Experimental Epidemiology (Clinical Trial)

Experimental Epidemiology (Clinical Trial)
Lecturer: Hui Jin 2017/4/21

Overview of research studies Introduction of Clinical Trials
Randomized Controlled Trials Alternatives to Randomized trials The presentation will include a discussion about: Why clinical trials are important How clinical trials work How clinical trials advance patient care How participants are protected Some of the barriers to participating in clinical trials And finally, I’ll talk about the summary 2017/4/21

Overview to Research Studies
Why Do Research Studies? To collect data on usual and unusual events, conditions, & population groups To test hypotheses formulated from observations and/or intuition Ultimately, to understand better one’s world and make “sense of it” Why do we do some research studies? We can describe healthy phenomenon to and compare health conditions in different countries. Certaintly, we pay more attention to explore what cause disease. 2017/4/21

Overview to Research Studies
Various types of research studies Many classified as “Epidemiological Studies” Epidemiology is defined as: The study of the distribution of a disease or condition in a population and the factors that influence that distribution. 2017/4/21

Classifications of Research Studies: Two Main Types
Observational studies: Groups are studied & contrasts made between groups The observed data collected are analyzed Experimental Studies: Study the impact of a certain therapy Ultimately the investigator controls factor being studied Clinical Trial---RCT( Randomized Controlled Trials) The main advantage of observational studies is that they are feasible. The main drawback is the likelihood that there are systematic differences in treatment groups other than the treatment itself, which lead to misleading conclusions about the effects of treatment. Randomized controlled trials are the standard of excellence for scientific studies of the effects of treatment. We will consider them in detail first, then consider alternative ways of answering the same question. 2017/4/21

Clinical Trials Started in the 1920’s by:
The study of epidemics among colonies of experimental animals such as rats and mice. In modern usage, experimental epidemiology is often equated with : RANDOMIZED CONTROLLED TRIALS 2017/4/21

Clinical Trials Animal Studies Herd immunity
Reproduction of human disease to confirm aetiological cause Study pathogenetic mechanism Testing the efficacy of preventive and therapeutic measures (vaccines and drug) Completing the natural history of disease 2017/4/21

Clinical Trials Advantages
Easy manipulation; Rapid multiplication to provide outcome Disadvantages Not all diseases reproduced in animals; Conclusion may not be applicable in human (e.g.Typhoid vaccine) 2017/4/21

What is a clinical trial?
A clinical trial is a controlled experiment in human subjects which involves an intervention and observation of the subsequent effect of that intervention. Disease … Desire to impact on patient condition (i.e., improve outcome) CT tests whether new treatment is effective or better than another treatment

FFD: "… a prospective study that compares the effect and value of an intervention against a control in human beings." Pocock: "… a planned experiment involving patients, designed to identify a more appropriate treatment for future patients." Meinert: "… a planned experiment designed to assess the efficacy of a treatment in man 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 patients in both groups are enrolled, treated, and followed over the same time period."

The term “clinical trial” is preferred over “clinical experiment” since the latter may connote disrespect for the value of human life.

What is a clinical trial?
Clinical Trials What is a clinical trial? A prospective study comparing the effect and value of intervention(s) against a control in human beings Four aspects: prospective, from cause to effect; intervention, a force given by investigator; control, comparative in nonstudy factor; human beings, not rat or mice. Clinical trials are research studies involving people. Clinical trials are the final step in a long research process that includes preliminary laboratory research and animal testing. Clinical trials try to answer specific scientific questions to find better ways to prevent, detect, or treat diseases, or to improve care for people with diseases. In cancer research, for example, a clinical trial is designed to show how a certain anticancer approach—for instance, a promising drug, a new surgical procedure, a new diagnostic test, or a possible way to prevent cancer—affects the people who receive it. 2017/4/21

Figure 7.1. The structure of a clinical trial
2017/4/21

Clinical Trials Aims to provide scientific proof of an etiological or a risk factor which may permit modification or control of diseases to measure the effectiveness and the efficiency of a preventive, control or a treating measure Judge whether a factor is a risk factor, to danger people health. 2017/4/21

Why Are Clinical Trials Important?
Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat disease The more people take part, the faster we can: - Answer critical research questions - Find better treatments and ways to prevent disease It is important to understand what clinical trials do to fight disease: · Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat disease. · Clinical trials contribute to knowledge and progress against disease. Many of today’s most effective treatments are based on previous study results. Because of progress made through clinical trials, many people treated for various diseases are now living longer. · The more people that participate in clinical trials, the faster we can answer the critical research questions that will lead us to better treatment and prevention options for a range of diseases. 2017/4/21

Types of Clinical Trials
PHASE I TRIAL Phase II TRIAL Phase III TRIAL Phase IV TRIAL

Phase I Trial Objective : To determine an acceptable range of doses and schedules for a new drug Usually seeking maximum tolerated dose Participants often those that have failed other treatments Important, however, that they still have “normal” organ functions

Phase II Trial Objective: To determine if new drug has any beneficial activity and thus worthy of further testing / investment of resources. Doses and schedules may not be optimum Begin to focus on population for whom this drug will likely show favorable effect

Phase III Trial Objective : To compare experimental or new therapies with standard therapy or competitive therapies. Very large, expensive studies Required by FDA for drug approval If drug approved, usually followed by Phase IV trials to follow-up on long-range adverse events – concern is safety

Characterization of Trials
Phase Single Center Multi Center Randomized Non-Rand. I Never Yes Sometimes II Rare III Use of Historical Controls Carrying out a multi-center randomized clinical trial is the most difficult way to generate scientific information.

What Are the Different Types of Clinical Trials?
Treatment Prevention Early detection/screening Diagnostic Quality of life/supportive care There are at least 5 types of clinical trials: 1. Treatment trials seek to find out: · What new treatment approaches can help people who have a disease · What is the most effective treatment for people with that disease 2. Prevention trials seek to find out what approaches can prevent a disease from developing in people who have never had it 3. Early-detection/screening trials seek to discover new ways of finding a disease in people before they have any symptoms 4. Diagnostic trials seek to find out how new tests or procedures can better identify a disease in people when we think it is there 5. Quality-of-life/supportive care trials seek to find out what kinds of new approaches can improve the comfort and quality of life of people with a disease 2017/4/21

Treatment Trials Clinical Trials
What new treatments can help people with a particular disease? What is the most effective treatment for people with that disease? Most clinical trials are treatment trials. These clinical trials involve people who have a disease. These studies try to answer specific questions about the effectiveness of a new treatment or a new way of using an existing treatment. 2017/4/21

Who is the population of interest? What is the intervention?
What is the question? Who is the population of interest? What is the intervention? How will the efficacy of the intervention be assessed? 2017/4/21

What is the Question? Clinical Trials Primary Secondary
most important (i.e., central question) ideally, only one stated in advance basis for design and sample size Secondary related to primary also stated in advance limited in number but usually more than 1 Primary endpoint: total mortality Secondary endpoint: myocardial infarction 2017/4/21

Basic Steps in Conducting a RCT
Clinical Trials 1- Drawing up a protocol 2- Selecting reference and experimental populations 3- Randomization 4- Manipulation or intervention 5- Follow up 6- Assessment of outcome 2017/4/21

RANDOMIZE Select suitable sample Not Eligible
Reference or Target Population Select suitable sample Not Eligible Make necessary exclusions No Consent RANDOMIZE Experimental group Control group Manipulation and Follow up Assessment 2017/4/21

Clinical Trials 1- Drawing a protocol A. Background of the study
B. Objectives 1- Primary question and response variable 2- Secondary question and response variable 3- Subgroups hypotheses 4- Adverse effects C. Design of the study 1- Study population a) Inclusion criteria b) Exclusion criteria Study meaning, why to do this research such as evaluate the drug effect Buidling a house, you have to design, the size, function, rooms 2017/4/21

1- Drawing a protocol (con’t)
2- Sample size assumptions and estimates 3- Enrollment of participants a) Informed consent b) Assessment of eligibility c) Baseline examination d) Intervention allocation (randomization) 4- Intervention a) Description and schedule b) Measures of compliance 5- Follow up visit description and schedule Flowchart 2017/4/21

6- Ascertainment of response variables a) Training b) Data collection c) Quality control 7- Data analysis 8- Termination policy D. Organization 1- Participating investigators a) Data coordinating center b) Labs and other special units c) Clinical centers 2017/4/21

2- Study administration a) Steering committees b) Data monitoring committee c) Funding organization Appendix Definitions of eligibility criteria Definitions of response variable 2017/4/21

2- Selecting Reference and Experimental Population
The first, entry criteria, is intended to restrict the heterogeneity of patients in the trial. Common exclusion criteria are atypical disease, the presence of other diseases, an unusually poor prognosis (which may cause patients to drop out of the assigned treatment group), and evidence of unreliability. Second, patients can refuse to participate in a trial. Patients who refuse to participate are usually systematically different—in socioeconomic class, severity of disease, other health-related problems/ and other ways— from those who agree to enter the trial. For these reasons, patients in clinical trials are usually a highly selected, biased sample of all patients with the condition of interest (Fig. 7.3). Because of the high degree of selection in trials, it often requires considerable faith to generalize the results of clinical trials to ordinary practice settings. It is the subset of the population of the condition or characteristics of interest defined by eligibility criteria. Three account for the losses: ineligible, eligible but no entry or no cooperation with the conduct of the trial.---highly selected biased sample 2017/4/21

Population at Large Population w/o condition Definition of the condition Population with the condition Entry criteria Ineligible Study Population Eligible but not enrolled Enrollment Study sample 2017/4/21

For example 2017/4/21

Study Populations should be 1- Chosen randomly 2- Stable population (to avoid losses) 3- Informed (Written consent) 4- Representative 5- Eligible Therefore, study population should be chosen randomly, represent the characteristics of target population. Or else the result deviate the truth, and the conclusion does not apply for the general population. Ethical requirement. 2017/4/21

Comparison groups No Intervention (receiving nothing) Observation (Hawthorne effect) Placebo Treatment (placebo effect) Usual Treatment COMPARISON GROUPS No Intervention Do patients receiving the experimental treatment end up better than those receiving nothing at all? Comparing treatment with no treatment measures the total effects of health care, both specific and nonspecific. Blank control 2017/4/21

Hawthorne effect: People tend to change their behavior because they are the target and attention in a study, regardless of the specific nature of the intervention they might be receiving. placebo effect: a placebo, an intervention that is indistinguishable from the active treatment—in physical appearance, color, taste, and smell—but does not have a specific, known mechanism of action. To avoid subjective bias 2017/4/21

Ethical Considerations
A well designed trial can answer important public health questions w/o impairing the welfare of the individuals International Ethical Guidelines for Biomedical Researches Involving Human Subjects Nazi Racism , Nazi human experimentation was a series of medical experiments on large numbers of prisoners Violate humanitarian 2017/4/21

3- Randomization Randomization tends to produce study groups comparable with respect to known and unknown risk factors, removes investigator bias in the allocation of the participants, and guarantees that statistical tests will have valid significance levels analogous to flipping a coin— whereby each patient has an equal (or at least known) chance of being assigned to any one of the treatment groups. Positive and negative 2017/4/21

3- Randomization An independent central unit should be responsible of the process of randomization and assigning people to intervention groups Those recruiting or entering patients into a trial should not be aware of the next intervention assignment 2017/4/21

Randomization Clinical Trials
Explain slide. Random number table made by statistician 2017/4/21

Why is Randomization Important?
Clinical Trials Why is Randomization Important? So all groups are as alike as possible Provides the best way to prove the effectiveness of a new agent or intervention If participants or health care providers choose a particular group based on what they think is best, then one of the groups would likely be very different than the other, making comparison between the groups difficult. Randomization eliminates this bias because participants have an equal chance of being assigned to either group and the subgroups are as similar as possible. Comparing similar groups of people taking different treatments for the same disease (or class of disease) is a way to ensure that the study results are caused by the treatments rather than by chance or other factors. 2017/4/21

Done immediately after randomization
Baseline Assessment Done immediately after randomization Analysis of baseline comparability Stratification and subgrouping according to prognostic variables Evaluation of change Natural history analysis * Imbalance can yield misleading results 2017/4/21

Intervention application 1) Concurrent parallel study design
4- Manipulation Intervention application 1) Concurrent parallel study design 2) Cross over study design 2017/4/21

Study Population Therapy A Therapy B Outcome Outcome
Concurrent Parallel Study Population Randomize Therapy A Therapy B Outcome Outcome 2017/4/21

Cross-over Study Design
Population Randomize Group II Group I 1 1 . Here, drug a is a intervention, drug b is a control therapy. There are two stages. First stage, group I is intervention group and group ii is control group, and compare the outcome between them. Then, after washout period, meaning Medicines are ineffective in vivo, group I is control group given drug b, and group ii is given drug a. so it is named cross over study design. 2 Drug B Drug A 2 2017/4/21

Data Collection and Quality Control
Problems in data collection Missing data Incorrect data Excess variability Minimizing poor quality data Available protocol and manual Development of forms Training Pretesting Techniques to reduce variability (Repeat and Blind assessment) 2017/4/21

Concealment (Blinding)
Masking of treatment from patient, clinician, designer, analyst Of greatest importance if outcome is subjective Protect against bias in outcome assessment Sometimes may not be feasible blinding, an attempt to make the various participants in a study unaware of which treatment patients have been offered, so that the knowledge does not cause them to act differently, thereby damaging the internal validity of the study Unware of which patients are intervention group, or control group 2017/4/21

Quality Monitoring Monitoring of forms Monitoring of procedures
Completeness and consistency even over time Monitoring of procedures Extreme lab values Internal QC system Monitoring of drug handling Quality of drug preparation and misslabelling Discoloration or breaking of the capsules or tablets and changes over time Proper coding of the medications 2017/4/21

Assessing and Reporting Adverse Effects
Should be well defined as the response variable especially the important ones Comparing the rate of different adverse effects in both groups Adverse effects are not considered in sample size calculation Length of follow up give more opportunity for adverse effect to arise Redness, fever, itching, difficulty breath, vomiting, etc 2017/4/21

Participant Adherence (Lost to Follow)
The shorter a study the more likely is the adherence to the intervention regimen Single daily dose drug is preferable than a multiple daily dose drug Patient’s belief in his susceptibility to consequences of the disease Serious consequences make participants more likely to adhere Higher level of education Multicenter trial Some methods to control lost to follow 2017/4/21

Specific groups Compliance (non-compliance) is the extent to which patients follow (neglect) medical advice. responders (nonresponders): the outcomes of patients who initially do (not) improve after treatment No comparing responders with nonresponders to make a conclusion 2017/4/21

Lost to Follow Treatment B n=1,000 Treatment A n=1,000 0 lost 200 lost
Ten years Follow up Miss the information of 200 lost, you could not know the outcome of these people. It is a puzzle, even for the scientist, who use different methods to solve it, but disagree with each other. 600 alive 200 dead 750 alive 250 dead 2017/4/21

Monitoring Response Variables
The investigator’s ethical responsibility to the study participants demands that results in terms of safety and clinical benefit be monitored during the trial. There are ethical, scientific and economic reasons for evaluation of a trial. Data Monitoring Committee 2017/4/21

Close Out Frequently used plan is to follow each participant to a common termination date or when this is not feasible. Post - Study Follow up Data clean up and verification Storage of study material Dissemination of results 2017/4/21

Treatment Trials Placebos are almost never used:
Placebos are used only when no standard treatment exists Patients are told of this possibility before deciding to take part Placebos (treatments, often drugs, designed to look like the medicine being tested but that don’t contain any active ingredient) are almost never used in treatment trials. Placebos are used in treatment trials only when we don’t yet have a known approach (standard agent) for a particular disease. Patients are told if this is a possibility before they decide whether to take part. 2017/4/21

Prevention Trials Evaluate the effectiveness of ways to reduce the risk of a particular disease Enroll healthy people at high risk for developing that disease Unlike treatment trials, prevention clinical trials are studies involving healthy people who are at high risk for developing a particular disease. These studies try to answer specific questions about and evaluate the effectiveness of ways to reduce the risk of disease. 2017/4/21

Prevention Trials Action studies (“doing something”)
Agent studies (“taking something”)—also called “chemoprevention studies” There are two kinds of prevention trials: · Action studies (“doing something”) focus on finding out whether actions people take, such as exercising more or quitting smoking, can prevent disease. · Agent studies (“taking something”) focus on finding out whether taking certain medicines, vitamins, minerals, or food supplements (or a combination of them) may lower the risk of disease. Agent studies are also called “chemoprevention studies.” 2017/4/21

Chemoprevention Trials
Phase 3 chemoprevention trials compare a promising new agent with either a: --Standard agent --Placebo Chemoprevention trials also go through phases, as outlined earlier for treatment trials. However, phase 3 chemoprevention trials compare a promising new agent with either a standard agent or a placebo with two or more groups of people. 1. One group takes the promising new agent (called the study agent). 2. The other group takes either: · A standard agent, already being used for disease prevention · A placebo Placebos are used in prevention trials when we don’t yet have a known approach (standard agent) for prevention. 2017/4/21

Alternatives to Randomized Trials
Randomized, controlled, blinded trials are the standard of excellence for comparisons of treatment effects over time. However, its limitation: lack of adequate patient Costly Time-consuming absence of conclusive evidence Sometimes a practice may have become so well established, in the absence of conclusive evidence of its benefit, that it is difficult to convince physicians and potential participants that a trial is needed. 2017/4/21

Alternatives to randomized trials usually make use of large databases such as those collected for patient care, billing, or administration. secondary data analysis, answering the research question was not the primary reason for collecting the data. 2017/4/21

secondary data’s advantages: Higher degree of confidence, even subgroups analysis more generalizable relatively inexpensive relatively short time 2017/4/21

secondary data’s disadvantages: Carelessly collected and classified Missing some important variables making biased comparisons The trade-off between speed and ease, or between validity 2017/4/21

Comparisons across time and place
non-concurrent controls (historical) or concurrent controls: similar patients in the past, but methods of diagnosis, treatments and prognosis change with time. So RCT is taken as a standard of validity to avoid bias. Different settings or same settings: it is preferable to choose both treated and control patients from the same setting, because a variety of factors often result in very different prognoses in different settings, independently of the treatment under study. Control patients can be chosen from a time and place different from the experimental patients. This approach is convenient but a particularly difficult task. 2017/4/21

Uncontrolled trials Assumption: whatever improvement is observed after treatment is because of treatment. This assumption may be unwarranted for several reasons. Unpredictable Outcome Nonspecific Effects Regression to the Mean Predictable Improvement describe the course of disease in a single group of patients who have been exposed to the intervention of interest. Unpredictable Outcome: In situations where the clinical course is extremely variable for a given patient and from one patient to another, assessing treatment effects by observing changes in the course of disease after treatment is unreliable. Nonspecific Effects In uncontrolled trials, there is no way of separating Hawthorne and placebo effects from treatment effects. But if there are control patients who receive the same attention as the treated ones and a placebo, then these effects cancel out in the comparison. Regression to the Mean Treatments are often tried because a manifestation of disease, e.g., a particularly high blood pressure or fever, is extreme or unusual. In this situation, subsequent measurements are likely to show improvement for purely statistical reasons. As discussed in Chapter 2, patients selected because they represent an extreme high value in a distribution are likely, on the average, to have lower values for later measurements. If those patients are treated after first being found abnormal and the effects of treatment are assessed by subsequent measurements, improvement could be expected even if treatment were ineffective. Predictable Improvement The usual course of some diseases is to improve; if so, therapeutic efforts may coincide with improvement but not cause it. For example, patients tend to seek care for many acute, self-limited diseases, such as upper respiratory infections or gastroenteritis, when symptoms are at their worst. They often begin to recover after seeing the doctor because of the natural course of events regardless of what was done. 2017/4/21

Nonrandom allocation of treatment
If caring for the patients decide Have all the advantages and disadvantages of cohort studies. caring for the patients decide. When this is done, the study has all the advantages and disadvantages of cohort studies. 2017/4/21

Summary RCT, a special case of a cohort study with randomly allocated intervention highly selected Patients, reducing generalizability. Blinding all participants minimize bias but is not always possible or successful Alternative methods weaken internal validity of the study 2017/4/21

Compromises with the ideal include making comparisons to experience with past patients, to past experience with the same patients, or to a concurrent group of patients who are not randomly allocated. When these compromises are done, the internal validity of the study is weakened. 2017/4/21

Homework To search an article about clinical medicine study using epidemiological methods, such as case-control study, cohort study, clinical trial study, published in Pubmed To write a review about it more than 500 words, to explain its advantage and disadvantage. the file title is your name + student number To send it to before December 10th Notice: the score of the review as a part of total score

Question? Assigned readings, session 6 and 7
Topic: Clinical trials; randomization; intention-to-treat analysis; per-protocol analysis; blinding Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010;152:

Experimental Epidemiology (Clinical Trial)

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