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Introduction to clinical research
-Publish or Perish-
Introduction to clinical research
-Publish or Perish-
林隆堯Long-Yau Lin MD, MPH, ScD
Chung-Shan Medical University
林隆堯Long-Yau Lin MD, MPH, ScD
Chung-Shan Medical University
Considerations of study design
Considerations of study design
1. The question to be answered or hypothesis to be answered
2. Subjects 3. Research models and methods 4. Methods of data acquisition 5. Type of data analysis 6. Data reporting
1. The question to be answered or hypothesis to be answered
2. Subjects 3. Research models and methods 4. Methods of data acquisition 5. Type of data analysis 6. Data reporting
Steps in Clinical ResearchSteps in Clinical Research
1. Develop a question engendered and/or motivated by experience.
2. State the question as a testable hypothesis ( if you cannot do it, you still do not have a good question).
3. Search the literature to see if it has been answered totally or partially
4. Revise ( perhaps) the question and hypothesis based on your reading of the literature.
1. Develop a question engendered and/or motivated by experience.
2. State the question as a testable hypothesis ( if you cannot do it, you still do not have a good question).
3. Search the literature to see if it has been answered totally or partially
4. Revise ( perhaps) the question and hypothesis based on your reading of the literature.
Step in Clinical Research-continued
Step in Clinical Research-continued
5. Determine what tools, materials, personnel, time, and so forth are necessary to obtain and analyzed the data based on your reading of the literature.
6. Given the preceding requirements, is the study feasible?
7. Revise ( perhaps) the question and hypothesis and/or alter the variables according to your resources and time.
8. Choose the appropriate subjects ( including controls, if appropriate) from whom data on the variables can be obtained.
5. Determine what tools, materials, personnel, time, and so forth are necessary to obtain and analyzed the data based on your reading of the literature.
6. Given the preceding requirements, is the study feasible?
7. Revise ( perhaps) the question and hypothesis and/or alter the variables according to your resources and time.
8. Choose the appropriate subjects ( including controls, if appropriate) from whom data on the variables can be obtained.
Steps in Clinical Research-continued
Steps in Clinical Research-continued
9. Revised ( perhaps) the question, hypothesis,and variables to match the subjects to whom you have access.
10. If you are still interested ( and this is what separates the true clinical researchers from the dabblers), devise your methods to collect the data from subjects.
11. Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research.
12. Only now should you collect the data. Unfortunately, many novices begin this step too soon thereby compromising the study’s worth.
9. Revised ( perhaps) the question, hypothesis,and variables to match the subjects to whom you have access.
10. If you are still interested ( and this is what separates the true clinical researchers from the dabblers), devise your methods to collect the data from subjects.
11. Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research.
12. Only now should you collect the data. Unfortunately, many novices begin this step too soon thereby compromising the study’s worth.
Steps in Clinical Research-continued
Steps in Clinical Research-continued
13. Analyze the data, with the help of a biostatistician.
14. Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers).
15. After it is accepted ( and it might take several attempts), REJOICE, and take your spouse out to dinner. Better yet, let him or her take you out to dinner.
13. Analyze the data, with the help of a biostatistician.
14. Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers).
15. After it is accepted ( and it might take several attempts), REJOICE, and take your spouse out to dinner. Better yet, let him or her take you out to dinner.
The question to be answered or hypothesis to
be answered
The question to be answered or hypothesis to
be answered
The questionThe question
1. The importance of the question How big a burden of the illness? How important is the answer to cost-
containment in providing health services? Is the answer to this question a key component
of a larger question? 2. What is the status of the area?
How much exploring is still needed Is the researcher still fishing or stalking the
game? 3. How well supported is the hypothesis?
1. The importance of the question How big a burden of the illness? How important is the answer to cost-
containment in providing health services? Is the answer to this question a key component
of a larger question? 2. What is the status of the area?
How much exploring is still needed Is the researcher still fishing or stalking the
game? 3. How well supported is the hypothesis?
The Question-continuedThe Question-continued 4. What are the characteristics of the
phenomena involved in the question? The incidence or prevalence of exposure or risk The time span over which the phenomena evolve The incidence or prevalence of the outcome?
5. Is it ethical to conduct an experimental study to answer the question? Will some of the subjects be exposed to undue risk?
6. Is the research plan practical? 7. Does the investigator have the necessary
time and resources to implement? 8. Will the answer be unambiguous?
4. What are the characteristics of the phenomena involved in the question? The incidence or prevalence of exposure or risk The time span over which the phenomena evolve The incidence or prevalence of the outcome?
5. Is it ethical to conduct an experimental study to answer the question? Will some of the subjects be exposed to undue risk?
6. Is the research plan practical? 7. Does the investigator have the necessary
time and resources to implement? 8. Will the answer be unambiguous?
Factors that might possibly help to develop a
reasonable research question
Factors that might possibly help to develop a
reasonable research question 1. Literature review
2. Time 3. Cost of materials, tests, assistants,etc. 4. Sufficient number and types of subjects 5. Ability to gather and store data 6. Critical mass of colleagues interested in
clinical research 7. Ethical issues.
1. Literature review 2. Time 3. Cost of materials, tests, assistants,etc. 4. Sufficient number and types of subjects 5. Ability to gather and store data 6. Critical mass of colleagues interested in
clinical research 7. Ethical issues.
General suggestions for generations for generating
a reasonable question
General suggestions for generations for generating
a reasonable question 1. Generate on idea 2. Identify a simple question 3. Modify the question 4. Form a hypothesis
1. Generate on idea 2. Identify a simple question 3. Modify the question 4. Form a hypothesis
Literature SearchLiterature Search
As in your mind, so in your sort of search; you’ll find what you desire -Robert Browning
As in your mind, so in your sort of search; you’ll find what you desire -Robert Browning
MedlineMedline The United States National Library of Medicine
has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries. This is ( Medical Literature Analysis and Retrieval System or MEDLARS). One of these data bases is called MEDLINE. It is a bibliographic file of articles, and it is the most comprehensive , economical and widely used system.
Citations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches.
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries. This is ( Medical Literature Analysis and Retrieval System or MEDLARS). One of these data bases is called MEDLINE. It is a bibliographic file of articles, and it is the most comprehensive , economical and widely used system.
Citations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches.
PubMed ( www.pubmed.gov)
PubMed ( www.pubmed.gov) PubMed, a service of the National Library of Medicine, provides access to
over 11 million citations from MEDLINE (the NLM's premier bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the health care system, and preclinical sciences) and additional life sciences journals. PubMed includes links to many sites providing full text articles and other related sources.
PubMed provides access to bibliographic information that includes MEDLINE, OLDMEDLINE, as well as:
ｷｷ The out-of-scope citations (e.g., articles on plate tectonics or astrophysics) from certain MEDLINE journals, primarily general science and chemistry journals, for which the life sciences articles are indexed for MEDLINE.
ｷｷ Citations that precede the date that a journal was selected for MEDLINE indexing.
ｷｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM.
Note: 1. PubMed provides access to citations from Medline and HealthStar and other additional NLM databases. 2. Coverage extends back to the early 1950’s and continues to the present with new data added weekly.
PubMed, a service of the National Library of Medicine, provides access to over 11 million citations from MEDLINE (the NLM's premier bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the health care system, and preclinical sciences) and additional life sciences journals. PubMed includes links to many sites providing full text articles and other related sources.
PubMed provides access to bibliographic information that includes MEDLINE, OLDMEDLINE, as well as:
ｷｷ The out-of-scope citations (e.g., articles on plate tectonics or astrophysics) from certain MEDLINE journals, primarily general science and chemistry journals, for which the life sciences articles are indexed for MEDLINE.
ｷｷ Citations that precede the date that a journal was selected for MEDLINE indexing.
ｷｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM.
Note: 1. PubMed provides access to citations from Medline and HealthStar and other additional NLM databases. 2. Coverage extends back to the early 1950’s and continues to the present with new data added weekly.
Cochrane data basesCochrane data bases The Cochrane Collaboration is an international non-profit and
independent organization, dedicated to making up-to-date, accurate information about the effects of healthcare readily available worldwide. It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist, Archie Cochrane.
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library.
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups, with editorial teams overseeing the preparation and maintenance of the reviews, as well as application of the rigorous quality standards for which Cochrane Reviews have become known.
The activities of the Collaboration are directed by an elected Steering Group and are supported by staff in Cochrane Entities (Centres, Review Groups, Methods Groups, Fields/Networks) around the world.
The Cochrane Collaboration is an international non-profit and independent organization, dedicated to making up-to-date, accurate information about the effects of healthcare readily available worldwide. It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist, Archie Cochrane.
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library.
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups, with editorial teams overseeing the preparation and maintenance of the reviews, as well as application of the rigorous quality standards for which Cochrane Reviews have become known.
The activities of the Collaboration are directed by an elected Steering Group and are supported by staff in Cochrane Entities (Centres, Review Groups, Methods Groups, Fields/Networks) around the world.
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections 1. Probability sampling
Simple random sampling Systemic sampling Stratified random sampling Cluster sampling
2. Non-probability sampling Convenience sampling Quota sampling Purposive sampling Haphazard sampling
3. Combination of probability and non-probability samples
1. Probability sampling Simple random sampling Systemic sampling Stratified random sampling Cluster sampling
2. Non-probability sampling Convenience sampling Quota sampling Purposive sampling Haphazard sampling
3. Combination of probability and non-probability samples
Sample sizeSample size The size of the sample for a study should be
large enough to show clinically relevant differences between study groups with statistical significance, and small enough to be practical and feasible.
Using confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty, but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimate.
Attrition of subjects should be considered in advance.
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance, and small enough to be practical and feasible.
Using confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty, but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimate.
Attrition of subjects should be considered in advance.
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficult.
The original estimates of adequate sample size must take into account.
Attrition rates greater than 30 percent make interpretation of the results very difficult.
The original estimates of adequate sample size must take into account.
Methods for assignment of participants to each groupMethods for assignment of participants to each group Case control group: A proper comparison
requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the intervention.
Random allocation; the groups are same with respect to 1. The dependent variable before the
independent variable was introduced 2.Variables other than those considered to be
independent and dependent through the life of study
Case control group: A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the intervention.
Random allocation; the groups are same with respect to 1. The dependent variable before the
independent variable was introduced 2.Variables other than those considered to be
independent and dependent through the life of study
Random allocationRandom allocation Random allocation allows us to
assume, within calculable limits of probability, that the groups are the same with respect to1. The dependent variable before the independent variable was introduced.
2. Variables other than those considered to be independent and dependent throughout the life of study.
Random allocation allows us to assume, within calculable limits of probability, that the groups are the same with respect to1. The dependent variable before the independent variable was introduced.
2. Variables other than those considered to be independent and dependent throughout the life of study.
MatchingMatching Pair matching: it is a specific match, in which
comparison subject is found for each intervention subject.
Non-paired matching: There is no attempt is made to find specific comparison subjects for each intervention subjects. 1. Frequency matching: The distribution of the
confounding variable in the experimental intervention group is stratified, and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum.
2. Mean matching: Attempts are made to match the sample means for the confounding variable in question.
Pair matching: it is a specific match, in which comparison subject is found for each intervention subject.
Non-paired matching: There is no attempt is made to find specific comparison subjects for each intervention subjects. 1. Frequency matching: The distribution of the
confounding variable in the experimental intervention group is stratified, and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum.
2. Mean matching: Attempts are made to match the sample means for the confounding variable in question.
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1. Strength of causation ( speculation versus assertion)
2. Orientation in time 3. Orientation to the process:
prospective versus retrospective 4. Description versus comparison 5. Observation versus
experimentation
1. Strength of causation ( speculation versus assertion)
2. Orientation in time 3. Orientation to the process:
prospective versus retrospective 4. Description versus comparison 5. Observation versus
experimentation
Requirement of all studiesRequirement of all studies
1. Firmly establishing a study objective or hypothesis 2. Methods of assembling groups of study subjects,
including developing specific case definition and avoiding systemic errors
3. Making valid and reliable observations, consideration of biased surveillance, blinding, and variability among observers
4. Handling incomplete observations, such as individuals who are lost to follow-up, who fail to return questionnaire, or who appear to change their status during the study
5. Selecting appropriate comparison groups, including identifying and controlling for important factors that may impact on the study hypothesis
1. Firmly establishing a study objective or hypothesis 2. Methods of assembling groups of study subjects,
including developing specific case definition and avoiding systemic errors
3. Making valid and reliable observations, consideration of biased surveillance, blinding, and variability among observers
4. Handling incomplete observations, such as individuals who are lost to follow-up, who fail to return questionnaire, or who appear to change their status during the study
5. Selecting appropriate comparison groups, including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation 1. Is there evidence from true experiments in
humans? 2. Is the association strong? 3.Is the association consistent from study to study? 4. Is the temporal relationship correct? 5. Is there a dose-response gradient? 6. Does the association make epidemiologic sense? 7. Does the association make biologic sense? 8. Is the association specific? 9. Is the association analogous to a previously
proven causal association?
1. Is there evidence from true experiments in humans?
2. Is the association strong? 3.Is the association consistent from study to study? 4. Is the temporal relationship correct? 5. Is there a dose-response gradient? 6. Does the association make epidemiologic sense? 7. Does the association make biologic sense? 8. Is the association specific? 9. Is the association analogous to a previously
proven causal association?
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the process Prospective: Concurrent or non-concurrent,
the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcome.
Retrospective: The researcher selects a group of individuals expressly because they already experienced the outcome under study. It is then asked, in retrospect, if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome.
Prospective: Concurrent or non-concurrent, the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcome.
Retrospective: The researcher selects a group of individuals expressly because they already experienced the outcome under study. It is then asked, in retrospect, if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome.
Descriptive versus Comparative StudiesDescriptive versus
Comparative Studies Descriptive: It reveals the reality of
the issue of interest. Comparative: It involves the
hypothesis testing. It is important to emphases that
both kinds of studies can have important scientific value when used to address the appropriate question.
Descriptive: It reveals the reality of the issue of interest.
Comparative: It involves the hypothesis testing.
It is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question.
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention, experimental or otherwise.
Experimental Study :A study in which conditions are under the direct control of the investigator.
Observational study does not involve any intervention, experimental or otherwise.
Experimental Study :A study in which conditions are under the direct control of the investigator.
Cross-sectional StudiesCross-sectional Studies
1. They avoid the difficult task of tracking individuals over long periods of time.
2. Information is generally available from public sources.
3. By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality.
1. They avoid the difficult task of tracking individuals over long periods of time.
2. Information is generally available from public sources.
3. By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality.
Ecology StudyEcology Study
Study based on group environment rather than individual environment.
These studies subject to ecologic fallacy.
Ecologic variables may be used in many study designs, not just those that are cross-sectional. They are frequently found in time series analyses.
Study based on group environment rather than individual environment.
These studies subject to ecologic fallacy.
Ecologic variables may be used in many study designs, not just those that are cross-sectional. They are frequently found in time series analyses.
Observational Study : Case-Control Study
Observational Study : Case-Control Study Potential economy
Good for rare disease Good for multiple risk factors The results can only give approximations of
actual rates with which the outcome occurs Past exposure is sometimes not reliable. The control group should be carefully selected. 5-steps in case-control study: Hypothesis
development, establishment of definitions, case selections, control selection, and exposure determination.
Potential economy Good for rare disease Good for multiple risk factors The results can only give approximations of
actual rates with which the outcome occurs Past exposure is sometimes not reliable. The control group should be carefully selected. 5-steps in case-control study: Hypothesis
development, establishment of definitions, case selections, control selection, and exposure determination.
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)
Why only some medical students present for vaccination against hepatitis B.
Why some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls). In this example both cases and controls have a disease ( which is the reason for their surgery). It is the experience of postoperative complications which identifies the cases.
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)
Why only some medical students present for vaccination against hepatitis B.
Why some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls). In this example both cases and controls have a disease ( which is the reason for their surgery). It is the experience of postoperative complications which identifies the cases.
Observation Study: Cohort StudyObservation Study: Cohort Study Individuals with certain baseline characteristics are
observed from this baseline until a previously defined endpoint is reached.
Four ways: 1. Single heterogeneous group followed from baseline to outcome 2.Two homogenous group followed from
baseline to outcome 3. The purely descriptive cohort study 4. Epidemiologic cohort
Four Steps in cohort study: 1. Assembling the initial cohort2. Devising a scheme for tracking the cohort’s
members.3. Developing objective outcome criteria and an
unbiased method of ascertaining outcome status4. Measurement of other factors ( confounders) that
might influence the outcome.
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reached.
Four ways: 1. Single heterogeneous group followed from baseline to outcome 2.Two homogenous group followed from
baseline to outcome 3. The purely descriptive cohort study 4. Epidemiologic cohort
Four Steps in cohort study: 1. Assembling the initial cohort2. Devising a scheme for tracking the cohort’s
members.3. Developing objective outcome criteria and an
unbiased method of ascertaining outcome status4. Measurement of other factors ( confounders) that
might influence the outcome.
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-up
Detect long-term adverse effects of medical intervention
Investigate continued health care usage Evaluate patient well-being in the longer
term Clarify the natural history of a disease
Determine whether patients need long term follow-up
Detect long-term adverse effects of medical intervention
Investigate continued health care usage Evaluate patient well-being in the longer
term Clarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「 experimental
」 testing hypotheses and not observational studies
並不是一種「正規的標準治療方法」，仍具有不確定的療效與危險性 。
新藥療效的評價，因試驗的動物不同有所差異，毒性反應亦可能有所不同。
Clinical Trials must be 「 experimental
」 testing hypotheses and not observational studies
並不是一種「正規的標準治療方法」，仍具有不確定的療效與危險性 。
新藥療效的評價，因試驗的動物不同有所差異，毒性反應亦可能有所不同。
Experimental Studies ( Clinical Trials)
Experimental Studies ( Clinical Trials) 1. It is a concurrent, prospective comparison of two or
more groups; 2. One or more of the groups is deliberately exposed
to an intervention, usually a medical therapy, while at least one group(the controls) is not exposed or receives a more standard therapy;
3. The study groups are generated from a single, homogeneous pool of subjects. Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group;
1. It is a concurrent, prospective comparison of two or more groups;
2. One or more of the groups is deliberately exposed to an intervention, usually a medical therapy, while at least one group(the controls) is not exposed or receives a more standard therapy;
3. The study groups are generated from a single, homogeneous pool of subjects. Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group;
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4. All study participants (subjects, treating clinicians, and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group. This “blinding” may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure;
4. All study participants (subjects, treating clinicians, and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group. This “blinding” may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure;
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5. Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured. This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed. In general, control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff.
5. Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured. This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed. In general, control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff.
新藥臨床試驗簡介新藥臨床試驗簡介 新藥研發是一成本高、時間長的高科技專業，
從實驗室中，確定新藥分子活性，到病人體內反應 (From Bench to Bed) ，需經過多重的試驗階段，包括臨床前的藥物合成、藥物動力學、藥效、藥理、毒性學評估等，以及最重要的臨床試驗階段，而這即是一般人有些許概念的臨床第一、二、三期試驗。
新藥研發是一成本高、時間長的高科技專業，從實驗室中，確定新藥分子活性，到病人體內反應 (From Bench to Bed) ，需經過多重的試驗階段，包括臨床前的藥物合成、藥物動力學、藥效、藥理、毒性學評估等，以及最重要的臨床試驗階段，而這即是一般人有些許概念的臨床第一、二、三期試驗。
臨床醫療 醫師 病人 對症下藥，因人而
異 信賴 同儕審查
臨床醫療 醫師 病人 對症下藥，因人而
異 信賴 同儕審查
新藥臨床試驗 試驗主持人 受試者 依計劃書 依 GCP
試驗委託者稽核 法規單位查核
新藥臨床試驗 試驗主持人 受試者 依計劃書 依 GCP
試驗委託者稽核 法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類 Phase I ------ Investigation of safety, PK/PD, dose finding. Phase II ----- Preliminary efficacy, dose ranging, small scale. Phase III ---- Efficacy and safety, pivotal, large scale. Phase IV ----- Large scale Post-marketing surveillance.
Phase I ------ Investigation of safety, PK/PD, dose finding. Phase II ----- Preliminary efficacy, dose ranging, small scale. Phase III ---- Efficacy and safety, pivotal, large scale. Phase IV ----- Large scale Post-marketing surveillance.
No Drug Approval Without:
** Patient Benefit: - feeling better and/or
- living longer** Evidence-based efficacy and safety
療效的介定療效的介定 Primary efficacy endpoints 臨床療效指標 vs 替代性指標 ---二者具相關性，且有因果關係
Primary efficacy endpoints 臨床療效指標 vs 替代性指標 ---二者具相關性，且有因果關係
什麼是 Clinical endpoint ？什麼是 Clinical endpoint ？
通常指 clinical outcome. 如下舉例：骨質疏鬆症：骨折發生率。癌症： 活時間長
短和存活率。高血酯症：心血管疾病死亡率。
Avoid misleading about the actual clinical effects.
1. Arrhythmia Suppression : encainide, flecainide, and moricizine --- VPC after MI --- mortality.
2. Lipid Lowering: clofibrate, Niacin --- TG, TC --- Mortality. 3. Osteoporosis in Postmenopausal Women: Sodium fluoride
--- BMD --- brittle, fracture. 4. 避免自行創造 endpoint.5. 選擇不恰當的 endpoint, 會造成試驗失敗 , 血本無歸
通常指 clinical outcome. 如下舉例：骨質疏鬆症：骨折發生率。癌症： 活時間長
短和存活率。高血酯症：心血管疾病死亡率。
Avoid misleading about the actual clinical effects.
1. Arrhythmia Suppression : encainide, flecainide, and moricizine --- VPC after MI --- mortality.
2. Lipid Lowering: clofibrate, Niacin --- TG, TC --- Mortality. 3. Osteoporosis in Postmenopausal Women: Sodium fluoride
--- BMD --- brittle, fracture. 4. 避免自行創造 endpoint.5. 選擇不恰當的 endpoint, 會造成試驗失敗 , 血本無歸
什麼是 surrogate endpoint ？
什麼是 surrogate endpoint ？
Reliably effective substitute for the clinical outcome.
Lab. measurements (LDL-C, BP, CD4 cell count, viral load), BMD, QT interval, tumor response or physical signs.
Reliably effective substitute for the clinical outcome.
Lab. measurements (LDL-C, BP, CD4 cell count, viral load), BMD, QT interval, tumor response or physical signs.
Randomized clinical trial of intraoperative autotransfusion in surgery for abdominal
aortic aneurysm
Randomized clinical trial of intraoperative autotransfusion in surgery for abdominal
aortic aneurysm
British Journal of Surgery, Vol 91, 1443-1448, Nov. 2004
安全性︰ AE安全性︰ AE Adverse Event / Adverse
Experience (AE) Adverse Drug Reaction (ADR) Serious Adverse Event (SAE) Toxicity (intoxication) (ex. Apresoline: Brain tumor, HR
increase 5 beats/ min, shock, SLE)
Adverse Event / Adverse Experience (AE)
Adverse Drug Reaction (ADR) Serious Adverse Event (SAE) Toxicity (intoxication) (ex. Apresoline: Brain tumor, HR
increase 5 beats/ min, shock, SLE)
PhamacovigilancePhamacovigilance 財團法人藥害救濟中心。 = Post-marketing surveillance.
identifying and quantitatively assess the risks related to the use of drugs in the entire population, or in specific population subgroups.
財團法人藥害救濟中心。 = Post-marketing surveillance.
identifying and quantitatively assess the risks related to the use of drugs in the entire population, or in specific population subgroups.
統計方法的選擇 . Randomization and stratification Hypothesis Testing (margin determination) ---
Comparisons --- 較優性 (superiority) , 不劣於 (non-inferiority) , 相等性 (equivalence)
Sample size, power, type 1 error, p value, 95% CI, Missing value management, etc.
Types of Hypothesis ：新的治療確有幫助嗎？對照藥是 --- 安慰劑 --- ，符合倫理嗎？其療效比目前所使用之治療方式來的更好嗎？它會導致何種副作用？其優點（療效）多於缺點（副作用）嗎？哪一種病人在接受這種治療時最能得到幫助？
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心，可以執行第一、二、三期的臨床試驗。
統計方法的選擇 . Randomization and stratification Hypothesis Testing (margin determination) ---
Comparisons --- 較優性 (superiority) , 不劣於 (non-inferiority) , 相等性 (equivalence)
Sample size, power, type 1 error, p value, 95% CI, Missing value management, etc.
Types of Hypothesis ：新的治療確有幫助嗎？對照藥是 --- 安慰劑 --- ，符合倫理嗎？其療效比目前所使用之治療方式來的更好嗎？它會導致何種副作用？其優點（療效）多於缺點（副作用）嗎？哪一種病人在接受這種治療時最能得到幫助？
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心，可以執行第一、二、三期的臨床試驗。
Clinical Trial: Data Analysis/ Statistics-
Summary of Clinical TrialSummary of Clinical Trial 以科學研究言，臨床試驗實是醫學研究中重要的一環。一個設計
嚴謹、有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗，不論其結果是成功（治療有效）或失敗，都提供了有用的資訊，以促成醫學的進步。衛生署積極推動人體試驗委員會的認證標準，希望更進一步來規範及督促ＩＲＢ，盡到確保臨床試驗品質及受試者人權的責任；如此一來，受試者就不必有白老鼠的擔憂。
一個具科學意義且成功的優良臨床試驗，不可諱言地常常伴隨有巨大商業利益，但這也表示某種疾病的治療上有了新的進展，對全球的病患，帶來了一個好消息，這些絕非金錢所能衡量。
部分人士將臨床試驗視之為產業，讓「臨床試驗」沾上了些許商業氣息，也容易被污名化，因而引起臨床試驗的受試者多淪為白老鼠的聯想。（ --- 爭議性）
好的臨床試驗可與國際接軌，獲得第一手資料。並來為本土的疾病，找尋出新藥以及新的療法。
以科學研究言，臨床試驗實是醫學研究中重要的一環。一個設計嚴謹、有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗，不論其結果是成功（治療有效）或失敗，都提供了有用的資訊，以促成醫學的進步。衛生署積極推動人體試驗委員會的認證標準，希望更進一步來規範及督促ＩＲＢ，盡到確保臨床試驗品質及受試者人權的責任；如此一來，受試者就不必有白老鼠的擔憂。
一個具科學意義且成功的優良臨床試驗，不可諱言地常常伴隨有巨大商業利益，但這也表示某種疾病的治療上有了新的進展，對全球的病患，帶來了一個好消息，這些絕非金錢所能衡量。
部分人士將臨床試驗視之為產業，讓「臨床試驗」沾上了些許商業氣息，也容易被污名化，因而引起臨床試驗的受試者多淪為白老鼠的聯想。（ --- 爭議性）
好的臨床試驗可與國際接軌，獲得第一手資料。並來為本土的疾病，找尋出新藥以及新的療法。
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難 遺失受試者同意書 (Informed Consent)以及人體試驗委員
會 (IRB) 同意書 ( 函 ) 的遺失：最好影印數份，分別保存 未按計劃書收納病患 隨機盲性作業之疏失 病人退出試驗（ drop out ）方面的疏失 Drug count 不符 ( 病人的用藥數量與給藥的數量或所剩的藥
量不符 ) 試驗期中，試驗計畫書 (protocol) 有所修改時，尤其更改主
要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核， 未遵守 GCP 精神，統計分析不對，結論不適當 檢驗數據不全，製造假數據，藥物不良反應報告不實或病歷記載
不全 ，個案報告表 (case report form) 填表不實或不全 研究協調者 (Research coordinator) 或研究護士 經驗不足，
試驗主持人 (Principal investigator) 經驗不足，不夠敬業，有些甚至掛名而已，態度不夠嚴謹 ，試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足，結構不齊全，經驗不足
受試者 ( 病人 ) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會 (IRB) 同意書 ( 函 ) 的遺失：最好影印數份，分別保存
未按計劃書收納病患 隨機盲性作業之疏失 病人退出試驗（ drop out ）方面的疏失 Drug count 不符 ( 病人的用藥數量與給藥的數量或所剩的藥
量不符 ) 試驗期中，試驗計畫書 (protocol) 有所修改時，尤其更改主
要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核， 未遵守 GCP 精神，統計分析不對，結論不適當 檢驗數據不全，製造假數據，藥物不良反應報告不實或病歷記載
不全 ，個案報告表 (case report form) 填表不實或不全 研究協調者 (Research coordinator) 或研究護士 經驗不足，
試驗主持人 (Principal investigator) 經驗不足，不夠敬業，有些甚至掛名而已，態度不夠嚴謹 ，試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足，結構不齊全，經驗不足
受試者 ( 病人 ) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar, i.e., comparable studies, leading to a quantitative summary of the pooled results.
A statistical synthesis of the data from separate but similar, i.e., comparable studies, leading to a quantitative summary of the pooled results.
SurveillanceSurveillance
Systemic ongoing collection, collation, and analysis of data and the timely dissemination of information to those who need to know so that action can be taken.
Example: 1. Alosetron ( Latronex,
GlaxoWellcome) 2. Lorcainide
Systemic ongoing collection, collation, and analysis of data and the timely dissemination of information to those who need to know so that action can be taken.
Example: 1. Alosetron ( Latronex,
GlaxoWellcome) 2. Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1. Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations);
2. Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome);
3. Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed;
4. Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future.
1. Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations);
2. Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome);
3. Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed;
4. Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future.
Unique considerations to clinical trials
Unique considerations to clinical trials
1. Defining the eligible population and selecting subjects
2. Development of the treatment protocol
3. Selecting alternative treatment
1. Defining the eligible population and selecting subjects
2. Development of the treatment protocol
3. Selecting alternative treatment
Quasi-Experimental Studies
Quasi-Experimental Studies
1. The inability to randomize individual study subjects;
2. The availability of only a single study group;
3. The prohibition of keeping one group as a control ( being required to provide all groups with some intervention);
4. The inability of pre-testing any of the groups to determine baseline characteristics.
1. The inability to randomize individual study subjects;
2. The availability of only a single study group;
3. The prohibition of keeping one group as a control ( being required to provide all groups with some intervention);
4. The inability of pre-testing any of the groups to determine baseline characteristics.
Some examples of questions and the methods of research
design
Some examples of questions and the methods of research
design Question 1.What is the history of infant feeding practices in Taiwan? 2. What anticipatory guidance is given for injury control on
routine check-up? 3. What is the pattern of growth in children with Down
Syndrome? 4. What are the characteristics of teenage youngsters on
probation for drug abuse? 5. What is the relationship of dietary counseling during
well-baby checks to iron deficiency anemia in infants? 6. What is the influence of policy on mean family income
and hospital days per child using aggregated data 7. Is prednisone combined with trimethoprrim-
sulfamethoxazole alone? 8. What is the change in injury potential in a group of
infants after parents are given an educational program? ( assuming some factors such as maturation, selective
attrition, effects of testing, etc., are unavoidable.)
Question 1.What is the history of infant feeding practices in Taiwan? 2. What anticipatory guidance is given for injury control on
routine check-up? 3. What is the pattern of growth in children with Down
Syndrome? 4. What are the characteristics of teenage youngsters on
probation for drug abuse? 5. What is the relationship of dietary counseling during
well-baby checks to iron deficiency anemia in infants? 6. What is the influence of policy on mean family income
and hospital days per child using aggregated data 7. Is prednisone combined with trimethoprrim-
sulfamethoxazole alone? 8. What is the change in injury potential in a group of
infants after parents are given an educational program? ( assuming some factors such as maturation, selective
attrition, effects of testing, etc., are unavoidable.)
Method 1. Descriptive 2. case studies
3. Observational (longitudinal) cohort
4. Cross-sectional
5. Cross-sectional or Quasi-Experimental
6. Ecologic
7. Clinical trial
8. Quasi-Experimental
Method 1. Descriptive 2. case studies
3. Observational (longitudinal) cohort
4. Cross-sectional
5. Cross-sectional or Quasi-Experimental
6. Ecologic
7. Clinical trial
8. Quasi-Experimental
Data acquisitionData acquisition
Data Collection, Management, and Analysis
Data Collection, Management, and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1. The investigators’ and the subjects’ orientations in time;
2. The investigators, and the subjects’ orientation in the process;
3.Description versus comparison of subjects;
4. Passive observation versus active experimentation to “manipulate” the subjects.
1. The investigators’ and the subjects’ orientations in time;
2. The investigators, and the subjects’ orientation in the process;
3.Description versus comparison of subjects;
4. Passive observation versus active experimentation to “manipulate” the subjects.
Deciding what to collectDeciding what to collect Consider exactly what information is needed to
answer the research question and what is the most cost-effective way to obtain the data.
Consider what type of data to be collected Nominal: People or events in unordered categories (
e.g., black or white, dead or alive) Ordinal: People or events in ordered categories (
e.g., ranks, score, 1 or 2 plus of edema) Continuous: Numbers are assigned or attached that
have absolute meaning as a count or measurement by an objective scale( e.g., age, weight, score ( sometimes).
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the data.
Consider what type of data to be collected Nominal: People or events in unordered categories (
e.g., black or white, dead or alive) Ordinal: People or events in ordered categories (
e.g., ranks, score, 1 or 2 plus of edema) Continuous: Numbers are assigned or attached that
have absolute meaning as a count or measurement by an objective scale( e.g., age, weight, score ( sometimes).
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine: Data collected routinely for other purposes independent of the study 9e.g., medical records, vital statistics, census data, hospital discharge abstracts, and national or local routine health surveys).
Programmatic: Data collected as part of a service program but not specifically related to a research project ( e.g., patient-visit data, billing data, and vouchers).
Primary: Data specifically collected to address research questions( e.g., questionnaire and patient observations).
Routine: Data collected routinely for other purposes independent of the study 9e.g., medical records, vital statistics, census data, hospital discharge abstracts, and national or local routine health surveys).
Programmatic: Data collected as part of a service program but not specifically related to a research project ( e.g., patient-visit data, billing data, and vouchers).
Primary: Data specifically collected to address research questions( e.g., questionnaire and patient observations).
ValidityValidity
1. Construct validity 2. Content validity ( face validity) 3. Criterion validity 4. Internal consistency
( Cronbach’s alpha) 5. External Validity
1. Construct validity 2. Content validity ( face validity) 3. Criterion validity 4. Internal consistency
( Cronbach’s alpha) 5. External Validity
ReliabilityReliability
1. Inter-rater reliability 2. Intra-rater reliability
Kappa alpha statistic 3. Test-retest reliability 4. Split-half reliability
1. Inter-rater reliability 2. Intra-rater reliability
Kappa alpha statistic 3. Test-retest reliability 4. Split-half reliability
Illustration of data collection
Illustration of data collection
Use of matched birth/infant death records
Birth weight code Medical record Billing data NHIB prevalence, incidence and
case-fatality data.
Use of matched birth/infant death records
Birth weight code Medical record Billing data NHIB prevalence, incidence and
case-fatality data.
Selecting Instrument/Data Collection Method
Selecting Instrument/Data Collection Method
Relevance to the Research Question Feasibility of Collection Validity and Reliability of Measure Data Management Procedure
Procedures manual Coding manual Data entry
Data Analysis
Relevance to the Research Question Feasibility of Collection Validity and Reliability of Measure Data Management Procedure
Procedures manual Coding manual Data entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1. The failure to analyze data on those individuals who were eligible for the study but who, for some reason, were excluded.
2. The use of multiple tests of significance when comparing two groups.
3. Insufficient sample size.
1. The failure to analyze data on those individuals who were eligible for the study but who, for some reason, were excluded.
2. The use of multiple tests of significance when comparing two groups.
3. Insufficient sample size.
Communication of resultsCommunication of results
Writing an abstract Presentation Publication
Writing an abstract Presentation Publication
Funding considerationFunding consideration Become acquainted with the basic facts about
public and private funding sources in general. Define areas of research interest and identify
sources of support with similar research interests and priorities.
Obtain detailed information on the funding history, eligibility requirements, ad application procedures of identified sources of support.
Write a letter of intent, including the proposed funding necessary, to those organizations that seem most appropriate. For sources of support that respond with a request for a full proposal, prepare and submit one that complies with the source’s specific instructions regarding format, content, length, number of copies, and application deadlines.
Become acquainted with the basic facts about public and private funding sources in general.
Define areas of research interest and identify sources of support with similar research interests and priorities.
Obtain detailed information on the funding history, eligibility requirements, ad application procedures of identified sources of support.
Write a letter of intent, including the proposed funding necessary, to those organizations that seem most appropriate. For sources of support that respond with a request for a full proposal, prepare and submit one that complies with the source’s specific instructions regarding format, content, length, number of copies, and application deadlines.
Ethical standards for research involving human
subjects
Ethical standards for research involving human
subjects Nuremburg Codes. Helsinki Declaration. Informed consent. IRB.
Nuremburg Codes. Helsinki Declaration. Informed consent. IRB.
1949:The Nuremberg Code
1949:The Nuremberg Code 美國的法官於 1947 年在所謂的 「醫師的審判」
（ Doctors' Trial ）中訂定了紐倫堡條約（ Nuremberg Code ），為關於醫學研究倫理上最重要的文件。 紐倫堡條約一共有十條，第一條即開宗明義地說出：「受試者的自願同意是絕對必要。」 (The voluntary consent of the human subject is absolutely essential.) 。此後，任何臨床醫學實驗在進行以前都必須獲得受試者的同意。所謂之「同意」係指受試者必須處在沒有任何壓力、脅迫、利誘、哄騙的情形下，並且不受隱瞞，實驗者必須明白告知受試者實驗的目的、對個人的影響與研究成果對社會可能之預期貢獻等。
Art. 1: The voluntary consent of the human subject is absolutely essential. Art. 9: During the course of the experiment the human subject should be at
liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible.
美國的法官於 1947 年在所謂的 「醫師的審判」（ Doctors' Trial ）中訂定了紐倫堡條約（ Nuremberg Code ），為關於醫學研究倫理上最重要的文件。 紐倫堡條約一共有十條，第一條即開宗明義地說出：「受試者的自願同意是絕對必要。」 (The voluntary consent of the human subject is absolutely essential.) 。此後，任何臨床醫學實驗在進行以前都必須獲得受試者的同意。所謂之「同意」係指受試者必須處在沒有任何壓力、脅迫、利誘、哄騙的情形下，並且不受隱瞞，實驗者必須明白告知受試者實驗的目的、對個人的影響與研究成果對社會可能之預期貢獻等。
Art. 1: The voluntary consent of the human subject is absolutely essential. Art. 9: During the course of the experiment the human subject should be at
liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible.
1964: Helsinki Declaration
1964: Helsinki Declaration
• 世界醫學協會 (World Medical Association) 經過幾年的研議，在 1964 年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 ” Recommendations guiding physicians in biomedical research involving human subjects” ，通稱為「赫爾新基宣言」
• 1975, 29th Tokyo Revision• 1983, 35th Venice Revision• 1989, 41th Hong Kong Revision• 1996, 48th Somerset West Revision• 2000, 52nd Edinburgh Revision
• 世界醫學協會 (World Medical Association) 經過幾年的研議，在 1964 年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 ” Recommendations guiding physicians in biomedical research involving human subjects” ，通稱為「赫爾新基宣言」
• 1975, 29th Tokyo Revision• 1983, 35th Venice Revision• 1989, 41th Hong Kong Revision• 1996, 48th Somerset West Revision• 2000, 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declaration• Introduction
• The health of my patients will be my first consideration.• Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjects.• Clinical research vs. Non-clinical research.
• Basic Principles （ 1 ）需事先徵求受試人在自由意志情況下之自願同意，且此受試人必須具有同意之法律能力；（ 2 ）受試人對於實驗所涉及之內容，有一定程度之瞭解；（ 3 ）實驗本身設計的目的是為人類社會之福祉；（ 4 ）進行人體實驗前必須先有實驗室及動物實驗依據；（ 5 ）盡力避免對人體身心的傷害，一旦實驗進行中發現對人體有害，應立即停止；（ 6 ）必須在合法機關監督下，由具備資格者進行實驗；且必須事先擬好補償措施；
• Medical Research combined with clinical care (Clinical research)• Non-therapeutic biomedical research involving human subjects(Non-
clinical biomedical research).• 試驗計畫書 (protocol) 應經一獨立委員會審查“ specially appointed committee
independent of the investigator and the sponsor” （通則第 4 條） ─ 人體試驗委員會：美國─” Institutional Review Board”, 台灣─ “ Ethics Committee”
赫爾辛基宣言之精神 自主：受試驗者是在被充分告知相關訊息後，自由決定要參加的。 有益：參加試驗的風險相對於可能有的好處是可以接受的。受試驗者參加試驗後並不會犧牲
其權利，仍會受到已證明有效的最佳照顧。 赫爾辛基宣言之功能 - 道德勸說 , 效果…
• Introduction• The health of my patients will be my first consideration.• Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjects.• Clinical research vs. Non-clinical research.
• Basic Principles （ 1 ）需事先徵求受試人在自由意志情況下之自願同意，且此受試人必須具有同意之法律能力；（ 2 ）受試人對於實驗所涉及之內容，有一定程度之瞭解；（ 3 ）實驗本身設計的目的是為人類社會之福祉；（ 4 ）進行人體實驗前必須先有實驗室及動物實驗依據；（ 5 ）盡力避免對人體身心的傷害，一旦實驗進行中發現對人體有害，應立即停止；（ 6 ）必須在合法機關監督下，由具備資格者進行實驗；且必須事先擬好補償措施；
• Medical Research combined with clinical care (Clinical research)• Non-therapeutic biomedical research involving human subjects(Non-
clinical biomedical research).• 試驗計畫書 (protocol) 應經一獨立委員會審查“ specially appointed committee
independent of the investigator and the sponsor” （通則第 4 條） ─ 人體試驗委員會：美國─” Institutional Review Board”, 台灣─ “ Ethics Committee”
赫爾辛基宣言之精神 自主：受試驗者是在被充分告知相關訊息後，自由決定要參加的。 有益：參加試驗的風險相對於可能有的好處是可以接受的。受試驗者參加試驗後並不會犧牲
其權利，仍會受到已證明有效的最佳照顧。 赫爾辛基宣言之功能 - 道德勸說 , 效果…
知情同意（ Informed Consent ） -Helsinki Declaration 通則第 11, 12, 13,
14,15,16條
知情同意（ Informed Consent ） -Helsinki Declaration 通則第 11, 12, 13,
14,15,16條 「說清楚很麻煩，不說又不行」 --- 知道、了解、有效同意 –• 受試者同意書是醫師和病人溝通的橋樑。必須用非常淺顯口語化
的文字說明。必須讓病人能了解，計劃之目的、病人需做的檢查及治療、配合事項、接受治療可能有的副作用、以及其他權利及義務，不可以過於誇大宣傳療效。
告知之範圍：受試者應被告知試驗目的、方法、收納 /排除 / 退出標準其他可能的替代療法，尊重病患隱私權，並主動告知最新訊息，受試者權益（ human rights ）保護與保密， 配套保障措施。【保險：非過失、非故意 】 ，彼此的義務與責任，誠實說明 /感同身受組織、檢體、血液等的保存期限與用途，實驗之預期利益及潛在風險；並應被告知其有不加入以及任意退出之自由 (赫爾辛基宣言通則第 13 條）
• 告知之態度：醫師應避免病患對醫師之依賴關係而「不得不」同意（ consent under duress) ( 赫爾辛基宣言通則第 14 條）
• 受試者為無行為能力人時，應取得其法定代理人之同意；受試者雖然為未成年人，但只要具備意思能力，也應一併取得其本人同意 (赫爾辛基宣言通則第 16 條）
「說清楚很麻煩，不說又不行」 --- 知道、了解、有效同意 –• 受試者同意書是醫師和病人溝通的橋樑。必須用非常淺顯口語化
的文字說明。必須讓病人能了解，計劃之目的、病人需做的檢查及治療、配合事項、接受治療可能有的副作用、以及其他權利及義務，不可以過於誇大宣傳療效。
告知之範圍：受試者應被告知試驗目的、方法、收納 /排除 / 退出標準其他可能的替代療法，尊重病患隱私權，並主動告知最新訊息，受試者權益（ human rights ）保護與保密， 配套保障措施。【保險：非過失、非故意 】 ，彼此的義務與責任，誠實說明 /感同身受組織、檢體、血液等的保存期限與用途，實驗之預期利益及潛在風險；並應被告知其有不加入以及任意退出之自由 (赫爾辛基宣言通則第 13 條）
• 告知之態度：醫師應避免病患對醫師之依賴關係而「不得不」同意（ consent under duress) ( 赫爾辛基宣言通則第 14 條）
• 受試者為無行為能力人時，應取得其法定代理人之同意；受試者雖然為未成年人，但只要具備意思能力，也應一併取得其本人同意 (赫爾辛基宣言通則第 16 條）
藥物臨床試驗責任險 富邦產開賣【 2005/01/21 經濟日報】
藥物臨床試驗責任險 富邦產開賣【 2005/01/21 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」，這是繼第一產後，第二家 ------ ，傷亡的最高理賠金為每人 200萬元，累計的賠償金額不得超過 1,000萬元。
受試者、試驗主持人與其他成員的名單，必須註明在保單契約內，若受試者與醫療機構產生醫療試驗的糾紛，其中的訴訟費用，才可包含在承保範圍內。
受試對象、藥物種類、成分及內、外科別等因素，會影響整體費率。 根據市場經驗，每張保費的平均價格約 20萬元， ------ ，費率差距甚大。
富邦產險新推出「藥物臨床試驗責任保險」，這是繼第一產後，第二家 ------ ，傷亡的最高理賠金為每人 200萬元，累計的賠償金額不得超過 1,000萬元。
受試者、試驗主持人與其他成員的名單，必須註明在保單契約內，若受試者與醫療機構產生醫療試驗的糾紛，其中的訴訟費用，才可包含在承保範圍內。
受試對象、藥物種類、成分及內、外科別等因素，會影響整體費率。 根據市場經驗，每張保費的平均價格約 20萬元， ------ ，費率差距甚大。
Real LifeReal Life
Check your work before you present
Check your work before you present
楊 XX涉擅作人體實驗 高雄長庚：已停職接受調查中
2003/11/03 14:13 記者林澄洋／高雄報導
楊 XX涉擅作人體實驗 高雄長庚：已停職接受調查中
2003/11/03 14:13 記者林澄洋／高雄報導
高雄 XX 醫院一名醫師被檢舉違規私下進行人體實驗，把病人當成白老鼠，引起病人相當的恐慌，醫院則是在緊急會議之後出面解釋，這名醫師己經被停職調查。衛生署強調，如果醫師有違法情形， -----
高雄 XX 醫院一名醫師被檢舉違規私下進行人體實驗，把病人當成白老鼠，引起病人相當的恐慌，醫院則是在緊急會議之後出面解釋，這名醫師己經被停職調查。衛生署強調，如果醫師有違法情形， -----
Clinical Pharmaceutical Medicine:
An Inexact Science with a large black box between molecular interactions and patient response.
What we are dealing with:
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activity activity Efficacy/SafetyEfficacy/Safety
But most of time you get this:
上市前 vs. 上市後上市前 vs. 上市後
醫療藥品使用量醫療藥品使用量美洲 40 %
歐洲 20 %
日本 15 %
台灣 0.5
%
韓國 1.5
%
中國大陸 2 %
ASEAN( 東亞十國 ) 3 %
其它 15 %International Conference on Harmonization, (ICH): US, EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【 2005/01/20 民生報】 【記者楊惠君／報導】
輪狀病毒疫苗人體試驗 暫停收案 【 2005/01/20 民生報】 【記者楊惠君／報導】 參與口服輪狀病毒疫苗人體試驗的 3 個月大女嬰猝死，雖然法醫相驗初步認為死因為窒息，與疫苗關係不大；但衛生署對此案十分重視，負責該項人體試驗的台大小兒科教授黃立民昨前往說明。 在法醫解剖報告及藥廠解碼之前， 4 家參與臨床試驗的醫院即日起先暫停收新案。
參與口服輪狀病毒疫苗人體試驗的 3 個月大女嬰猝死，雖然法醫相驗初步認為死因為窒息，與疫苗關係不大；但衛生署對此案十分重視，負責該項人體試驗的台大小兒科教授黃立民昨前往說明。 在法醫解剖報告及藥廠解碼之前， 4 家參與臨床試驗的醫院即日起先暫停收新案。
默沙東 : 治療關節炎藥品偉克適全球下市中央社記者陳惠珍台北 10/1/2004 默沙東 : 治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 10/1/2004 MSD 藥廠 指出，公司生產治療關節炎及急性疼痛藥物 (VIOXX) ，因病患服用十八個月後，恐有增加心臟方面副作用的危險性， --- 。
默沙東公司總裁表示︰「我們深信採取這樣的處理方式，是為能顧及患者最大利益 --- 。
股價由US50跌到落US26 。消費者團體對 Merck 藥廠提出集體訴訟， --- 接踵而來的訴訟及賠償，將導致龐大的損失。
MSD 藥廠 指出，公司生產治療關節炎及急性疼痛藥物 (VIOXX) ，因病患服用十八個月後，恐有增加心臟方面副作用的危險性， --- 。
默沙東公司總裁表示︰「我們深信採取這樣的處理方式，是為能顧及患者最大利益 --- 。
股價由US50跌到落US26 。消費者團體對 Merck 藥廠提出集體訴訟， --- 接踵而來的訴訟及賠償，將導致龐大的損失。
醫葯新聞︰不同解讀，見仁見智 醫葯新聞︰不同解讀，見仁見智 OO 醫學院 OOO 名譽教授宣布：『白鳳豆錠劑抗癌
通過臨床試驗 』 ----- 。 OO 電視台最新特報： XX 醫院宣布 --- SARS疫苗將進入臨床試驗，最快明年上市， --- ？
OOO 教授 / 院士研發肝癌疫苗有成，已經申請專利，不排除和大藥廠合作進行臨床試驗， --- ？
吸煙也能抗癌？中研院發表驚人的研究報告，療效是目前最常用抗肺癌藥物的 1.5 到 13倍，已經申請專利，預估兩年後上市， --- 。
OO 醫學院 OOO 名譽教授宣布：『白鳳豆錠劑抗癌通過臨床試驗 』 ----- 。
OO 電視台最新特報： XX 醫院宣布 --- SARS疫苗將進入臨床試驗，最快明年上市， --- ？
OOO 教授 / 院士研發肝癌疫苗有成，已經申請專利，不排除和大藥廠合作進行臨床試驗， --- ？
吸煙也能抗癌？中研院發表驚人的研究報告，療效是目前最常用抗肺癌藥物的 1.5 到 13倍，已經申請專利，預估兩年後上市， --- 。
* 2004/11/1 頭版︰肺癌末期有救 華陽複方神奇療效 （記者 : 王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方，可以延長肺癌末期病患的壽命，平均長達33.5 個月， FDA 核准進行第三期臨床試驗，預計 2 年後成為史上市， -- 。
* 2004/11/1 頭版︰肺癌末期有救 華陽複方神奇療效 （記者 : 王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方，可以延長肺癌末期病患的壽命，平均長達33.5 個月， FDA 核准進行第三期臨床試驗，預計 2 年後成為史上市， -- 。 * 2004/11/09︰衛署強調華陽複方仍算食品，
業者聲稱抗癌療效將開罰《記者王菁菁／台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者：方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者：方怡驊 940127
古早的中藥材紅麴菌，被研究製成可以降血脂的藥品「壽美降脂一號」 ，經過三年的西藥臨床試驗，與 Statin 的藥效類似。是國內第一個依照西藥遊戲規則，確認療效的中藥。
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check list Q1.Why was the study done?
1. What is the question to be answered?2. Is it a practical issue or a theoretical issue?
Q2:What are prior hypotheses?Q3:How would you label the study in epidemiology?
1. Is it a descriptive study, survey, case control study, cohort study,experimental study, meta-analysis or a surveillance?Q4.What is the study subjects?Q5.What are the comparison subjects?Q6.Could there have been bias in the selection of study subjects and comparison subject?
1. What is the population? Is it a representative sample? Did the subjects randomly selected?
2. Are there any standard selection process? Are there any rationale of the process?
3. How did the sample size been determined?4. Are there any missing data?
Q1.Why was the study done? 1. What is the question to be answered?2. Is it a practical issue or a theoretical issue?
Q2:What are prior hypotheses?Q3:How would you label the study in epidemiology?
1. Is it a descriptive study, survey, case control study, cohort study,experimental study, meta-analysis or a surveillance?Q4.What is the study subjects?Q5.What are the comparison subjects?Q6.Could there have been bias in the selection of study subjects and comparison subject?
1. What is the population? Is it a representative sample? Did the subjects randomly selected?
2. Are there any standard selection process? Are there any rationale of the process?
3. How did the sample size been determined?4. Are there any missing data?
Monson check list ( continued)Monson check list ( continued) Q7.Could there have been bias in the collection of information?
1. What is the measurement scale? Quality or Quantity?2. Any repeated measurement?
Q8.What provision was made to minimize confounding?1. Restriction, matching or stratification?
Q9.What was the measure of association and stability in the association?
1. Relative risk or Odds ratio?2. 95 ％ confidence interval been presented?
Q10.What is the major result of the study?Q11.How might bias have affected the results?Q12.How might random misclassification have affected the result?Q13.Is the interpretation of the data appropriate?
1. Did the conclusion been well supported? Did the conclusion answer the proposed question?
2. Did the biological plausibility been well generalized?
Q7.Could there have been bias in the collection of information?1. What is the measurement scale? Quality or Quantity?2. Any repeated measurement?
Q8.What provision was made to minimize confounding?1. Restriction, matching or stratification?
Q9.What was the measure of association and stability in the association?
1. Relative risk or Odds ratio?2. 95 ％ confidence interval been presented?
Q10.What is the major result of the study?Q11.How might bias have affected the results?Q12.How might random misclassification have affected the result?Q13.Is the interpretation of the data appropriate?
1. Did the conclusion been well supported? Did the conclusion answer the proposed question?
2. Did the biological plausibility been well generalized?
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months: randomised controlled trial
Linda Diggle, senior research nurse, a Jonathan Deeks, senior medical statistician. b
a Oxford Vaccine Group, University Department of Paediatrics, John Radcliffe Hospital, Oxford OX3 9DU, b ICRF/NHS Centre for Statistics in Medicine, Institute of Health Sciences, University of Oxford, Oxford OX3 7LF
Correspondence to: L Diggle [email protected]
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months: randomised controlled trial
Linda Diggle, senior research nurse, a Jonathan Deeks, senior medical statistician. b
a Oxford Vaccine Group, University Department of Paediatrics, John Radcliffe Hospital, Oxford OX3 9DU, b ICRF/NHS Centre for Statistics in Medicine, Institute of Health Sciences, University of Oxford, Oxford OX3 7LF
Correspondence to: L Diggle [email protected]
AbstractAbstractObjective: To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants. Design: Randomised controlled trial. Setting: Routine immunisation clinics in eight general practices in Buckinghamshire. Participants: Healthy infants attending for third primary immunisation due at 16 weeks of age: 119 infants were recruited, and 110 diary cards were analyzed. Interventions: Immunisation with 25 gauge, 16 mm, orange hub needle or 23 gauge, 25 mm, blue hub needle. Main outcome measures: Parental recordings of redness, swelling, and tenderness for three days after immunisation. Results: Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 0.66 (95% confidence interval 0.45 to 0.99), P=0.04), and by the third day this had decreased to a seventh (relative risk 0.13 (0.03 to 0.56), P=0.0006). Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 0.39 (0.23 to 0.67), P=0.0002), and this difference remained for all three days. Rates of tenderness were also lower with the longer needle throughout follow up, but not significantly (relative risk 0.60 (0.29 to 1.25), P=0.17). Conclusions: Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation. On average, for every five infants vaccinated, use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction. Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs.
Objective: To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants. Design: Randomised controlled trial. Setting: Routine immunisation clinics in eight general practices in Buckinghamshire. Participants: Healthy infants attending for third primary immunisation due at 16 weeks of age: 119 infants were recruited, and 110 diary cards were analyzed. Interventions: Immunisation with 25 gauge, 16 mm, orange hub needle or 23 gauge, 25 mm, blue hub needle. Main outcome measures: Parental recordings of redness, swelling, and tenderness for three days after immunisation. Results: Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 0.66 (95% confidence interval 0.45 to 0.99), P=0.04), and by the third day this had decreased to a seventh (relative risk 0.13 (0.03 to 0.56), P=0.0006). Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 0.39 (0.23 to 0.67), P=0.0002), and this difference remained for all three days. Rates of tenderness were also lower with the longer needle throughout follow up, but not significantly (relative risk 0.60 (0.29 to 1.25), P=0.17). Conclusions: Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation. On average, for every five infants vaccinated, use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction. Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs.
Thank YouThank You
