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Nicola Robinson, E-mail: nicky. ... marketing surveillance (PMS) has focussed on follow up of observational cohorts .... Audit of the template and identification.
Chin J Integr Med 2013 Jul;19(7):494-497

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FEATURE ARTICLE Methodological Approaches to Developing and Establishing the Body of Evidence on Post-marketing Chinese Medicine Safety LIAO Xing (廖

星)1 and Nicola Robinson2

ABSTRACT Evidence based medicine demands the highest form of scientific evidence to demonstrate the efficacy and clinical effectiveness for any therapeutic intervention in order to provide best care. It is however accepted that in the absence of scientific evidence, personal experience and expert opinion together with professional judgement are critical. Obtaining evidence for drug safety, postmarketing surveillance (PMS) has focussed on follow up of observational cohorts exposed to a particular drug in order to estimate the incidence of adverse drug reactions (ADRs). Evidence on PMS of Chinese herbal products is still limited, in particular for herbal injections. The aim of this article is to suggest a new model of ascertaining the safety of Chinese medicine using a more comprehensive approach for collecting data. To collect safety data on the Chinese herbal injection, Kudiezi, a Prof. Nicola Robinson mixed methods approach is proposed using 18 hospital information systems to detect ADRs in order to prospectively observe 30,000 patients over 3 years. Evidence will also be collected using a questionnaire survey and through a sample of semi structured interviews. This information based on the expert opinion and the experience of clinicians will produce additional data on the frequency and types of side effects in clinical practice. Furthermore semi structured interviews with a random sample of patients receiving the injection will be carried out to ascertain any potential side effects missed. It is hoped that this comprehensive approach to data collection will accumulate wider evidence based on individual traditional Chinese medicine care and treatment and provide important feedback to the national data collection system to ensure completeness of ADR data recording, monitoring and any potential wider effects through developing improved ADR guidelines. KEYWORDS post-marketing medicine, Chinese medicine, observational study, expert opinion, evidence

Introduction – the Need for Evidence The evidence based medicine (EBM) movement began seriously in the 1980's, evolving from clinical epidemiology. (1) This introduction of scientific methodology and synthesis of data has significantly influenced clinical decision making. The systematic review and meta analysis are regarded as the highest form of scientific evidence and a gold standard to be achieved in EBM. The traditional evidence pyramid shows the level of the evidence needed to demonstrate clinical effectiveness. (2) The strongest evidence for a therapeutic intervention is that provided by systematic review of randomized, blind, placebo controlled trials, with allocation concealment, complete follow-up, homogeneous patient populations and strictly defined medical condition. The aim of EBM was to bridge the gap between clinical practice and public health by using population

health sciences to inform the delivery of best clinical practice. David Sackett's definition of EBM is frequently quoted—"Evidence-based medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients."(3) It was first suggested in 1992(4) and it was subsequently adopted by the Cochrane Collaboration(5) and the Centre for Evidence Based Medicine.(6) ©The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2013 Supported by National Natural Science Foundation of China (General Program, No. 81202776) and the Sixth-Science Foundation of Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences (No. Z0215) 1. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing (100700), China; 2. Faculty of Health and Social Care, London South Bank University, UK Correspondence to: Prof. Nicola Robinson, E-mail: nicky. [email protected] DOI: 10.1007/s11655-013-1502-y

Chin J Integr Med 2013 Jul;19(7):494-497

Evidence based practice demands we use of current best evidence in order to provide best care. Evidence based medicine seeks to empower clinicians so that if scientific evidence is unavailable then personal experience and expert opinion come into play, together with professional judgement. This is accepted as the norm in the West when developing clinical guidelines. Making decisions about healthcare requires up to date and reliable evidence. Tonelli defended the importance of expert opinion, but pointed out that "critics argued that expert opinion would seem to be a separate, complex type of knowledge that would not fit into hierarchies otherwise limited to empirical evidence alone''.(7) For traditional Chinese medicine (TCM), evidence has been built up historically through case reports, expert opinion, clinical practice, clinicians' knowledge and experience and the use of clinical historical Chinese texts. This case by case accumulation of TCM knowledge was added to and further developed with case series, cohort/ longitudinal/observational studies of groups of patients. The emphasis in TCM is that of practitioner skill and individualised treatment, therefore perhaps conforming to a different hierarchy of evidence to that of conventional Western medicine. Clinical trials along the lines of that used in the West have become more and more important for TCM in order to comply with building a homogeneous picture of clinical effectiveness and efficacy. However vital information can be missed if the systematic review [or randomized controlled trials (RCTs)] is the only information that is used to inform practice. Over the past two decades, the clinical effectiveness and efficacy of Chinese medicine has already gained much legitimacy as a result of the accumulation of evidence from the systematic review and meta-analysis (and RCTs). Of importance is how to integrate the conventional EBM principles into TCM without compromising their integrity. 'Even excellent external evidence may be inapplicable or inappropriate for an individual patient' which may mean that there may be over reliance on the RCT which is an artificial and idealised version of practice.(3) Prof. Sir Michael Rawlins in his Harveian oration in 2008 eloquently stated the need to replace the hierarchies of evidence and 'embrace a diversity of approaches'. (8) He suggests that investigators should continue to build the evidence base not only by

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developing and improving their research methodology but by also considering the nature of evidence, in particular that of observation and the judgement needed to interpret evidence. Combining evidence is a necessary component of decision making. The population based methods that have dominated EBM are now being increasingly challenged given the acknowledgement of the complexity of systems interaction and the suggestion of more of a move towards personalized medicine in the future.(9)

Evidence of Safety – Post-Marketing Surveillance A number of approaches are used in postmarketing surveillance to monitor the safety of licensed drugs. These have included spontaneous reporting databases, prescription event monitoring, electronic patient records, disease registries and record linkage between health databases.(10) By reviewing collected data using data mining techniques, potential safety concerns can be highlighted. Recently in the West, there have been withdrawals of medicines from the market which demonstrate the inadequacy of postmarketing surveillance, and the need for better strategies to monitor the safety of new drugs. By implementing the use of a drug registry, a prospective observational cohort of eligible patients exposed to a particular drug can be studied in order to ascertain drug safety in specific populations. Systematic patients follow up, although costly can then establish the incidence of any adverse events. The evidence on post-marketing Chinese medicine safety is insufficient. In 2008 there were over 9,000 different TCM preparations approved for sale by the Chinese government and 58,000 approval numbers granted.(11) TCM use continues to increase worldwide and pharmacovigilance is critical. The Chinese herbal medicine injection was created and developed in mainland China during the 1950s. As the government has promoted this method of Chinese medicine delivery, the use of Chinese herbal medicine injection has been increasing in recent years. A survey of adverse drug reactions (ADR) case reports associated with TCM over a 20-year period identified that 42% (2,732 cases) were associated with TCM injections.(12) It is now very important and urgent to collect, evaluate and demonstrate the evidence for safety of particularly for this type of delivery using a systematic approach.

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Establishing the Body of Evidence on Postmarketing Chinese Medicine Safety Prof. XIE Yan-ming from Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, firstly posed questions on the body of evidence of post-marketing Chinese medicine safety in China. She emphasized that such kind of body of evidence should at least include ADR case reports from literature, ADRs reported from RCTs, data analysis from spontaneous and hospital information systems and registry studies. This section of the article outlines the proposed method for collecting evidence on ADRs using various postmarketing surveillance techniques for a series of Chinese herbal injections. A comprehensive body of evidence covering a range of sources derived from different scientific, clinical and patient based information is planned in order to inform the evidence base. This project will also provide critical feedback to the national data collection system to ensure completeness of ADR recording and its monitoring. Prof. Xie and her research group from the Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences are carrying out a national research project on evaluating safety for ten postmarketing injections. Each injection will be studied in an observational study which will observe 30,000 patients who have used at least one of ten specific injections over a 3-year period in hospitals. For example, Kudiezi Injection is a herbal injection (extracted from Irexis sonchifolia ), which has been used for patients since 1970 and sold in the Chinese market since 1997.(13) It can be used to treat coronary heart disease, angina and cerebral infarction in clinical practice. The work on Kudiezi Injection is in collaboration with London South Bank University in order to explore a development of a comprehensive patient safety profile. Just one article to explore safety about Kudiezi Injection has been reported from a literature review in 2012.(14) Several systematic reviews on the effectiveness of Kudiezi for acute cerebral infarction has already been carried out and published,(15,16) but a similar systematic review on its safety is not possible due to the lack of data in published clinical trial research. If herbal injections are to be introduced into Western countries, developing the body of evidence of patient safety is key. This information will be influential in discussions with policy makers for wider and routine use in other countries.

Chin J Integr Med 2013 Jul;19(7):494-497

The aim of this section is to outline and discuss how the body of evidence on ADRs for Kudiezi could be comprehensively developed by using a mixed method approach (Figure 1). This will be achieved by using information collected from systematic review of the published literature on any ADR case reports thought to be related to the use of Kudiezi herbal injections, interviews with stakeholders, expert clinicians, patients, observational data through post marketing surveillance, data collected systematically from published literature and the national spontaneous reporting system for ADR. The intention will be to develop, design and implement a new guideline for collecting ADR material. 1. ADR case reports from literature 2. Expert opinion of clinicians 3. Patient feedback 4. Retrospective data mining from the national spontaneous system of ADRs and 18 hospital information systems 5. A prospective observational study on 30,000 using Kudiezi 6. Development and implementation and audit of comprehensive guidelines with clinicians 7. Guideline 8. Systematic review on efficacy and effectiveness

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Figure 1. Inverse Pyramid for Safety Evaluation on Post-marketing Surveillance of TCM

Although ADR mining on Kudiezi from the national spontaneous system for ADR reporting, together with a retrospective analysis from 18 hospital information systems will be carried out to detect the ADR signals, other methodologies will be required in order to provide a comprehensive picture. This process will also include a prospective observational study of 30,000 hospitalized patients using Kudiezi (from 15 hospitals) who will be observed over a 3-year period to observe the frequency of ADRs and which will provide an estimate of the incidence of ADRs of Kudiezi. This prospective observational data collected on ADRs will provide important information which could influence legislative bodies and policy makers in other countries. The importance of collecting evidence based

Chin J Integr Med 2013 Jul;19(7):494-497

on the expert opinion of clinicians was highlighted earlier in this article. Clinicians will be surveyed on their perceptions on the incidence of patients reporting of ADRs, frequency and types of any side effects reported, how the product is used within their clinical practice, what determines its use and which specific criteria dictate when it is not safe to use the injection (as observed in clinical practice). This will be carried out by initially surveying clinicians likely to be responsible for administering the herbal injection. A random sample of 10% of these clinicians will be selected to take part in semi structured interviews to provide more in depth qualitative data. This information will be critical to further inform the development of guidelines.

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REFERENCES 1. Claridge J, Fabian T. History and development of evidence based medicine. World J Surg 2005;29:547-553. 2. Sackett DL, Strauss SE, Richardson WS, Rosenberg W, Haynes RB. Evidence-based medicine: how to practice and teach EBM. 2nd ed. Edinburgh: Churchill Livingstone; 2000. 3. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn't. BMJ 1996;312:71-72. 4. Evidence-Based Medicine Working Group. Evidence-based medicine. A new approach to teaching the practice of medicine. JAMA 1992;268:2420-2425. 5. "Evidence-based health care and systematic reviews". The Cochrane Collaboration. http://www.cochrane.org/about-us/ evidence-based-health-care. Retrieved 4 January 2013.

Semi structured interviews with patients will also be carried out to ascertain the occurrence of ADRs, comorbidities and other symptoms which occur during treatment, which may be related to the injection and any reported benefits thought to be related to the injection. This will rely on patient feedback and involvement and will also ascertain the acceptability of the injection. Such patient involvement in research processes is now an essential part of any research in the west.

6. "What is EBM?". CEBM – Centre for Evidence Based Medicine. http://www.cebm.net/?o=1014. Retrieved Retrieved 4 January 2013. 7. Tonelli MR. In defense of expert opinion. Acad Med 1999;74:1187-1192. 8. Rawlins M. De testimonio: on the evidence for decisions about the use of therapeutic interventions. Lancet 2008;372:2152-2161. 9. Li NY, Abbott KV, Rosen C, An G, Hebda PA, Vodovotz Y. Translational systems biology and voice pathophysiology.

Existing guidelines will be validated using the data collected and the development of new potential comprehensive guidelines with clinicians on ADRs based on the example of Kudiezi injection will be explored.

Laryngoscope 2010;120:511-515. 10. McNeil JJ, Piccenna L, Ronaldson K, Ioannides-Demos LL. The value of patient-centred registries in phase IV drug surveillance. Pharm Med 2010;24:281-288. 11. Wang H, Ye X, Gao Q, Wu C, Qian Y, Luo B, et al. Pharmacovigilance in traditional Chinese medicine safety

In the last phase of the project a guideline template will be implemented in a sample of hospitals based on the in depth enquiry of ADRs and feedback obtained. Audit of the template and identification of the changes potentially required for its use in routine practice will be identified and any potential recommendations will be highlighted and provided to the Chinese government.

surveillance. Pharmacoepidemiol Drug Safety (Chin) 2009;18:357-361. 12. Lu QL, Fang JJ. A survey of twenty years ADR caused by traditioonal Chinese medicine. Adverse Drug Reactions J (Chin) 2001;91:18-21. 13. Zhang LL. Research on marketing strategy of Tong Hua Die mai ling. Masters Thesis (Chin) 2007;F830:33. 14. Liao X, Shen H, Xie YM, Zhang W, Yang W, LU ZG. Literature review report on safety evaluation about Kudiezi

Conclusion It is hoped that this method will enable the collection of a comprehensive body of TCM evidence using data derived from a wide area of practice based on clinician and patient responses to inform the evaluation on the safety on the herbal injection, Kudiezi. This project will also provide critical feedback to the national data collection system to ensure completeness of ADR recording and its monitoring.

injection. China J Chin Mate Med (Chin) 2012;18:2786-2788. 15. Zuo ZJ, Huang QM. A systematic review of Kudiezi Injection in the treatment of angina pectoris. China Med Herald (Chin) 2011;4:32-35,73. 16. Jiang YB, Chen KJ.Systematic evaluation on the effect of Diemaining Injection in treating acute cerebral infarction. Chin J Clin Rehabil (Chin) 2006;27:100-101. (Received March 5, 2013) Edited by ZHANG Wen