or payers. In order to reduce the risks of decision-making mistakes, it is important to know three principles: (1) to know the changes in various influencing factors that could influence the economical effectiveness of options; (2) to understand the tolerance of options to changes in each factor; (3) to know the probability distribution of economy of options. Thus, it is available to grasp the proper decision-making principles and decision-making methodology under risk conditions. The uncertainty analysis helps solve the above issues. Therefore, CM pharmacoeconomics evaluation research must be carried out together with uncertainty analysis, so as to improve the reliability of the research results and reduce the risks of decision mistakes. With regard to the method of analysis, both traditional statistical methods and sensitivity analysis can be used to address uncertainty. Traditional statistical methods are suitable for independent cost and effectiveness, its measurement accuracy is able to be estimated by directly calculating 95% confidence intervals. For the confidence intervals of cost-effectiveness ratios, as the case may be, the ellipse method, Taylor series method, box method, the Filler's theorem and nonparametric bootstrap method may be used to calculate the confidence intervals of cost-effectiveness ratios. If the data distribution of cost-effectiveness ratios is not known, nonparametric bootstrap method and jack knife method may be used to calculate the confidence intervals of costeffectiveness ratios.(9)
Data Analysis Affirmative sensitivity analysis methods can be applied. For example, one-way sensitivity analysis, multiway sensitivity analysis, threshold analysis, analysis of extremes and scenarios analysis, etc.
Evaluation Methods Optional CEA, CUA, CBA, CMA methods can be used to analyze postmarketing pharmacoeconomics
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evaluation for CM.(10,11)
Standards for Reporting Methods and Results This guideline refers to the format of GPEC.(2) The guideline we drafted defines the process of postmarketing CM pharmacoeconomics evaluation. It aims to provide patients with optimum therapy while minimizing their financial burden through postmarketing CM pharmacoeconomics evaluation. It is of great importance to provide people with safe, economical effective medical services and optimize the configurations of CM resources.
Discussion Today, as medical costs grow year by year, it is becoming increasingly difficult for limited medical resources to meet the medical needs. The efficacy and safety of drugs have been unable to be taken as the sole guideline for clinical decisionmaking. For health policy makers, in particular, it is more and more important to allocate limited health resources in a more effective way. Undoubtedly, pharmacoeconomics evaluation is a good solution to this problem. The evidence of scientifically designed and strictly implemented pharmacoeconomics evaluation of CM will guide the clinical application of Chinese patent drugs, and allow them to play a more important role in healthcare services than previously. Compared with chemical drugs, Chinese patent drugs have their own distinctive features. Chinese patent drugs are made from natural plants and animals, with a wide variety of ingredients, high requirements in the production process, difficulties in performing quality control, and variance of different product batches. A Chinese patent drug often contains a variety of chemical constituents, with multi-stage, multi-level, multi-channel, multi-target systemic effects on the human body, hence, we usually have no way to evaluate their efficacy through a single indicator. Moreover, concomitant medications are widely seen in the clinical application of Chinese patent drugs, so, it is difficult to evaluate the contribution of each drug to the overall efficacy. In addition, due to misperception of Chinese patent drugs, various improper practices often take place in their clinical applications, e.g., violation against clinical contraindications, too long or too short treatment courses, and improper route of administration. As a result, the evaluations of safety, effectiveness and economics of Chinese patent drugs
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appear even more complicated than that of chemical drugs. The above features of Chinese patent drugs make it difficult to study and conduct pharmacoeconomics evaluation of CM. Pharmacoeconomics evaluation is referred to and is of guiding importance for the development of pharmaceutical policy, optimal allocation of medicine resources, the selection of prevention, diagnostic and treatment schemes, the establishment of pharmaceutical formulary lists, which is used for the research and development of new drugs, for drug pricing, and the control over the excessive growth of drug costs. The issue of the guideline provides support for the implementation of pharmacoeconomics evaluation of CM. Pharmacoeconomics evaluation will provide evidence-based support to demonstrate the advantages of CM in terms of convenience of drug administration, cost-effectiveness and efficacy. This is of great significance for the integration of Chinese patent drugs into modern health care systems.
Sciences; Prof. JI Shao-liang, Beijing University of Chinese Medicine; Prof. YI Dan-hui, Renmin University of China. And we thank Prof. WANG Nuo from Beijing Normal University for the help on the writing of the guideline.
REFERENCES 1. Zhang W, Xie YM, Yuwen Y. Exploration of how to formulate guidelines on post-marketing traditional Chinese medicine surveillance. China J Chin Mater Med (Chin) 2013;38:2943-2948. 2. Research Group of Pharmacoeconomics Evaluation of China. Guide to pharmacoeconomics evaluation of China (revision 2011). China J Pharm Econom (Chin) 2011;3:6-48. 3. FMCP Format Executive Committee. The AMCP format for formulary submissions (version 3.0). J Manag Care Pharm 2010;16:1-30. 4. Guidelines for pharmacoeconomic research, updated version. Diemen: College voor zorgverzekeringen; 2006. 5. Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory Committee (version 4.3). Canberra (ACT): Australian Government Department of Health and Ageing. 6. Chen W, Hu SL. Put up a platform of pharmacoeconomics
Conflict of Interest
study and practice. J China Prescr Drug (Chin) 2008;4:12-15.
The authors declared no potential conflicts of interest with
7. Tian F, Fu YK, Xie YM. Probe on the estimate methods of
respect to the research, authorship, and/or publication of this
sample size for postmarketing clinical evaluation of Chinese
guideline.
medicine. China J Chin Mater Med (Chin) 2011;36:1097-1102. 8. Yang L, Hu SL. Cost accounting of pharmacoeconomics
Author Contributions
evaluation, pharmacoeconomics research and evaluation
Xie YM provided suggestions and critical insights. Wang
centre. [EB/OL]. [2007-03-05]. http://sph.fudan.edu.cn:81/
X, Wang ZF and Chang YP drafted the Chinese version of
per/paper.shtmlcmd=uv&scope=pe&lan=zh&id=4028803b1
the guideline. Zhang W and Liao X contributed to the English
11d772801111d8982990006.
version of the guideline. All authors were involved in organizing and refining the guideline developing.
9. Yang L, Hu SL. Cost definition in pharmacoeconomics evaluation and existing controversy. Chin Pharm (Chin) 2003;14:670-672.
Acknowledgement We thank the following experts for their critical review of the manuscript of the guideline: Prof. WANG Yong-yan, China
10. Yang L, Hu SL, Chen W. Comparison of daily estmate method of five confidence intervals of cost-effectiveness ratios. Chin J Health Stat (Chin) 2004;21:150-153.
Academy of Chinese Medical Sciences; Prof. DU Xiao-xi,
11. Zhang F, Wang M, Du J. The research development of
National Center for ADR Monitoring of Drugs and the Center for
pharmacoeconomic evaluation on Chinese medicine. China
Drug Evaluation of China Food and Drug Administration; Prof.
J Pharm Econom (Chin) 2009;5:44-50.
CHAO En-xiang, China-Japan Friendship Hospital; Prof. WENG Wei-liang, Xiyuan Hospital, China Academy of Chinese Medical
(Received January 22, 2014) Edited by YU Ming-zhu
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REGULATION AND GUIDELINE Guideline for Postmarketing Chinese Medicine Pharmacoeconomic Evaluation WANG Xin (王 昕)1,2, WANG Zhi-fei (王志飞)1, XIE Yan-ming (谢雁鸣)1, ZHANG Wen (张 雯)1, LIAO Xing (廖 星)1, and CHANG Yan-peng (常艳鹏)1, for the Specialty Committee of Evaluation of Postmarketing Chinese Medicines of World Federation of Chinese Medicine Societies ABSTRACT Pharmacoeconomics is an important part of the postmarketing Chinese medicine (CM) evaluation, and postmarketing pharmacoeconomic evaluation can reveal the clinical and market value of CM. The purpose of establishing the guideline for pharmacoeconomic evaluation is to make the evaluation process and results regarding Chinese patent medicines both scientific and fair. Every country's guidelines for pharmacoeconomic evaluation act as reference guidelines, we have already drawn up the guideline that takes into account the special characteristics of CM; and these are in preparation for the postmarketing CM pharmacoeconomic evaluation. KEYWORDS
postmarketing evaluation, Chinese medicine, pharmacoeconomics, guideline
With the rapid development of China's medical and health industry, along the orientation directed by Good Manufacturing Practice, more and more new products and new dosage forms of Chinese patent drugs have been introduced to the market, and the annual consumption of Chinese patent drugs have shown a significant growth. Diversified drugs provide more choices for both doctors and patients; however, the broadened variety of drugs exposed a more evident issue: many drugs are similar in terms of functions and indications. For this reason, it is necessary to make pharmacoeconomic evaluation, then those drugs with good efficacy but low/moderate cost can be identified. These are more in line with national policies of healthcare reforms, allowing patients to enjoy safe, effective and healthy healthcare services, and achieving the best therapy at the lowest cost. Pharmacoeconomic evaluation is one of the important means of evaluation of postmarketing Chinese medicines (CMs). It is also an extension of the evaluation of new CMs. The development of the guideline is one of the research tasks of "study on key technologies for evaluation of postmarketing CMs", a major national science and technology project for "major new medicine development" of the State Ministry of Science and Technology in 2009. This study accumulated a wealth of experiences in postmarketing CMs pharmacoeconomic evaluation, and eventually led to the development of the relevant guideline. Upon adoption by the experts committee, the guideline is to be studied, verified, supplemented
and applied in clinical institutions. Now, the guideline has become relatively sophisticated and a consensus has been achieved among experts and professionals. The guideline will provide technical support for the proper evaluation of postmarketing CMs, thus making the postmarketing CMs pharmacoeconomic evaluation more scientific, rational and operable.(1) Pharmacoeconomics is an emerging cross science aiming to address the issue of medical and medicinal resources arrangements. Its research and evaluation are conducted mainly from the the perspectives of society, patients, medical institutions and insurers. The range of cost and output to be measured varies with different research perspectives. Evaluation of pharmacoeconomics is of great importance in CMs pre-marketing review and postmarketing evaluation. To date, 33 countries and territories have had their relevant
©The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2014 Supported by the Research on Key Techniques of Reevaluation of Postmarketing Chinese Medicines, the Ministry of Science and Technology (No. 2009ZX09502-030), the Seventh-Science Foundation of China Academy of Chinese Medical Sciences (No. ZZ070817), and National Natural Science Foundation of China (General program, No. 81202776) 1. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing (100700), China; 2. Beijing Bionovo Medicine Development Co., Ltd., Beijing (100024), China Correspondence to: Prof. XIE Yan-ming, Tel: 86-10-64014411, E-mail: [email protected] DOI: 10.1007/s11655-014-1749-y
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authorities developing a total of 40 guidelines on pharmacoeconomics evaluation. These are used to direct and regulate pharmacoeconomics evaluation. In China, pharmacoeconomics research is a recently developed field, and in order to standardize the pharmacoeconomics research of the country, in 2011, China introduced "the Guide to Pharmacoeconomics Evaluation of China" (GPEC).(2) Compared with general Western medicines, CM has a higher patient tolerance, which is dependent on particular resources; there is unstability between different batches. These features result in unique challenges in the implementation of pharmacoeconomics evaluation of CM. The economic study of CM is still in its infancy, and there are difficulties to overcome in the study and in its implementation. Methods of economic evaluation for CM are still emerging. On the basis of GPEC, this article takes a lead to develop proposed guideline for postmarketing CM pharmacoeconomics evaluation from a technical perspective. It aims to regulate the design and practice of the programs of CM pharmacoeconomics evaluation, thus allowing for the evaluation to be made scientific and rational.
moreover, as it is time-consuming and strenuous, it is hard to be widely applied within a short time.(2)
Piggy-Back Combining pharmacoeconomics studies with drug clinical trials, and performing economics evaluation during drug clinical trial (phase Ⅳ) is a common method that medicine manufacturers use in the pharmacoeconomics study of new drugs. It features good credibility and internal validity, but it is low in external validity.(2)
Retrospective Cohort Design Much relevant data can be directly obtained, accordingly the cost is low, the research time is short, and it features good external validity. In a cohort design, it is necessary to control all possible confounding factors such as age, sex, severity of disease, and complications. As it is susceptible to selection bias, which must be identified and controlled.(2)
Mixed Method Design
The guideline applies to the pharmacoeconomics evaluation of CMs that have been already sold in the market, including Chinese patent drugs, Chinese crude drugs that have approval reference numbers, and other CM preparations serving as drugs.
Mixed method design is a comprehensive method integrating the above methods in one. In general, to further the adequate data of clinical effect obtained from prospective clinical trials or retrospective cohort designs, it is necessary to collect relevant cost data through retrospective/cross sectional investigations. Mixed method design is a method of pharmacoeconomics evaluation consuming less time and efforts than the other methods.(2)
Normative References
Cost
The guideline has referred to the following references which are essential for this document: the GPEC (revision 2011),(2) and guide to pharmacoeconomics evaluation of USA (revision 2009),(3) Netherland (revision 2006)(4) and Australia (revision 2007).(5)
Cost means the resources (labor, capital, materials, and time) consumed in prevention, diagnosis and treatment items. It consists of cost identification, cost measurement, discounting analysis, and uncertainty analysis. In terms of socialization, the cost of pharmacoeconomics evaluation comprises direct and indirect cost, each of which consists of medical costs and non-medical costs.(2)
Scope
Terms and Definitions The following terms and definitions are applied to the guideline.
Pragmatic Clinical Trial Pragmatic clinical trial is specially designed for pharmacoeconomics research. It is able to reflect the treatment effects under realistic conditions, with good external validity. However, due to the absence of external restrictions, poor subject compliance and many confounding factors, the internal validity is poor;
Direct medical costs comprise the costs directly related to treatment and interventions, e.g., prevention, diagnosis, treatment cost, etc. Direct non-medical costs related to treatment and interventions should also be input into the analysis, e.g., patients' travel costs, and nutrition costs. Indirect costs generally comprise the loss of productivity arising from the disease or death. These also need to be apportioned in the calculations.
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Intangible costs comprise financial loss through aches and pains arising from a particular disease, status or intervention. Incremental costs comprise extra costs of one medical intervention compared to another one.
Effectiveness In the pharmacoeconomics evaluation of CM, there is a priority to use effectiveness indicators in the study and its evaluation.(2) If only effect indicators under test conditions are available, it is recommended that the analysis should not be made until the estimated clinical effect indicators of the relevant models are worked out. If model estimate is infeasible, the clinical effect indicators can still be adopted in the evaluation, but the possible bias between ideal conditions and realistic conditions must be pointed out, and a sensitivity analysis should also be carried out. In order to improve the comparability between different intervention measures, pharmacoeconomics evaluation of CM should adopt final endpoints. If it is unfeasible to obtain final endpoints, it is also viable to adopt key intermediate endpoints to perform the analysis. In such a case, relevant references and the basis of the analysis must be provided to clarify the connections and relevance between final endpoints and intermediate endpoints.
Utility In the measurement of health utility, when the subject population are healthy people, it is recommended to use a generic utility scale.(2) If the subject population are people suffering from a disease, and the utility scale for such a disease is available, it is recommended to use the disease specific utility scale. When the subject group are people suffering a disease, but no utility scale for such a disease is available, it is recommended to use a generic utility scale. The measurement tools of health utility can be found in GPEC.
Benefit Direct benefit means the healthcare resources that the intervention measure saves. It is quite important that repetitive calculations are avoided when measuring direct benefits, to prevent the change of healthcare resources being stated in both cost and variables of health output at the same time.(2) Indirect benefits refer to the benefits from the reduction of loss on patients' health and time and the recovery of productivity after intervention measures
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that are carried out. Intangible benefits comprise the relief or avoidance of physical or mental pain as well as the comfort and joy brought by recovery after a certain intervention measure that is taken. As no income on money exchange is produced in the quantitization of the two benefits, it is to be measured in a correct way.
Cost Effectiveness Analysis The guideline depends on applying the restricted optimal method, i.e. maximized cost effect and minimized effect cost. The health results are represented in physical or natural units. The natural units are either various clinical indicators such as a reduction in blood pressure (in mm Hg), an improvement in a clinical scale scoring, or in clinical endpoints such as days of disability, number of lives saved and extension of lifespan. This is a widely applied method in pharmacoeconomics evaluation. When the clinical effects (e.g. efficacy and safety) of the drug as the research subject is the same with that of a comparison group, it is applicable to use cost-minimization analysis (CMA), namely, applicable to directly compare the costs.(2)
CMA It is also known as minimum cost analysis. It is a most cost-effective method of pharmacoeconomics evaluation, which is applicable when the results of two optional treatment programs are the same (in terms of efficacy and safety). In short, this method directly compares costs.(2)
Cost Utility Analysis Cost utility analysis (CUA) takes quality-adjusted life years (QALYs) as health output, to evaluate two or more optional medical interventions, it is a special form of cost-effectiveness analysis (CEA) effects represented by QALYs. QALYs take quality of life (QOL) and change of quantity into account, as it employs a single cost indicator (currency) and utility indicator (QALYs), it is suitable for comparison between different treatment drugs with different clinical resultant indicators.(2)
Cost Benefit Analysis Cost benefit analysis (CBA) e mp l oy s t he standards of Pareto improvement of benefit economics as the theoretical fundamentals. It is a method in which costs and results are translated into currency units, to perform economics evaluation on two or more optional medical interventions. However, because it is difficult to calculate the benefit accurately, this
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method is seldom used. Today, more common ways to estimate benefit are human capital approach (HCA) and willingness to pay (WTP).(6)
Discounting Discounting is the conversion of future costs and results into a present value.(2) In general, the discount rate is the market interest rate. It is recommended to use national one-year steering interest rates or the interest rate of national debt for discounting. For health output, it is recommended to perform discounting and sensitivity analysis using the same discount rate with that of cost.
Main Contents of Pharmacoeconomics Evaluation Objective and Perspective Postmarketing CM pharmacoeconomics evaluation aims to perform postmarketing CM CEA, to provide the most cost-effective drug therapy and intervention options, monitor adverse drug reaction (ADR), and optimize the configurations of drug resources. Pharmacoeconomics evaluation of CM can benefit the state, corporations, medical service providers (e.g. hospitals), third-party payers, and end consumers, respectively from the perspective of society, industry, medical service providers, insurers, and patients. The purpose and objective of evaluation may vary with the position and views of evaluators. Pharmacoeconomics evaluation of CM, from the perspective of society, aims to realize the optimum configurations and best utilization of drug resources of the whole society, and maximize improvements in the health of the whole population. Pharmacoeconomics evaluation of CM, from the perspective of the medical service providers and insurers, aims to understand how to achieve the highest income at the lowest cost, and to realize maximum benefits of their own. From the perspective of patients, the aim is to investigate how to realize the maximum improvement in personal health for the smallest personal financial burden. Researchers should identify their research perspective according to the research objective and reporting objective, and should always insist that the same research perspective is applied throughout the study. Once the research perspective is decided, a series of evaluation processes including research design, analysis method, cost and effectiveness estimates shall also be established.
Evaluated Drugs As most CM falls under the category of class A drugs for basic national medical insurance and workrelated insurance, which are generic medicines, their cost-effectiveness has been proven, so no evaluation needs to be carried out. For new drugs to be enlisted into the category of class B drugs for basic national medical insurance and work-related insurance, the pharmacoeconomics evaluation may be made to compare the incremental cost-effectiveness ratio between the new drugs and conventional drugs, thereby providing the basis for deciding whether a CM can be enlisted into the category of class B drugs of each province. No evaluation needs to be made for new drugs developed for acquired immune deficiency syndrome (AIDS), cancers, rare diseases, for diseases for which there are no current effective therapies, drugs for emergency incidents, drugs with insufficient or rare substitutes, drugs without prominent therapeutic advantages or cost advantages. However, the evaluation is to be made for drugs newly put on sale and with many substitutes. For those CMs with traditional efficacy, economics evaluation is to be made on key issues. In addition, the objects of the evaluation also include those CMs oriented to a disease for which both Chinese and Western therapy options are in place, or whose substitutes of different brands in the same species vary widely in quality, and there are a variety of drug forms available.
Design of Evaluation Design of pharmacoeconomics evaluation includes pragmatic clinical trials, piggy-back trials, retrospective cohort design, modeling method and mixed method design. (7) Pragmatic clinical trials of pharmacoeconomics is a common method used in pharmacoeconomics evaluation. It is also acceptable to perform Meta-analysis of secondary data, but it is essential to ensure the homogeneity of the research literature. (8) Diagnosis should be made through integrating disease with certifications.
Selection of Evaluation Indicators As CMs are medicines processed in specified formula and methods, they contain a variety of ingredients, able to produce multiple effects. Before making the evaluation, a set of observation indicators and judgment standards must be set in place. More
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than one indicator can be set for clinical effects, including primary/secondary efficacy, auxiliary efficacy, and ADR. The standards for efficacy evaluation should refer to domestic and international scoring standards. CM stresses comprehensive efficacy, and totally adjusts bodily functions, accordingly, the standards for efficacy evaluation is to be set depending on particular research objectives and which drugs are being compared. When a CM has multiple curative effects, the object of measurement and evaluation should be its primary efficacy. Further, biological and physiological indicators, clinical effect indicators and health indicators are to be used in the evaluation. The efficacy of CM should be evaluated in accordance with widely-accepted efficacy evaluation standards for the relevant disease.
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Description of Products, Description of Target Population and Financial Burden of Disease A survey should be carried out regarding the total cost of medicine undergoing pharmacoeconomics evaluation incurred for a specific disease, to make a macro study on the economic loss brought by the disease, thereby providing a basis for selecting preferred patients. To perform pharmacoeconomics evaluation on a product, the target population, inclusion standards and exclusion standards must be identified. To describe the target population, the type of subject is to be described in epidemiologic terms such as type and severity of disease, age, sex, socioeconomic characteristics, complications or other risk factors.
Clarifying the Clinical Orientation of Drugs The evaluation of clinical effect can be made either by means of integrating disease with certification or by means of a comprehensive evaluation. As a patient may suffer from more than one disease, they may need to take other medicines while the evaluated medicine is being administered. Therefore, synergistic or antagonistic effects may arise between the evaluated medicine and other medicine, this may adversely affect the judgment on the effect of the evaluated medicines. In such a case, a comparison can be made on the same patient before and after treatment with the evaluated medicine, or comparison can be made on the patients in pairs, so as to eliminate the impact of the combination therapy on the evaluated medicine. Basically, the therapy of CM does not use a single CM, but adopts combination therapy (hereinafter referred to as "basic therapy") in which one CM is used together with other ones or Western drugs. Therefore, there are three therapy options: the evaluated CM + basic therapy group, the conventional drugs for comparison + basic therapy group, and the basic therapy group. The efficacy of the three groups should be measured, then compare each of them with the basic therapy group, thereby learning the efficacy of the evaluated CM and the drugs for comparison. To judge the efficacy of a CM, in addition to normal physical and medical tests, the CM diagnosis before and after treatment should also be taken into account. Furthermore, a comparison should be made with the predicted CM diagnosis results under the above said theoretical assumptions, to make the evaluation as close as possible to the truth.
The scope of application of the drug is to be illustrated. If the scope is narrow, the restrictions are to be precisely pointed out; if the scope is wide, the indications are to be clearly defined. In addition, the combined use of drugs should also be taken into account in clinical application. As some CM is a multi-layer and multi-target medicine, complicated in ingredients, its indications are complicated and unclear in clinical settings. The clinical orientation is to be expressly defined in pharmacoeconomics evaluation; cost-output analysis should be performed over relevant indications. In order to identify clinical orientation, before pharmacoeconomics evaluation is made, relevant clinical surveys and analysis are to be made so as to clarify the clinical orientation of the drugs.
Selection of Drugs for Comparison Economic evaluation of CM is based on the comparison between different therapy methods; accordingly it is very important to select proper drugs for comparison. In principle, justice and equality must be observed in the selection of drugs for comparison. The comparison of drug is usually the standard therapy option and common therapy option, which could be medicine or non-medicine options. The standard comparison is the first choice of therapy whose effect has been proven in conventional medical treatment. The conventional drugs with similar indications should be selected as the drugs for comparison; if the drug is classified as a new therapy, the drugs with the closest indications will be chosen as the drug comparison. If for some disease there are
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still no effective medical measures or no intervention is recommended, placebo can be selected for comparison, but the clinical reasonability without medical intervention is to be ascertained.
Requirements for Evaluators They must have been well-trained, own relevant expertise, skills, experiences, know well the background and requirements of research, and have good ethics.
Cost Measurement In terms of socialization, the cost of pharmacoeconomics evaluation comprises direct costs and indirect costs, each of which consists of medical costs and non-medical costs, respectively. Costs are the product of the vector quantity and unit price of resources. The quantity of each resource is to be set out in natural units. The unit price of direct costs uses the market retail price.
culture), ADR risk, the percentage of clinical trial discontinuation due to ADR or treatment failure, are usually used to evaluate the effectiveness of medicine. In general, the observation for pharmacoeconomics evaluation on chronic disease lasts months even years, outcome indicators such as morbidity, recurrence rate, mortality, QOL, etc. can be measured. The utility and benefit indicators may also be used in the effectiveness measurement for pharmacoeconomics evaluation. Which indicator is to be adopted depends on the research objective, research perspective, research design, expected effect of drugs and the features of the disease. The effectiveness indicator can be used as the first choice in postmarketing CM pharmacoeconomics evaluation. If conditions permit, it is viable to translate the results of health measurement into the benefit indicators stated in currency units.
ADR Monitoring There are three methods for the calculation of indirect non-medical cost, i.e., HCA, WTP method and friction cost method. Among all, the most common method is HCA, which measures the socioeconomic loss arising from disease or death in annual average wages. (8) WTP capital means the highest amount that a patient is willing to pay for ensuring health or receiving a certain treatment or intervention; such data is obtained by questionnaires given to subjects. To use this method, the research assumptions, method of questioning, the scope of benefits measured, and language used in the questionnaire should be explained. As the responses of subjects are affected by the healthcare system and many other factors, this method requires further improvements. The basis for friction cost method is the loss of production brought by disease depending on the time that the manufacturer spent on the recovery of production. It is the cost spent in substitute of the subject. It is usually affected by the unemployment rate in the market; the period when productivity suffers loss is called the friction period.(9)
Effectiveness Measurement An effectiveness indicator is used in effectiveness measurement in pharmacoeconomics evaluation. Various substitute indicators, including biological or physiological measurements (e.g., blood pressure, blood glucose, blood lipids, hematological indicators, viral markers, and negative conversion of pathogen
It is hard to identify and foresee all safety issues of a drug; generally, we determine risk, type and features of ADR of the drug through large-scale, long-term clinical monitoring. The pharmacoeconomics evaluation should cover the economic loss caused by ADR as the cost analysis and risk benefit evaluation of ADR.
Discounting of Costs and Benefits Discounting refers to converting the future costs and results into a present value. In general, CM pharmacoeconomics evaluation takes a long time, once the research time is longer than one year, the cost and effectiveness must be discounted. In order to improve the comparability between research studies, it is essential for all research to adopt the same discounting rate. It is recommended to perform sensitivity analysis on the discounting.(9)
Treatment of Uncertainty Pharmacoeconomics evaluation of CM features strong predictability, that is to say, all the data used in CM pharmacoeconomics evaluation research is not the actual data collected from the application of the options in an actual population, but from the application of the options in samples. There are many factors influencing the values of cost and income data of the sample and an actual population. The change of these factors is more or less uncertain due to the effect of differences in research conditions and individual patient. Moreover,
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the dependence of the representativeness, veracity and reliability of the sample data on the scientificity and rationality of the design on pharmacoeconomics evaluation of CM could be included in these factors. All these impact may lead to bias between data of samples and data of actual populations. Therefore, the resulting deviation or errors of evaluation conclusion finally reveal the risk and loss for the patients or payers. In order to reduce the risks of decision-making mistakes, it is important to know three principles: (1) to know the changes in various influencing factors that could influence the economical effectiveness of options; (2) to understand the tolerance of options to changes in each factor; (3) to know the probability distribution of economy of options. Thus, it is available to grasp the proper decision-making principles and decision-making methodology under risk conditions. The uncertainty analysis helps solve the above issues. Therefore, CM pharmacoeconomics evaluation research must be carried out together with uncertainty analysis, so as to improve the reliability of the research results and reduce the risks of decision mistakes. With regard to the method of analysis, both traditional statistical methods and sensitivity analysis can be used to address uncertainty. Traditional statistical methods are suitable for independent cost and effectiveness, its measurement accuracy is able to be estimated by directly calculating 95% confidence intervals. For the confidence intervals of cost-effectiveness ratios, as the case may be, the ellipse method, Taylor series method, box method, the Filler's theorem and nonparametric bootstrap method may be used to calculate the confidence intervals of cost-effectiveness ratios. If the data distribution of cost-effectiveness ratios is not known, nonparametric bootstrap method and jack knife method may be used to calculate the confidence intervals of costeffectiveness ratios.(9)
Data Analysis Affirmative sensitivity analysis methods can be applied. For example, one-way sensitivity analysis, multiway sensitivity analysis, threshold analysis, analysis of extremes and scenarios analysis, etc.
Evaluation Methods Optional CEA, CUA, CBA, CMA methods can be used to analyze postmarketing pharmacoeconomics
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evaluation for CM.(10,11)
Standards for Reporting Methods and Results This guideline refers to the format of GPEC.(2) The guideline we drafted defines the process of postmarketing CM pharmacoeconomics evaluation. It aims to provide patients with optimum therapy while minimizing their financial burden through postmarketing CM pharmacoeconomics evaluation. It is of great importance to provide people with safe, economical effective medical services and optimize the configurations of CM resources.
Discussion Today, as medical costs grow year by year, it is becoming increasingly difficult for limited medical resources to meet the medical needs. The efficacy and safety of drugs have been unable to be taken as the sole guideline for clinical decisionmaking. For health policy makers, in particular, it is more and more important to allocate limited health resources in a more effective way. Undoubtedly, pharmacoeconomics evaluation is a good solution to this problem. The evidence of scientifically designed and strictly implemented pharmacoeconomics evaluation of CM will guide the clinical application of Chinese patent drugs, and allow them to play a more important role in healthcare services than previously. Compared with chemical drugs, Chinese patent drugs have their own distinctive features. Chinese patent drugs are made from natural plants and animals, with a wide variety of ingredients, high requirements in the production process, difficulties in performing quality control, and variance of different product batches. A Chinese patent drug often contains a variety of chemical constituents, with multi-stage, multi-level, multi-channel, multi-target systemic effects on the human body, hence, we usually have no way to evaluate their efficacy through a single indicator. Moreover, concomitant medications are widely seen in the clinical application of Chinese patent drugs, so, it is difficult to evaluate the contribution of each drug to the overall efficacy. In addition, due to misperception of Chinese patent drugs, various improper practices often take place in their clinical applications, e.g., violation against clinical contraindications, too long or too short treatment courses, and improper route of administration. As a result, the evaluations of safety, effectiveness and economics of Chinese patent drugs
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appear even more complicated than that of chemical drugs. The above features of Chinese patent drugs make it difficult to study and conduct pharmacoeconomics evaluation of CM. Pharmacoeconomics evaluation is referred to and is of guiding importance for the development of pharmaceutical policy, optimal allocation of medicine resources, the selection of prevention, diagnostic and treatment schemes, the establishment of pharmaceutical formulary lists, which is used for the research and development of new drugs, for drug pricing, and the control over the excessive growth of drug costs. The issue of the guideline provides support for the implementation of pharmacoeconomics evaluation of CM. Pharmacoeconomics evaluation will provide evidence-based support to demonstrate the advantages of CM in terms of convenience of drug administration, cost-effectiveness and efficacy. This is of great significance for the integration of Chinese patent drugs into modern health care systems.
Sciences; Prof. JI Shao-liang, Beijing University of Chinese Medicine; Prof. YI Dan-hui, Renmin University of China. And we thank Prof. WANG Nuo from Beijing Normal University for the help on the writing of the guideline.
REFERENCES 1. Zhang W, Xie YM, Yuwen Y. Exploration of how to formulate guidelines on post-marketing traditional Chinese medicine surveillance. China J Chin Mater Med (Chin) 2013;38:2943-2948. 2. Research Group of Pharmacoeconomics Evaluation of China. Guide to pharmacoeconomics evaluation of China (revision 2011). China J Pharm Econom (Chin) 2011;3:6-48. 3. FMCP Format Executive Committee. The AMCP format for formulary submissions (version 3.0). J Manag Care Pharm 2010;16:1-30. 4. Guidelines for pharmacoeconomic research, updated version. Diemen: College voor zorgverzekeringen; 2006. 5. Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory Committee (version 4.3). Canberra (ACT): Australian Government Department of Health and Ageing. 6. Chen W, Hu SL. Put up a platform of pharmacoeconomics
Conflict of Interest
study and practice. J China Prescr Drug (Chin) 2008;4:12-15.
The authors declared no potential conflicts of interest with
7. Tian F, Fu YK, Xie YM. Probe on the estimate methods of
respect to the research, authorship, and/or publication of this
sample size for postmarketing clinical evaluation of Chinese
guideline.
medicine. China J Chin Mater Med (Chin) 2011;36:1097-1102. 8. Yang L, Hu SL. Cost accounting of pharmacoeconomics
Author Contributions
evaluation, pharmacoeconomics research and evaluation
Xie YM provided suggestions and critical insights. Wang
centre. [EB/OL]. [2007-03-05]. http://sph.fudan.edu.cn:81/
X, Wang ZF and Chang YP drafted the Chinese version of
per/paper.shtmlcmd=uv&scope=pe&lan=zh&id=4028803b1
the guideline. Zhang W and Liao X contributed to the English
11d772801111d8982990006.
version of the guideline. All authors were involved in organizing and refining the guideline developing.
9. Yang L, Hu SL. Cost definition in pharmacoeconomics evaluation and existing controversy. Chin Pharm (Chin) 2003;14:670-672.
Acknowledgement We thank the following experts for their critical review of the manuscript of the guideline: Prof. WANG Yong-yan, China
10. Yang L, Hu SL, Chen W. Comparison of daily estmate method of five confidence intervals of cost-effectiveness ratios. Chin J Health Stat (Chin) 2004;21:150-153.
Academy of Chinese Medical Sciences; Prof. DU Xiao-xi,
11. Zhang F, Wang M, Du J. The research development of
National Center for ADR Monitoring of Drugs and the Center for
pharmacoeconomic evaluation on Chinese medicine. China
Drug Evaluation of China Food and Drug Administration; Prof.
J Pharm Econom (Chin) 2009;5:44-50.
CHAO En-xiang, China-Japan Friendship Hospital; Prof. WENG Wei-liang, Xiyuan Hospital, China Academy of Chinese Medical
(Received January 22, 2014) Edited by YU Ming-zhu
