1. 1 Clinical Trial 報告者：郭梅珍、江倫志、王美華 指導教授：周桂如教授 報告日期： 98.12.08

2. 2 大綱 一、 Definition 二、 Design Principles 1.Sample size and power estimates 2.Randomization 3.Treatment masking 4.Design factors 三、 Stages

3. 3 大綱 四、 Type of clinical trials 1.Parallel group 2.Higher-order designs for two treatments 3.2x2 cross-over trial （ AB/BA design ） 4. 3 or more treatments 5.Multicenter trials

4. 4 大綱 五、 Special types of clinical trials 1.Single-Patient clinical trials 2.Multicenter trials 3.National versus Multinational clinical trials 4.Continuation and compassionate plea trials 5.Validation of clinical tests and measure 6.Clinical trials to evaluate medical devices 7.Clinical trials in elderly patients 8.Comparing different dosage forms or treatment modalities 9.Combination medicine trials 10.Marketing-Oriented clinical studies 11.Quality of life trials

5. 5 Definition Is a planned experiment designed to assess the efficacy of a treatment by comparing the outcomes in a group of patients treated with the test treatment with those observed in a comparable group of patients receiving a control treatment,where patient in both groups are enrolled,treated,and followed over the same time period.

6. 6 Within-patient Comparison 1. Simultaneous comparison 2. Cross-over comparison

7. 7 Sample size and power estimate The number of subjects in a clinical trial should be large enough to provide a reliable answer to the questions addressed,but should also be the minimum necessary to achieve this aim  Statistic considerations  Practice considerations  Literature review

8. 8 Power Effect size variable scale precision Variability Sample size compliance

9. 9 Sample size calculation 最常使用 -Single outcome, dichotomous response  需要四項資訊 P1 – 對照組成功的比例 P2 – 治療組成功的比例 α–type I error ，通常設為 0.05 1-β– 能正確地辨明兩組之間差異的統計檢力 (power)  各組需要的個案數可由下列公式計算

10. 10  舉例來說，如果假設 p1=90% 、 p2=95% 、 α= 0.05 、 β= 0.1

11. 11 quantitative measurements ，如血壓值等   需要四項資訊  μ1 – 對照組的平均值、及 σ(SD)  δ(μ2 -μ1) – 預期治療組比上對照組的差異 α 1-β  各組需要的個案數可由下列公式計算

12. 12

13. 13 Sample Size Determination Information Required Study objectives Test for equivalence Test for non-inferiority Test for superiority (clinically/statistically) Study design Parallel or crossover Group sequential design Other designs Primary study endpoint(s) Continuous or discrete Multiple study endpoints

14. 14 Sample Size Determination Information Required Clinically meaningful difference Clinically important difference Non-inferiority/superiority margin Equivalence/similarity limit Significance level 1% or 5% Desired power 80% or 90% Other information, e.g., Stratification? 1:1 ratio or 2:1 ratio? Log-transformation?

15. 15 Major principles in clinical trials Minimizing bias Maximizing precision  Identify possible sources of bias.  Are the trial results robust relative to these bias?

16. 16 Randomization － In clinical studies, bias is controlled by blinding and randomization Simple Randomization Permuted block randomization Stratification － to achieve balance in two arms ； by hospital,prognostic factor;no more than 3 factors Dynamic randomization Cluster randomization

17. 17 Simple Randomization Tossing a coin Using a table of random numbers  ＊ For two treatments assign:  A for digits 0-4, B for 5-9  0 5 2 7 8 4 3 7 4 1 6 8 3 8 5 1 5 6 9 6 etc.  A B A B B A A B A A B B A B B A B B B B etc.

18. 18 Permuted Blocks Randomization a. With a 1-digit random number table For two treatments, blocks of two patients assign AB for digits 0-4 BA for digits 5-9 0 5 2 7 8 4 3 7 etc. AB BA AB BA BA AB AB BA etc.

19. 19 For three treatments, blocks of three patients assign ABC for digit 1 ACB for digit 2 BAC for digit 3 BCA for digit 4 CAB for digit 5 CBA for digit 6 and ignore 0 and 7-9 0 5 2 7 8 4 3 7 etc. - CAB ACB - - BCA BAC - etc.

20. 20 For two treatments, blocks of four patients assign AABB for digit 1 ABAB for digit 2 ABBA for digit 3 BBAA for digit 4 BABA for digit 5 BAAB for digit 6 and ignore 0 and 7-9 0 5 2 7 8 4 3 7 etc. - BABA ABAB - - BBAA ABBA - etc.

21. 21 b. With a 2-digit random number table: For two treatments, blocks of 20 patients assign A for 0-9 and B for 10-19: 11 19 15 5 9 0 6 13 7 2 16 1 12 18 4 17 10 8 3 14 B B B AAAA B A A B A B B A B B A A B Block 1 14 12 0 1 19 8 7 17 11 18 2 15 5 9 4 16 10 6 13 3 B B AA B AA B B B A B AAA B B A B A Block 2, etc. It is advisable not to inform clinicians that blocking is being used and especially they should not know the block size.

22. 22

23. 23 If there are known factors that could affect the outcome (age, sex, baseline risk) Only one or few factors used for stratification Stratification

24. 24 SuccessRegimen ARegimen B OverallYes289 (83%)273 (78%) No61 (17%)77 (22%) Group 1 (Male) Yes234 (83%)81 (93%) No36 (17%)6 (7%) Group 2 (Female) Yes55 (69%)192 (73%) No25 (31%)71 (27%)

25. 25 假設以 Clinical trial 研究甲病病人放置導尿管 和尿道感染的關係 有 無 總和 實驗組：放置導尿管 60 139 199 控制組：未放置導尿管 40 161 201 總和 100 300 400 放導尿管的相對危險性（ Relative Risk ）： （ 60/199 ） / （ 40/201 ）＝ 1.52 χ 2 ： 5.59 ｐ＝ 0.018 結果發現性別在實驗組與控制組分派不公平，而造成 干擾實驗的公平判定，於是做分層分析

26. 26 分層分析：以 Mantel-Haenszel procedure ， 調整性別對相關危險性所造成的干擾 有 無 總和 實驗組：放置導尿管 35 114 149 控制組：未放置導尿管 3 0 120 150 總和 65 234 299 男性放導尿管的相對危險性（ Relative Risk ）： （ 35/149 ） / （ 30/150 ）＝ 1.17 χ 2 ： 0.53 ｐ＝ 0.465 男性病人

27. 27 有 無 總和 實驗組：放置導尿管 25 25 50 控制組：未放置導尿管 1 0 41 51 總和 35 66 101 女性放導尿管的相對危險性（ Relative Risk ）： （ 25/50 ） / （ 10/51 ）＝ 2.55 χ 2 ： 10.30 ｐ＝ 0.001 女性病人 Mantel-Haenszel procedure: MH 相對危險性 = = 1.51 (35×150/299) + (25×51/101) (30×149/299) + (10×50/101) Mantel-Haenszel χ 2 ： 5.16 ｐ＝ 0.023

28. 28 Random permuted Blocks within Strata

29. 29 Dynamic randomization 又稱為最小差異法 (Minimization method) 針對影響療效因子眾多，受試者人數亦多 而設計的較複雜先進的隨機分派方法。 受試者被分配到各治療組的機率為機動性 而非固定 機率大小視幾個重要影響療效共變數 (covariate) 在各治療組中分佈不平均程度 而定，分佈最不平均將優先調整

30. 30 將重要共變數在各治療組分佈的差異減至最低 若第六十一位受試者為 38 歲女性，本次發 作時間超過六個月，正使用其他抗鬱劑， 則加入何組好 ?  A=16+18+20+15=69  B=15+16+22+14=67

31. 31 Parallel design Recruited samples Treatment A Treatment B Outcome 1 Outcome 2 Randomization Cross-Over design Recruited samples Treatment A Treatment B Outcome 1 Outcome 2 Treatment B Treatment A Randomization

32. 32 Cluster randomization Use a group of individuals, a hospital, or a community as the unit of randomization  Cluster effect  Selection bias  confounding

33. 33 treatment masking  A randomized trial is "Blind" if the participant is not told which arm of the trial he is on ; also called masked  The more effective the blind, the less the bias

34. 34 Blinding 分四個層次

35. 35 Blinding — Open label (Open) — Single Blind — Double Blind — Triple blind  To maintain the blind a control must look, smell, taste and feel the same as the comparator of interest, whether the treatment is a placebo or an active control – maybe with double dummy.

36. 36 double dummy Occasions — No matching placebo available — Different frequencies  Example  A and placebo to B  B and placebo to A  A and B

37. 37 In an open-label trial the identity of treatment is known to all. In a single-blind trial the investigator and/or his staff are aware of the treatment but the subjects not, or vice versa.  A double-blind trial is one in which neither the subject nor any of the investigator or sponsor staff who are involved in the treatment or clinical evaluation of the subjects are aware of the treatment received. 

38. 38 Blind Design Study subject Investigatoranalyzer Single Blind Double Blind Triple Blind ○ ○ ○○ ○○

39. 39  2007 年 Lancet Neurology 上， FASTER 研 究（ ISRCTN35624812 ， NCT00161070 ）  是完全捨棄 double blind 的字眼，直接陳述 The trial was blinded (patients, treating physicians, nurses, and study site coordinators). The central pharmacist, who played no role in the care of the  patients, was the only person aware of treatment allocation

40. 40 Control Groups Placebo control Active comparator control Historical control No control (observational study)

41. 41 Type of comparison Superiority trial Equivalence trial Non-inferiority trial

42. 42 Superiority trial  A trial with the primary objective of showing that the response to the investigational product is superior to a comparative agent (active or placebo control  Purpose To show that the test drug is superior to a standard therapy or an active agent

43. 43 Equivalence trial  Purpose To show that the test drug can reach the same therapeutic effect as that of a standard therapy (or an active agent) or they are therapeutically equivalent

44. 44 Non-inferiority trial  “A trial with the primary objective of showing that the response to the investigational product is not clinically inferior to a comparative agent (active or placebo control).”

45. 45  Purpose To show that the test drug is no worse than a standard therapy or an active agent  Situations where it is applicable The test drug is less toxic The test drug is easier to administer The test drug is less expensive

46. 46 Protocol deviations Ineligible Ineligible patients Non-compliance Patient withdrawals Incomplete evaluation

47. 47 Analysis strategy Intention-to-treat analysis All randomized subjects May exclude those who never received treatment and/or those with no follow-up data per-protocol (PP) Completed major amount of protocol follow-up measurements available No major protocol violations

48. 48 Intention to treat randomization clofibrate n=1065 placebo n=2095 compliant n=708 compliant n=1813 Non-compliant n=882 Non-compliant n=357 Treatment acceptedTreatment allocatedPer cent mortality 15.0 24.6 15.1 28.2 All 18.2 All 19.4

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51. 51 Missing Data The strategies for dealing with missing data  Analysis of complete cases only  Analysis of all available data without data replacement  Last observation carried forward (LOCF) and other ad hoc methods for replacing missing values  Multiple imputations for replacement

52. 52 Response data Qualitative response – yes/no, success/fail, …  Quantitative response – mmHg, HbA1c %, …  Time to relapse – time to death, time to recurrent MI, …

53. 避免與控制試驗偏差與不公平的方法 方法 說明 設計 分析 限制收案條件 ＋ (restriction) 隨機分派病人 ＋ (randomization) 盲目 ＋ (blind) 分層分析 ＋ (stratification analysis) 多變項調整 ＋ (Multivariate adjustment) 研究階段 將納入研究的病人限制在某些特徵範圍內， 如性別會影響結果，則只收男病人 以隨機分派方法將病人分派到不同組，而 且讓每個病人都有相同機會納入不同組 利用盲目的方法來分派、處理與評估病人， 而病人也不知自己屬哪一組 將病人依干擾因子的狀況分成幾組後，分 別計算出各組的統計值（如 χ 2 與 RR ）， 再用 Mantel-Haenszel procedure 來合計結 果 使用數學模型技術調整干擾因子（較少用） （如 Cox Regression ）

54. 54 Endpoints Scientific: well accepted, clear and operable outcome measurements Survival>QOL>Symptomatic>Laboratory Primary and secondary endpoints Surrogate endpoints Safety and efficacy

55. 55 Stages Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions

56. 56 PHASE I TRIALS researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects Initial studies to determine the metabolism and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness; may include healthy participants and/or patients.

57. 57 PHASE II TRIALS the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks

58. 58 PHASE III TRIALS 1/2 the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely

59. 59 PHASE III TRIALS 2/2 Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling

60. 60 PHASE IV TRIALS Post-marketing studies to delineate additional information including the drug's risks, benefits, and optimal use.

61. 61

62. 62 Bridging study A supplementary study conducted in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen to allow extrapolation of the foreign clinical data to the population of the new region

63. 63 Application Process

64. 64 Clinical Trial Protocol 1 General Information 2 Background Information 3 Trial Objectives and Purpose 4 Trial Design 5 Selection and Withdrawal of Subjects 6 Treatment of Subjects 7 Assessment of Efficacy 8 Assessment of Safety

65. 65 Clinical Trial Protocol (cont.)  9 Statistics  10 Direct Access to Source Data/Documents  11 Quality Control and Quality Assurance  12 Ethics  13 Data Handling and Recordkeeping  14 Financing and Insurance  15 Publication Policy  16 Supplements

66. 66 Types of clinical trial Parallel groups design Crossover design Higher order design for two treatment Three or more treatments

67. 67 Parallel group trial (two arms) subjects Group 1 treatment 1 Group 2 Treatment 2 Randomly assigned to treatments, blindness endpoint

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69. 69

70. 70 Parallel group trial (multi-arms) subjects Group 1 treatment 1 Group 2 Treatment 2 Randomly assigned to treatments, blindness Group 3 Treatment 3 Etc… Randomly assigned to treatments, blindness endpoint

71. 71 Phase III RTC

72. 72 Factorial parallel design

73. 73 Parallel group trial Advantage No washout period (appropriate for long - acting drug) Possible unequal numbers of subjects per group statistical analysis is still possible when subjects are missing during the experiment

74. 74 Placebo effect The “placebo effect” is well documented Could be No treatment + placebo Standard care + placebo Matched placebos are necessary so patients and investigators cannot decode the treatment assignment There must be no differences between placebo and treatment in color, taste, smelling and appearance of the drug. Placebo must not have known effect on the outcome Some treatment could not be designed with placebo

75. 75 Placebo effect E.g. Vitamin C trial for common cold Placebo was used, but was distinguishable Many on placebo dropped out of study – not blinded Those who knew they were on vitamin C reported fewer cold symptoms and duration than those on vitamin who didn't know

76. 76 2x2 Crossover design subjects Treatment A Treatment B washout Treatment B Treatment A Period 1 Period 2 Randomization the series of treatments

77. 77 Example of crossover design Whelton et. al., “Effects of celecoxib and naproxen on renal function” Arch Intern Med (2000) 160:1465-1470 Experiment to compare effect of celecoxib vs. naproxen on renal function in elderly cohort 29 healthy elderly subjects took either celecoxib or naproxen for 10 days, had 7-day washout, then took other med for 10 days Randomized treatment order, single-blind design Phase III RTC

78. 78 2x2 (AB/BA) Crossover design 29 subjects Randomization the series of treatments Celecoxib naproxen Washout 7 days Period 1 10days Period 2 10 days naproxen celecoxib

79. 79 Crossover period Two period crossover. 1/2 receive A first and 1/2 B first Effect of order of interventions excluded. Multiple Period crossover. Order and sequence effects eliminated by design. Insertion of “Washout Period”.

80. 80 Crossover design Period 1 & 2 must be long enough to take effect Washout period must be long enough to avoid carry-over effect Participant = own control Assumptions No carry over effects. Completion of other experimental periods: no intervening events. Randomize: order of treatment for each patient (e.g. AB vs. BA)

81. 81 Crossover design Advantages Reduce variabilityReduce Sample Size Detect difference in response in individual patient Disadvantages Order of treatment should not matter carry over effect test for interaction Cannot apply with chronic disease (cannot go for long term cure) Cannot apply with stable disease

82. 82 Carry-over effect Carry-over is the persistence of a treatment applied in one period in a subsequent period of treatment observe the simultaneous effects of two or more treatments on given patients ignoring may lead us to make errors in interpretation

83. 83 Higher order design for two treatment 2 tx

84. 84 Higher order design for two treatment Balaam design Aims to obtain the within-subject estimator of the direct-by-period interaction Two treatments A B A B B A Crossover designBalaam design A B B A A B

85. 85 This study seek to determine whether treatment with montelikast is more effective than placebo in reducing nasal congestion. 31 subjects were enrolled in a double blinded, placebo controlled study using Balaam’s design.

86. 86 Balaam’s design 31 subjects Treatment(15) Placebo(16) washout Randomization placebo Treatment(8) placebo washout Treatment (7) Placebo(7) Placebo(9) Randomization O1 O3O2O4

87. 87 Design for three or more treatment Three formulation designs in six sequences are common. Subjects randomised in equal numbers to six possible sequences. For example, 18 subjects, three on each of the sequences ABC, ACB, BAC, BCA, CAB, CBA.

88. 88 Design for three or more treatment Latin square A B C B C A C A B A C B B A C C B A Each group has the same number of subj Each tx occurs only once with each subj Each tx occurs same number in each period Each tx could not followed by the same tx Williams Design

89. 89 Special Types of Clinical Trials

90. 90 Single-patient clinical trial

91. 91 Purposes of single-patient clinical trial  Single-patient clinical trials may be conducted to treat a special patient as well as to obtain information on a specific medicine.

92. 92 Reasons for a single-patient clinical trial It is uncertain ….. the patient’s current treatment is effective or is causing an adverse a new treatment would be beneficial for a specific patient the patient’s current dosage is correct the patient reacts the same to a generic as to a brand name medicine

93. 93 Type of single-patient clinical trial Two-treatment designs Two periods : (AB or BA design) Three periods : original control (ABA) or experimental treatment( BAB) Multiple pairs of periods : Each pair of treatments (AB) is presented two or more times in either an alternating (ABABAB) or randomized order (BAABABBA) Multiple periods : randomized pattern Multiple controls : control baseline periods

94. 94 Type of single-patient clinical trial (continue) Three or more treatment designs Three or more different treatments test medicine, placebo, and active control medicine Two or more doses test medicine, plus placebo and/or active control Numerous variation of these patterns

95. 95 Circumstances for single- patient clinical trial design The disease must be chronic The disease severity must be stable over the clinical trials duration The treatment’s effect should be manifested within a reasonable short time The effect should be rapidly reversible once each treatment is stopped

96. 96 Circumstances for single-patient clinical trial design (continue) The efficacy parameters chosen should be the most appropriate ones available Both patient and investigator should be blind to treatment A period effect should not be present, but if expected then treatments may be randomly allocated Patients should return to preexisting baselines between treatment legs

97. 97 Appropriate situations for single-patient clinical trial design Evaluate rate diseases when multicenter trials are impractical or inappropriate Determine whether a particular pt’s response treatment is a placebo response When a small percent of pt’s response to a specific treatment (relevant to determine) Evaluate a specific pt’s in detail to choose the best medicine therapy Evaluate whether adverse reaction in a specific patient is related to specific medicine

98. 98 Multicenter Trial

99. 99 Definition of multicenter trials Utilizes one protocol at more than one site, although the protocol is usually implemented and conducted in a somewhat different manner and style at each site.

100. 100 Golden rules Protocol designs be kept relatively simple and be the same at all centers That careful planning of the initiation, conduct and analysis of the trial be mandatory and that statisticians be involved in this process That communication problems be minimized through all possible techniques

101. 101 Advantages More rapid patient recruitment More complex protocols may be able to be conducted Less opportunity for one’s person’s biases to influence the design Greater likelihood for a heterogeneous patient population

102. 102 Disadvantages Administrative arrangements and management details are more complex Costs are usually greater for the clinical trial Statistical data analyses would be stronger from a single site Some Ethics Committees/IRBs may insist on changes to the protocol Individual investigators in large multicenter trials receive little recognition through the publications of results

103. 103 Coordinating and other resource centers in multicenter trials

104. 104 Resource centers  Data centers  Data Coordinating centers  Treatment Coordinating centers  Coordinating centers  Project offices  Central Laboratories  Reading centers  Quality control centers  Procurement and distribution centers

105. 105 Coordinating centers  General activities  Location  Staffing  Equipment  Relative cost  Internal allocation of funds

106. 106 Coordinating center activities by stage of trial  Initial design stage  Protocol development stage  Patient recruitment stage  Treatment and follow-up stage  Patient close-out stage  Termination stage  Post-trial follow-up stage （ optional ）

107. 107 Management of multiple clinical trails Management styles Spectra Styles at individual companies Styles of individuals

108. 108 Management of multiple clinical trails (continue) Management staff Investigator Coinvestigators and assistant investigators Members of IRBs Professional consultants Regulatory agency reviewers Trail coordinators Trail monitors Monitor committees, data review committees, and other staff

109. 109 Management of multiple clinical trails (continue) Management staff Project champions Project managers Statistical reviewers Executives at the sponsoring institution Contract organization staff and institution Data analysis committees Independent auditors of diagnosis, laboratory data, trail conduct Independent review committee of trail result and interpretation

110. 110 Management of multiple clinical trails (continue) Staff motivation and morale Selected project management areas in which great efficiencies Meeting conduct well-organized and targeted meeting Documents eliminate unnecessary paperwork Travel replace trips with telephone calls plus letters whenever possible Allocation of time

111. 111 National v.s. Multinational Clinical Trial

112. 112 Definition of multinational trials Single trial conducted in two or more countries which data combined Gaining more rapid patient enrollment Expediting the development of a new medicine Conducting a experience and being able to compare patients of different nationalities in the same trial

113. 113 Major reasons for conducting a multination trial Faining more rapid patient enrollment Expediting the development of a new medicine Conducting a trial that otherwise might be impossible Gaining experience and being able to compare patients of different nationalities in the same trial

114. 114 Multination clinical trials are usually accepted Patients with a rare disease are to be studies Extensive resources can be devoted to the clinical trial A simple designed and brief data collection form and straightforward

115. 115 Differences in culture Language Ethics Diet Customs religion

116. 116 Specific pointers in multinational clinical trial 1. Ensure that input is received from at least one physician consultant in each country participating in the clinical trial both prior to and during the protocol’s preparation 2. Ensure that as many physicians as practical review the protocol prior to submitting it for ethics committee review 3. Only includes sites in countries where clinical practice and culture are generally similar

117. 117 4. Ensure that an appropriate audit of the data may be made by the sponsor or regulatory authority 5. Consider a limited feasibility trial both to show that the larger trial is feasible and to identify potential problem areas that will need to be addressed 6. Styles of interacting with investigator vary among countries 7. Countries that differ markedly in medical practice, culture, regulations, or practical aspects should not be part of a multinational clinical trial

118. 118 Continuation and Compassionate Plea Trial

119. 119 Continuation trials An important consideration in investigational medicine trials of specified duration is whether patients who have benefited will be allowed to receive the medicine after completion of the trial. If they will be, a continuation protocol is generally provided. Patient :Receive medicine under this protocol for fixed, variable, or unspecified The existence of a continuation protocol is often identified in the initial “feeder” protocol

120. 120 Pros of conducting continuation trials Such trials help patient recruitment in earlier clinical trials They generate long-term data They help with ethics committee/IRB approval of concurrently run clinical trial of short duration After treatment in the continuation clinical trial stops

121. 121 Cons of conducting continuation trials If the medicine supply is limited the continuation trial may strain available, or even future, stock Toxicology studies may be inadequate to justify a long-term clinical trial Resources that could be reserved for other projects must be committed to the project

122. 122 Cons of conducting continuation trials Regulatory approval of the continuation trial may be a problem The precise dose and dosing schedule may be unknown Long-term data may be generated on a medicine that will never be developed

123. 123 Planning continuation protocols Spectrum 1 : number The number of clinical trials per continuation protocol may vary from 1:1 to all:1 Spectrum 2 : complexity The complexity of the continuation protocol designed may vary along the spectrum Spectrum 3 : artificiality

124. 124  Three spectra along which continuation protocols may be planned Separate continuation Protocol for each Short-term clinical trial One continuation Protocol for all Clinical trials Number of protocols A Few visit Few tests Few data collection Many visit Many tests Many data collection Complexity of protocol B Clinical trial design and Environment similar to Medical practice Highly artificial Clinical trial design High artificial environment Artificiality of protocols C

125. 125 Issues of continuation protocols Design specific versus general protocols Essential questions to address Semantic issues and combining data Potential dilemmas

126. 126 Compassionate Plea Trial Numerous terms are used for describing investigational medicine protocol that humanitarian in their purpose and intentionally have loose, or even virtually no entry (i.e., inclusion ) criteria restrictions. The term for such trials inclusion compassionate use, compassionate care humanitarian, treatment- IND, dual track, group C mechanism (i.e., for some trials of the national cancer institute), and parallel-track protocols.

127. 127 Justification for Compassionate Plea Trial The most basic reason is to receive medicine benefit This is justified on the basis of personal freedom of patients to have access to available treatment even if those treatment are experimental. Non- approved medicines are often part of reasonable medicine care, because a great deal is usually known about the medicine prior to its approval.

128. 128 Consideration in determining the value of a compassionate plea program Assess the appropriateness of s specific medicine for a compassion plea program Assess the impact of a compassionate plea program on the medicine’s development program Assess the impact of a compassionate plea program on the sponsor’s resources

129. 129 Pharmacoeconomic Trials

130. 130 Reasons for conducting economic analyses Influence policies of third-party payers Influence formulary committees at hospitals, HMOs, government agencies, or other groups Influence prescription behavior of physicians Influence purchasing behavior of customers

131. 131 Evaluation and objective Cost-effectiveness analysis Cost-utility analysis Cost-benefit analysis Cost-minimization analysis Cost-illness analysis

132. 132 Cost-benefit analysis Difficulties in measurements Diagnosis-related groups (DRG) Allocation of national resources Cost-benefit assessment by and for individual patients

133. 133 Validation of Clinical Tests and Measures

134. 134 Definition of Validation To be acceptable to the population meet five criteria To be easily complete To be consistent To be reproducible when administered on two separate occasion To be of value or use when complete

135. 135 Five characteristics Acceptability Feasibility Reproducibility Consistency Applicability

136. 136 Process of validation Evaluate tests for reliability (i.e. reproducibility) by the same patient Evaluate tests for reliability by the same rater and also for different raters Compare data with the gold standard Compare data with other markers of the disease, especially when no gold standard exists

137. 137 Compare data from the scale being validated with data obtained using other validated scales Establish the rate of false positives and false negatives Convene a panel of experts to discuss the topic Have a professional society publish the results at their evaluation

138. 138 Protocol for conducting a validation procedure or test Is the process, equipment, or test measuring producing what it purport to measure or produce Is it reliable both within patients and between patients? Is it accurate? Is it as precise as claimed?

139. 139 Clinical Trails in Elderly Patients

140. 140 Special patient populations Special populations include: Infants pregnant women lactating women black elderly patients patients decrease renal or liver function

141. 141 Special considerations in studies in elderly patients 1. Use reminder cards, mailings, and telephone calls prior to appoints 2. Arrange for transportation to and from the clinical trial sits 3. Conduct periodic reviews to ensure patient understanding and requirement

142. 142 Special considerations in studies in elderly patients 4. Conduct periodic checks on compliance 5. Include a sufficient number and frequency of tests of vital sign & other safety parameters 6. Avoid rigorous demands that might unduly strain some patients 7. Involve family members: to observe the patient for relevant signs and systems 8. Consider previous data : elderly patients are higher risk of adverse reactions than a younger adult population

143. 143 A greater percentage Elderly Patients Clinical Trails 1. Pathological changes : such as decreased renal and liver function 2. Decrease number of certain receptors 3. Altered homeostatic responses

144. 144 Many of problems associated with elderly patients 1. Multiple medicines 2. Multiple diseases 3. Poor diet and eating habits 4. Poor socialization and loneliness 5. Poor hygiene and sanitation 6. General physical debilitation

145. 145 Combination Medicine Trials

146. 146 Combination Medicine Trials Consist of two or more separate active ingredients that are combined to improve the efficacy, safty, compliance, or another characteristic of the separate ingredients or medicines

147. 147 FDA Regulatory Policy  The Food and Drug Administration (FDA) combination medicine policy states that each active ingredient in the combination must contribute to the overall safety and/or efficacy of the combination

148. 148 Potential advantages Obtain an enhanced clinical effect by two (or more) medicines acting via different mechanism Improve the therapeutic ratio by utilizing a smaller dose of one or more medicine avoids toxicity Multiple clinical effects are achieved in a disease or syndrome in which these activities are desired

149. 149 Potential advantages Decrease the magnitude of speak-to- trough differences in physiological responses Decrease the potential for medicine abuse Increase the duration of effective treatment by combining an immediate- release form of one medicine and a sustained release form of another Reduce the cost of medicine treatment

150. 150 Selected types of combination medicines Both ingredients act on the same symptom, disease, or problem Each ingredient act on the same symptom, disease, or problems Other type of combinations

151. 151 Criteria for development of combination medicines Complete pharmaceutical Dosage of only one component in the combination should be critical The combination provides an effect that is not possible to achieve from either medicine alone A population exits that can use the combination

152. 152 Marketing-Oriented Clinical Studies

153. 153 Marketing-Oriented Clinical Studies A marketing group that intends to sponsor clinical studies to evaluate a new medicine, device, therapy Should carefully review its goals before designing or providing input

154. 154 Decisions about the study The medical special and reputation of investigators The type of safety, efficacy, economic, quality of life, or other endpoints to focus on The comparative medicines to include The ability of investigators to initiate and complete the study within the desired time frame The reputation of the facility

155. 155 Number of Patients Large numbers of patients furnishing anecdotal information provide little value Focused on clinical significance of data, as well as on statistical significance

156. 156 Factors influencing the choice of comparison medicine The market leader The prototype The expected future market leader The major medicine in the same chemical class The major medicine in the same therapeutic class A similar type of combainition medicine Medicine on the market in a selected country

157. 157 Factors of Choosing investigators for marketing studies and trial Who are the best speakers Who are the most influential in professional societies Who are the most influential in political circles Who are willing to travel and speck about their clinical experiences with the new medicine

158. 158 Quality of Life Trials

159. 159 Definition The quality of life can only be described in individual terms Depends on present lifestyle, past experiences, hopes for the future, dreams and ambition

160. 160 Level of quality of life Overall assessment of well-being Broad Domains (e.g., Physical, Psychological, Economic, Social Components of Each Domain

161. 161 Perspectives Academicians Regulators Pharmaceutical companies Fomulary committees Physicians Ethicists

162. 162 Classification of QOF test Indexes Profiles Battery

163. 163 Indexes Evaluate multiple domains Test multiple components of each domain Measure the Well-Being Scale quality of life

164. 164 Profiles Yields a number of separate scores Sickness Impact Profile Test is an example of a profile

165. 165 Battery Multiple tests and measure several domains or several components of a single domain Each test is interpreted independently

166. 166 Methodological Principles Validation of Tests Frequency of Test Administration Patient Stratification Maintaining a Blind Statistical Analyses

167. 167 Validation of Tests The validity of a test or scale should be documented It is unnecessary to validate the general question posed to assess the overall top level

168. 168 Sensitivity of Tests The demonstration that a test or scale is sensitive to a patient’s change The fact that a test or scale validity measures one or more domains does not mean that the test is able to measure the change brought about by medicine

169. 169 Frequency of Test Administration Baseline assessments should be obtained prior to initiating therapy Obtained both prior to and subsequent to washout of any medicines the patient is using at the time of screening

170. 170 Patient Stratification The ability to stratify patients based on their baseline quality of life scores Based on results from a single test or according to a complex weighting of multiple test results that are combined

171. 171 Maintaining a Blind The staff members rating a patient as well as the patient should be blind to the treatment group’s identity and to responses of therapy It is important to avoid feedback from the investigator or staff in a controlled trial that systematically

172. 172 Statistical Analyses To analyze scales should be determined Close collaboration with a qualified statistician is essential to ensure that data are analyzed correctly

173. 173 Model of how clinical aspects of efficacy

174. 174 Selected psychosocial conditions for clinical trials(1) Illicit drug abuse Alcohol abuse Physical aggression Suicide attempts Development problems Memory impairment

175. 175 Selected psychosocial conditions for clinical trials(2) Threatening behavior expressed physically Number of social contacts Quality of social interactions Risk-seeking versus risk-averse behavior

176. 176 Seven dimensions fot choosing the most appropriate tests Dimension 1-overall assessment of quality of life Dimension 2-domains to be evaluated Dimension 3-perspective to be used Dimension 4-type of patient being evaluated Dimension 5-Theeraputic area and specific disease Dimension 6-Degree of validation of the individual tests Dimension 7-practical issues

177. 177 Ideal quality of life test Be rapid to complete Be reproducible Be valid either in a single patient population or across a large number if diseases Be widely accepter Not require excessive training of staff to administer Be easy to interpret Yield objective results

178. 178 Thank you for your attention