Chapter 13 Traditional Chinese Medicine Diagnostic Procedure

1. Chapter 13 Traditional Chinese Medicine Diagnostic Procedure

2. Outline • Introduction • A Proposed Study Design • Calibration • Validation • Discussion

3. Traditional Chinese Medicines (TCM) TCM is a 3000-year holistic medical system • Chinese herbal medicines • Acupuncture • Massage • Therapeutic exercise (Qigong, Taigie, etc)

4. Traditional Chinese Medicines • Chinese culture and philosophy • Clinical practice experiences • Materials including usage experiences of many medical herbs

5. Chinese Diagnostic Procedure • Inspection 望 observing the patient’s general appearance (strong or week, fat or thin), mind, complexion (skin color), five sense organs (eye, ear, nose, lip, and tongue), secretions, and excretions • Auscultation and Olfaction 聞 listening to the voice, expression, respiration, vomit, and cough, and smelling the breath and body odor

6. Chinese Diagnostic Procedure • Interrogation 問 asking questions about specific symptoms and the general condition including history of the present disease, past history, personal life history, and family history • Pulse taking and palpation 切 help to judge the location and nature of a disease according to the changes of the pulse

7. Syndrome Diagnosis • Eight principles Yin and Yang (i.e., negative and positive), cold and hot, external and internal, and Shi and Xu (i.e., weak and strong) • Five element theory Earth, metal, water, wood, and fire

8. Syndrome Diagnosis • Five Zang and six Fu Five Zang (or Yin organs) includes heart (including the pericardium), lung, spleen, liver, and kidney. Six Fu (or Yang organs) includes gall bladder, stomach, large intestine, small intestine, urinary bladder, and three cavities (i.e., chest, epiastrium, and hypogastrium). • Channels and collaterals The channels and collaterals are the representation of the organs of the body.

9. Fundamental Differences • Medical Theory/Mechanism • Medical Practice • Objective vs. subjective criteria for evaluability • Treatment • Single active ingredient versus multiple components • Fixed dose versus flexible dose

10. Medical Theory/Mechanism • Chinese doctors believe that all of the organs within a healthy subject should reach the so-called global dynamic balance or harmony • Once the global balance is broken at certain sites such as heart, liver or kidney, some signs and symptoms then appear to reflect the imbalance at these sites • An experienced Chinese doctor usually assesses the causes of global imbalance before a TCM with flexible dose is prescribed to fix the problem

11. Medical Practice • In practice, we tend to see therapeutic effect of WMs sooner than TCMs • TCMs are often considered for patients who have chronic diseases or non-life-threatening diseases • For critical and/or life-threatening diseases, TCMs are often used as the second line or third line treatment with no other alternative treatments • Different medical perceptions regarding signs and symptoms of certain diseases could lead to a different diagnosis and treatment for the diseases under study

12. Example • The signs and symptoms of type 2 diabetic subjects could be classified as the disease of thirsty reduction (消渴症) by Chinese doctors • The disease of type 2 diabetes is not recognized by Chinese medical literature although they have the same signs and symptoms as the well-known disease of thirsty reduction • This difference in medical perception and practice has an impact on the diagnosis and treatment of the disease

13. Objective vs. Subjective Criteria for Evaluability • For evaluation of a WM, objective criteria based on some well-established clinical study endpoints are usually considered. Response rate (CR plus PR based on tumor size) is considered a valid clinical endpoint for evaluating clinical efficacy of oncology drug products. • Chinese diagnostic procedure for evaluation of a TCM is very subjective. A commonly used Chinese diagnostic procedure consists of four major domains. Each domain contains a number of questions to capture patient’s signs, symptoms, and functional activities.

14. Treatment • TCM treatment is typically comprised of complicated prescriptions of a combination of several components • The use of Chinese diagnostic procedure is to find out what cause the imbalance among these organs • The dose and treatment duration are flexible in order to achieve the balance point • This concept leads to the so-calledpersonalized medicine, which minimizes intrasubject variability

15. Single Active Ingredient vs. Multiple Components

16. Western Medicines • Most western medicines (WM) contain a single active ingredient • After drug discovery, an appropriate formulation (or dosage form) is necessarily developed so that the drug can be delivered to the site action in an efficient way • At the same time, an assay is necessarily developed to quantitative the potency of the drug product • The drug product is then tested on animals for toxicity and humans (healthy volunteers) for pharmacological activities

17. TCMs • TCMs usually consist of multiple components with certain relative proportions among the components • The component, which contains major proportion of the TCM may not be the most active component , while the component has the least proportion of the TCM may be the most active component of the TCM • The relative component-to-component and/or component by food interactions are usually unknown which may have an impact on the evaluation of clinical efficacy and safety of the TCM

18. Fixed Dose vs. Flexible Dose

19. WMs • Most WMs contain a single active ingredient for a specific indication • It is often administered on the basis of a unit of fixed dose (say a 10 mg tablets or capsule)

20. TCMs • A TCM consists of multiple components with possible varied relative proportions among the components • A Chinese doctor usually prescribes a TCM (with a different relative proportions of the multiple components) based on the signs and symptoms of the patient according to his/her best judgment following a subjective Chinese diagnostic procedure • A TCM is not a fixed dose but an individualized flexible dose

21. WMs vs. TCMs • The approach of WM with a fixed dose is a population approach to minimize the between subject (or intersubject) variability, while the approach to TCM with an individualized flexible dose is to minimize the variability within each individual • An individualized flexible dose depends heavily upon the Chinese doctor’s subjective judgment, which may vary from doctor to doctor

22. Issues on TCM Clinical Trials • Test for Consistency The ability of reproducibility or consistency of clinical results is questionable • Animal Studies For some well-known TCMs, which have been used in humans for years and have a very mild toxicity profile, it is a question whether animal studies are necessary

23. Issues on TCM Clinical Trials • Stability Analysis Regulatory requirement for estimation of drug shelf-life for drug products with multiple components are not available • Regulatory Requirements Both regulatory authorities of China and Taiwan have published guidelines/guidances for clinical development of TCMs (see, e.g., MOPH, 2002; DOH, 2004a, 2004b)

24. Clinical Trials • Study objectives • A valid study design • Primary clinical endpoints • Sample size

25. TCM Clinical Trials • The commonly used TCM clinical endpoint is usually not applicable • The Chinese diagnostic procedure is an instrument (or questionnaire) which consists of a number of questions • Such a subjective instrument is necessarily validated for assessing treatment effect • We need to validate the Chinese diagnostic procedure with respect to a well-established clinical endpoint (as a reference marker)

26. A Proposed Study Design • Subjects will be screened based on criteria for western medicine • Qualified subjects will be diagnosed by the Chinese diagnostic procedure to establish baseline • Qualified subjects will then be randomized to receive either the test TCM or an active control (a well-established western medicine) • Participated physicians including Chinese doctors and western clinicians will also be randomly assigned to either the TCM arm or the arm of western medicine (WM)

27. Study Design Subgroup 1 Subjects who receive WM and evaluated by a TCM doctor and a western clinician

28. Calibration • x is the measurement of the well-established clinical endpoint • TCM diagnostic procedure consists of K items, say zi, i=1,…,K • x is normally distributed • y represent the scale (or score) summarized from the K TCM diagnostic items • For simplicity,

29. Calibration Models Model 1: y = α +βx + ε Model 2: y = βx + ε Model 3: y = α + β1x + β2x2 + ε Model 4: y = α xβε Model 5: y = αe β xε

30. Example:Stroke • Well-established clinical endpoint NIH Stroke Scale Score 0-42 over 22 very severe neurologic deficit • TCM diagnostic procedure 風証(wind syndrome)-6 questions 火熱証(fire-evil syndrome)-9 questions 痰証(sputum syndrome)-7 questions 血淤証(blood stasis syndrome)-5 questions 氣虛証(deficiency of vital energy)-8 questions 陰虛陽亢(Yin-deficiency & Yang-overabundant)-9 questions

31. NIH Stroke Scale Score (1) Level of Consciousness • Alert, keenly responsive (0 points) • Obeys, answers or resonds to minor stimulation (1 • points) • Responds only to repeated stimulation or painful • stimulation (excludes reflex response) (2 points) • Responds only with reflex motor or totally unresponsive • (3 points) • Ask the month, and patient age. Must be exactly right. • Answers both correctly (0 points) • Answers one correctly or patient unable to speak due to • any reason other than aphasia or coma (1 points) • Answers neither correctly, or too stuporous or aphasic • (2 points)

32. NIH Stroke Scale Score (2) • Ask patient to open and close eyes and then grip and release non-paretic hand • Performs both tasks correctly (0 points) • Performs 1 task correctly (1 points) • Performs neither task correctly (2 points) • Best Gaze: Only horizontal movements tested. Oculocephalic reflex use is ok, but not calorics • Normal (0 points) • Partial gaze palse (1 points) • Forced deviation or total gaze paresis not • overcome by oculocephalic maneuver (2 • points)

33. NIH Stroke Scale Score (3) • Visual fields tested by confrontation • No visual loss (0 points) • Partial hemianopia (1 points) • Complete hemianopia (2 points) • Bilateral hemianopia (blind from any cause including • cortical blindness) (3 points) • Facial palsy - encourage patient to smile and close eyes, or • grimace symmetry • Normal symmetrical movement (0 points) • Minor paryalysis (flattened nasolabial fold, asymmetry • on smiling) (1 points) • Partial paralysis (total or near total lower face paralysis) • (2 points) • Complete paralysis (absence of facial movement • upper/lower face) (3 points)

34. NIH Stroke Scale Score (4) • Right Arm Motor: Extend right arm palm down at 90 degrees (sitting) or 45 degrees (supine) • No drift - holds for full 10 seconds (0 points) • Drifts down before 10 seconds but does not • hit bed/support (1 points) • Some effort against gravity, but cannot get • up to 90 (or 45 if supine) degrees (2 points) • No effort against gravity, limb falls (3 points) • No movement (4 points)

35. NIH Stroke Scale Score (5) • Left Arm Motor: Extend left arm palm down at 90 degrees (sitting) or 45 degrees (supine) • No drift - holds for full 10 seconds (0 points) • Drifts down before 10 seconds but does not • hit bed/support (1 points) • Some effort against gravity, but cannot get • up to 90 (or 45 if supine) degrees (2 points) • No effort against gravity, limb falls (3 points) • No movement (4 points) • ……Other 7 questions

37. Y=12.537+0.822X X=(Y-12.537)/0.822

38. Validation • Validity (or accuracy) • Reliability (or precision) • Ruggedness (rater-to-rater’s variability)

39. Subgroup 2 Subjects who receive TCM and evaluated by a Chinese doctor A Subgroup 3 Subjects who receive TCM but evaluated by a Chinese doctor B

40. Validity • The validity itself is a measure of biasedness of the TCM instrument • A TCM instrument usually contains the four categories or domains, which in turn consist of a number of questions agreed by the community of the Chinese doctors • The questions may not be the right questions to capture the information regarding patient’s activity/function, disease status, and disease severity

41. Validity • Let X be the domain of interest that is unobservable and is normally distributed with mean θand variance τ2 f(Z)=f(Z1,…,ZK)=X, whereZ=(Z1,…,ZK)’ • Zfollows a distribution with mean μ=(μ1,… μK)’ and variance Σ • θ can be estimated by • The Bias is given by

42. Validity Based on the calibration curve, Consequently, E[(Y- α)/ β]=E(X), and It is desired to have the mean of Zi close to (α+βθ)/K.

43. Validity We wish to see

44. Validity Let . We claim that the TCM instrument is validated in terms of its validity if

45. Validity Let Then the (1-a)100% simultaneous CI for are given by where

46. Validity We can reject the null hypothesis that if any confidence interval falls completely outside (-d, d).

47. Reliability • The reliability measures the variability of the instrument, which directly relates to the precision of the instrument • The items for the TCM instrument are considered reliable if the variance is small

48. Reliability • We can test the hypothesis H0: Var(X)<Δ for some fixed Δ to verify the reliability of estimating θ by X • We derive that

49. Reliability Let N be the total number of patients. We can construct a (1-α)100% one-sided confidence interval for Var(X) as follows We can reject H0 and conclude that the items are not reliable in estimation of θ if ξ(X)>Δ.

50. Ruggedness • An acceptable TCM diagnostic instrument should produce similar results on different raters • It is desirable to quantify the variation due to rater and the proportion of rater-to-rater variation to the total variation