Evaluating traditional Chinese medicine using modern clinical trial design and statistical methodology: application to a randomized controlled acupuncture trial

Traditional Chinese medicine (TCM), used in China and other Asian counties for thousands of years, is increasingly utilized in Western countries. However, due to inherent differences in how Western medicine and this ancient modality are practiced, employing the so-called Western medicine-based gold standard research methods to evaluate TCM is challenging. This paper is a discussion of the obstacles inherent in the design and statistical analysis of clinical trials of TCM. It is based on our experience in designing and conducting a randomized controlled clinical trial of acupuncture for post-operative dental pain control in which acupuncture was shown to be statistically and significantly better than placebo in lengthening the median survival time to rescue drug. We demonstrate here that PH assumptions in the common Cox model did not hold in that trial and that TCM trials warrant more thoughtful modeling and more sophisticated models of statistical analysis. TCM study design entails all the challenges encountered in trials of drugs, devices, and surgical procedures in the Western medicine. We present possible solutions to some but leave many issues unresolved.     

Scottish women medical pioneers: Manchuria 1894-1912.

In Edwardian Britain, less than 2% of all registered medical practitioners were women. Yet during that era, women played a significant role in providing medical care and education in what were lonely, harrowing and difficult conditions in the Third World. This is the story of how a group of Scottish women doctors brought Western medicine to a remote region of Manchuria between 1894 and 1912.     

Novel approaches to incorporating pharmacoeconomic studies into phase III clinical trials for Alzheimer's disease

The societal and individual costs of Alzheimer's disease are significant, worldwide. As the world ages, these costs are increasing rapidly, while health systems face finite budgets. As a result, many regulators and payers will require or at least consider phase III cost-effectiveness data (in addition to safety and efficacy data) for drug approval and reimbursement, increasing the risks and costs of drug development. Incorporating pharmacoeconomic studies in phase III clinical trials for Alzheimer's disease presents a number of challenges. We propose several specific suggestions to improve the design of pharmacoeconomic studies in phase III clinical trials. We propose that acute episodes of care are key outcome measures for pharmacoeconomic studies. To improve the possibility of detecting a pharmacoeconomic impact in phase III, we suggest several strategies including; study designs for enrichment of pharmacoeconomic outcomes that include co-morbidity of patients; reducing variability of care that can affect pharmacoeconomic outcomes through standardized care management; employing administrative claims data to better capture meaningful pharmacoeconomic data; and extending clinical trials in open label follow-up periods in which pharmacoeconomic data are captured electronically by administrative claims. Specific aspects of power analysis for pharmacoeconomic studies are presented. The particular pharmacoeconomic challenges caused by the use of biomarkers in clinical trials, the increasing use of multinational studies, and the pharmacoeconomic challenges presented by biologicals in development for Alzheimer's disease are discussed. In summary, since we are entering an era in which pharmacoeconomic studies will be essential in drug development for supporting regulatory approval, payor reimbursement and integration of new therapies into clinical care, we must consider the design and incorporation of pharmacoeconomic studies in phase III clinical trials more seriously and more creatively.     

The applicability of the results of streamlined trials to clinical practice

During recent decades we have seen an encouraging development of trial methodology. Less effort, however, has been devoted to the application of findings of trials to the practice of medicine. We cannot expect results of controlled trials alone to determine standard therapy, for clinical judgements are also required. Both beneficial and adverse effects are often only detectable on the group level. There are generally very few indications that drug effects differ qualitatively in subgroups of patients. It is important not only to prove or disprove effects, but also to find out how to implement a proper therapy for a majority of eligible patients. Four examples from treatment after myocardial infraction show that drug usage may not always be based upon results of clinical trials. The adoption of Swedish guidelines for thrombolytic therapy in acute myocardial infarction is taken as an example of an apparently optimal application of trial results in practice.     

Using randomized controlled trials to evaluate socially complex services: problems, challenges and recommendations

BACKGROUND: Following the lead of evidence-based medicine, practice based on effectiveness research has become the new gold standard of contemporary public policy. Studies of this sort are increasingly demanded to evaluate services provided by mental health, social services and criminal justice systems. AIMS: The paper questions whether the simple randomized controlled trial (RCT) paradigm as applied in clinical trials can be used "off the rack" to evaluate socially complex service (SCS) interventions. These are services that are characterized by complex, diverse and non-standardized staffing arrangements; ambiguous protocols; hard-to-define study samples and unevenly motivated subjects and dependence on broader social environments. The difficulty of ensuring precise protocols, equivalent groups (tied to a meaningful target population) and neutral and equivalent trial environments under real world conditions are explored, as are the implications of not achieving standardization and equivalence. METHODS: Limitations of effectiveness research as a research tool and information source are examined by comparing the assumptions underpinning the simple RCT to the characteristics of SCS interventions, as illustrated by programs targeted to mentally disordered offenders in Britain. RESULTS: SCSs violate the assumptions underpinning the simple RCT model in ways that draw into sharp question the validity, reliability and generalizability of inferences of SCS trials. DISCUSSION: The RCT is not a panacea. Effectiveness research of SCS interventions that is based on the RCT model is unlikely to yield valid, reliable and generalizable inferences without becoming more complex in design and more sensitive to issues of selection bias, unmeasured variables and endogeneity. Ten recommendations are offered for stylizing the RCT design to the characteristics of socially complex services. IMPLICATIONS: It remains an empirical issue whether RCT-based services effectiveness research can inform mental health policy. Without major design innovations, it is more likely that the information generated by this research will have limited practical use, especially if the RCT model is unable to control for the effect of social complexity and the interaction between social complexity and dynamic systemic change. Scientific evaluations of services make clinical and economic sense so long as they are designed to meet the challenges of the services of which they promise greater knowledge.     

A semiparametric joint model for terminal trend of quality of life and survival in palliative care research

Palliative medicine is an interdisciplinary specialty focusing on improving quality of life (QOL) for patients with serious illness and their families. Palliative care programs are available or under development at over 80% of large US hospitals (300+ beds). Palliative care clinical trials present unique analytic challenges relative to evaluating the palliative care treatment efficacy which is to improve patients’ diminishing QOL as disease progresses towards end of life (EOL). A unique feature of palliative care clinical trials is that patients will experience decreasing QOL during the trial despite potentially beneficial treatment. Often longitudinal QOL and survival data are highly correlated which, in the face of censoring, makes it challenging to properly analyze and interpret terminal QOL trend. To address these issues, we propose a novel semiparametric statistical approach to jointly model the terminal trend of QOL and survival data. There are two sub‐models in our approach: a semiparametric mixed effects model for longitudinal QOL and a Cox model for survival. We use regression splines method to estimate the nonparametric curves and AIC to select knots. We assess the model performance through simulation to establish a novel modeling approach that could be used in future palliative care research trials. Application of our approach in a recently completed palliative care clinical trial is also presented.     

Evaluation of randomized controlled trials on complementary and alternative medicine

OBJECTIVES: Use of complementary and alternative medicine (CAM) is growing in all Western countries. The goal of this study was to evaluate quality of randomized controlled trials (RCTs) of CAM interventions for specific diagnoses to inform clinical decision making. METHODS: MEDLINE and related databases were searched for CAM RCTs. Visual review was done of bibliographies, meta-analyses, and CAM journals. Inclusion criteria for review and scoring were blinded RCT, specified diagnosis and intervention, complete study published between January 1, 1966 and July 31, 1998 in an English-language, peer-reviewed journal. Two reviewers independently scored each study. RESULTS: More than 5,000 trials were found, but only 258 met all study inclusion criteria. The main cause for rejection (> 90%) was that the study was not an RCT or had no blinding. Mean score across 95 diagnosis/intervention categories was 44.7 (S.D. +/- 14.3) on a 100-point scale. Ordinary least-squares regression found date of publication, biostatistician as author or consultant, published in one of five widely read English-language medical journals and diagnosis/intervention category of hypertension/relaxation as significant predictors of higher scores. CONCLUSIONS: The overall quality of evidence for CAM RCTs is poor but improving slowly over time, about the same as that of biomedicine. Thus, most services are provided without good evidence of benefit.     

Traditional birth care

The automatic transfer of the techniques of Western medicine to the care of pregnant women and management of delivery in developing countries is currently undergoing critical reassessment. Ironically, this move toward unquestioned use of Western medical procedures in the Third World is occurring at the same time as women in developed countries are rejecting such orthodoxy. For example, there had been a movement by physicians and patients in both France and England against the traditional view that women should lie on their back during delivery. Studies have shown that the duration of labor is reduced by 36% by women who deliver in an upright position and there is less risk of reduced fetal blood flow from pressure of the pregnant uterus on the mother's aorta and major blood vessels. However, in Africa, where upright deliveries had been traditional, Western aid agencies are vigorously promoting horizontal labor, allegedly because it is earlier to monitor. Similarly, while there is a trend in developed countries back to breastfeeding, feeding with commercial baby foods is considered a sign of modernization in many Third World countries. Finally, at the same time as women in Africa are being urged to deliver in hospitals, women in developed countries with no risk factors are questioning the advantage of hospital deliveries over home birth. Given the limited resources available for health care in developing countries, the emphasis on medical high technology may be unwise.     

护理学临床试验文献状况调查

本调查对发表在《中华护理学杂志》的临床文献进行系统的人工检索,并按照世界Cochrane协作网关于临床试验的分类标准进行分类。结果共检索了8459篇临床文献,检索出239篇临床试验文章,占文献总数的2.83％,其中RCT为97篇,占40.59％;CCT为142篇,占59.41％;且检索出的239篇多数集中在80年代和90年代,这说明中国护理学领域近十多年临床试验研究发展较快。     

Using observational data to estimate prognosis: an example using a coronary artery disease registry

With the proliferation of clinical data registries and the rising expense of clinical trials, observational data sources are increasingly providing evidence for clinical decision making. These data are viewed as complementary to randomized clinical trials (RCT). While not as rigorous a methodological design, observational studies yield important information about effectiveness of treatment, as compared with the efficacy results of RCTs. In addition, these studies often have the advantage of providing longer-term follow-up, beyond that of clinical trials. Hence, they are useful for assessing and comparing patients' long-term prognosis under different treatment strategies. For patients with coronary artery disease, many observational comparisons have focused on medical therapy versus interventional procedures. In addition to the well-studied problem of treatment selection bias (which is not the focus of the present study), three significant methodological problems must be addressed in the analysis of these data: (i) designation of the therapeutic arms in the presence of early deaths, withdrawals, and treatment cross-overs; (ii) identification of an equitable starting point for attributing survival time; (iii) site to site variability in short-term mortality. This paper discusses these issues and suggests strategies to deal with them. A proposed methodology is developed, applied and evaluated on a large observational database that has long-term follow-up on nearly 10 000 patients.     

Expectations,validity, and reality in gene expression profiling

ObjectiveTo provide a critical overview of gene expression profiling methodology and discuss areas of future development.ResultsGene expression profiling has been used extensively in biological research and has resulted in significant advances in the understanding of the molecular mechanisms of complex disorders, including cancer, heart disease, and metabolic disorders. However, translating this technology into genomic medicine for use in diagnosis and prognosis faces many challenges. In addition, gene expression profile analysis is frequently controversial, because its conclusions often lack reproducibility and claims of effective dissemination into translational medicine have, in some cases, been remarkably unjustified. In the last decade, a large number of methodological and technical solutions have been offered to overcome the challenges.Study Design and SettingWe consider the strengths, limitations, and appropriate applications of gene expression profiling techniques, with particular reference to the clinical relevance.ConclusionSome studies have demonstrated the ability and clinical utility of gene expression profiling for use as diagnostic, prognostic, and predictive molecular markers. The challenges of gene expression profiling lie with the standardization of analytic approaches and the evaluation of the clinical merit in broader heterogeneous populations by prospective clinical trials.     

Herausforderungen an die klinische Evaluation und Gesundheits?konomie auf dem Weg zur personalisierten Medizin

Healthcare systems across the globe are currently challenged by aging populations, increases in chronic diseases and the difficult task of managing a healthcare budget. In this health economic climate, personalized medicine promises not only an improvement in healthcare delivery but also the possibility of more cost-effective therapies. It is important to remember, however, that personalized medicine has the potential to both increase and decrease costs. Each targeted therapy must be evaluated individually. However, standard clinical trial design is not suitable for personalized therapies. Therefore, both scientists and regulatory authorities will need to accept innovative study designs in order to validate personalized therapies. Hence correct economic evaluations are difficult to carry out due to lack of clear clinical evidence, longitudinal accounting and experience with patient/clinician behavior in the context of personalized medicine. In terms of reimbursement, payers, pharmaceutical companies and companion diagnostic manufacturers will also need to explore creative risk-sharing concepts. Germany is no exception to the challenges that face personalized medicine and for personalized medicine to really become the future of medicine many health economic challenges first need to be overcome. The health economic implications of personalized medicine remain unclear but it is certain that the expansion of targeted therapies in current healthcare systems will create a host of challenges.     

Placebo-controlled trials of Chinese herbal medicine and conventional medicine comparative study

BACKGROUND: Chinese herbal medicine (CHM) is increasingly used in the West, but the evidence on its effectiveness is a matter of debate. We compared the characteristics, study quality and results of clinical trials of CHM and conventional medicine. METHODS: Comparative study of placebo-controlled trials of CHM and conventional medicine. Eleven bibliographic databases and searches by hand of 48 Chinese-language journals. Conventional medicine trials matched for condition and type of outcome were randomly selected from the Cochrane Controlled Trials Register (issue 1, 2003). Trials described as double-blind, with adequate generation of allocation sequence and adequate concealment of allocation, were assumed to be of high quality. Data were analysed using funnel plots and multivariable meta-regression models. RESULTS: 136 CHM trials (119 published in Chinese, 17 published in English) and 136 matched conventional medicine trials (125 published in English) were analysed. The quality of Chinese-language CHM trials tended to be lower than that of English-language CHM trials and conventional medicine trials. Three (2%) CHM trials and 10 (7%) conventional medicine trials were of high quality. In all groups, smaller trials showed more beneficial treatment effects than larger trials. CHM trials published in Chinese showed considerably larger effects than CHM trials published in English (adjusted ratio of ORs 0.29, 95% confidence intervals 0.17-0.52). CONCLUSIONS: Biases are present both in placebo-controlled trials of CHM and conventional medicine, but may be most pronounced in CHM trials published in Chinese-language journals. Only few CHM trials of adequate methodology exist and the effectiveness of CHM therefore remains poorly documented.     

Clinical importance,statistical significance and the assessment of economic and quality-of-life outcomes

The assessment of economic and quality-of-life outcomes of health care interventions is moving into a new era, with such assessments increasingly being made within the context of controlled clinical trials. Traditionally the measurement of many variables in economic evaluations, particularly costs, has been deterministic. In the context of clinical trials the measurement of variables is stochastic, with the standard principles of statistical inference being applied to analyse differences between treatments in terms of effectiveness. Economists participating in clinical research are therefore being called upon to specify the sample size for the economic component of the evaluation and to undertake statistical tests for differences in cost or cost-effectiveness. This paper discusses the current methodological issues surrounding stochastic measurement in clinical trials, discusses the additional issues raised by the assessment of economic and quality-of-life outcomes and specifies the challenges facing economists if they are to answer the questions now being posed about economic analysis by statisticians and clinical researchers. It is concluded that application of the standard principles of statistical inference to economic data is not straightforward and will require value judgements to be made about statistical significance and economic importance, which may differ from those already made in purely clinical studies.     

A global strategy for medical education: partners in reform

Summary. The onrush of beneficial change which now flows in medical education has never been stronger since the start of this century. Such activity has not been seen since the era of Flexner. There can be no doubt that the world scene is now set for decisive, effective action. The many tributaries of the stream of reform converge this year at Edinburgh, to diverge again into six Regional Conferences during 1994 in Africa, the Americas, the Eastern Mediterranean, Europe, South-East Asia and the Western Pacific. The centres of activity and connection cited below do not in any way make up a comprehensive catalogue. Rather, each development and each reform is a link in a chain, a module with which the World Federation for Medical Education (WFME) has been implicated. Each name given, each title stated, is intended as a marker, a nexus. These are among the partners to be mobilized and brought together for the task.     

The double-blind, randomized, placebo-controlled trial: gold standard or golden calf?

The double-blind randomized controlled trial (RCT) is accepted by medicine as objective scientific methodology that, when ideally performed, produces knowledge untainted by bias. The validity of the RCT rests not just on theoretical arguments, but also on the discrepancy between the RCT and less rigorous evidence (the difference is sometimes considered an objective measure of bias). A brief overview of historical and recent developments in "the discrepancy argument" is presented. The article then examines the possibility that some of this "deviation from truth" may be the result of artifacts introduced by the masked RCT itself. Can an "unbiased" method produce bias? Among the experiments examined are those that augment the methodological stringency of a normal RCT in order to render the experiment less susceptible to subversion by the mind. This methodology, a hypothetical "platinum" standard, can be used to judge the "gold" standard. The concealment in a placebo-controlled RCT seems capable of generating a "masking bias." Other potential biases, such as "investigator self-selection," "preference," and "consent" are also briefly discussed. Such potential distortions indicate that the double-blind RCT may not be objective in the realist sense, but rather is objective in a "softer" disciplinary sense. Some "facts" may not exist independent of the apparatus of their production.     

Matched-pair study showed higher quality of placebo-controlled trials in Western phytotherapy than conventional medicine

OBJECTIVES: Herbal medicine (phytotherapy) is widely used, but the evidence for its effectiveness is a matter of ongoing debate. We compared the quality and results of trials of Western phytotherapy and conventional medicine. STUDY DESIGN AND SETTING: A random sample of placebo-controlled trials of Western phytotherapy was identified in a comprehensive literature search (19 electronic databases). Conventional medicine trials matched for condition and type of outcome were selected from the Cochrane Central Controlled Trials Register (issue 1, 2003). Data were extracted in duplicate. Trials described as double-blind, with adequate generation of allocation sequence and adequate concealment of allocation were assumed to be of higher methodological quality. RESULTS: Eighty-nine herbal medicine and 89 matched conventional medicine trials were analyzed. Studies of Western herbalism were smaller, less likely to be published in English, and less likely to be indexed in MEDLINE than their counterparts from conventional medicine. Nineteen (21%) herbal and four (5%) conventional medicine trials were of higher quality. In both groups, smaller trials showed more beneficial treatment effects than larger trials. CONCLUSIONS: Our findings challenge the widely held belief that the quality of the evidence on the effectiveness of herbal medicine is generally inferior to the evidence available for conventional medicine.     

Levels of explanation and cautions for a critical clinical anthropology

The appearance of a critical approach to clinical anthropology raises a question of relevance. Critical medical anthropology itself has developed with a primary concern for the impact of capitalism on Third World health, the inequality of medical resource distribution both in the U.S. and abroad, and the hegemony of Western biomedicine over local medical systems. Such an orientation may be of but modest relevance for an understanding of clinical phenomena in the heartland of capitalism itself. In the U.S., both patients and clinicians tend to share multiple values, including commitment to capitalism and the biomedical paradigm. Moreover, various negative behavioral characteristics visible in the clinical setting (such as racism) are common outside medicine, and may not be profitably understood through usual critical orientations. A heuristic model that gives excessive weight to a single element (capitalism) of a single (macro) level of explanation may not be as useful as one that utilizes a multi-level, multi-element approach. The argument is made that such a broader, more holistic approach may offer greater understanding of so-called micro level processes--specifically the patient/clinician interaction in specific clinical settings. An example is provided from a midwest hospital. It is suggested that if change in the biomedical system is a goal of a critical clinical anthropology, the impact will be greater where objective and broad causal connections can be demonstrated with minimal use of rote or polemic arguments.