Types of Clinical Trials and Phases

1. HamidSoori Professor of Epidemiology Dept. of Epidemiology, School of Public Health ShahidBeheshti University of Medical Sciences انواع کارآزمايي های بالينیطرح ها و فازها

2. Some references

3. H Soori, Prof. of Epidemiology- SBMU انواع مطالعات تجربي • كارآزمايي باليني شاهددار اتفاقي شده (واحد مطالعه بيماران) و ... Randomized Controlled Trial (R.C.T) • كارآزمايي در عرصه يا بررسي محلي (واحد مطالعه افراد سالم)Field Trial • كارآزمايي در جامعه يا اجتماعي (واحد مطالعات اجتماعات)Community Trial • مطالعات تجربي حيواني • مطالعات تجربي آزمايشگاهي

4. Metaanalysis Systematic Review Clinical Trial Cohort Case-Control Cross-Sectional Ecological Studies Case Series Case Reports Animal Studies Lab studies , Commentaries

5. Randomized Clinical Controlled Trials كارآزمايي‌هاي باليني شاهد‌دار تصادفي

6. هر گونه پژوهش بر روي انسان‌ها كه به منظور كشف،‌ يا تأييد اثرات باليني، دارويي و يا ساير اثرات فارماكو ديناميكي يك فرآورده تحقيقاتي و يا به منظور شناسايي هرگونه واكنش نامطلوب يك فرآورده تحقيقاتي و يا مطالعه جذب، توزيع سوخت و ساز و دفع يك فراورده تحقيقاتي با هدف اثبات بي خطري و يا تأثير آن صورت مي‌گيرد. كارآزمايي باليني عبارتست از:

7. The earliest recorded clinical trial is documented in the Old Testament, and describes how Daniel (800 BC) followed a diet of pulses and water instead of the meat and wine recommended by King Nebuchadnezzar II. تاريخچه كارآزمايي باليني

8. اولين كارآزمايي منظم • The Scottish surgeon, James Lind in 1747, described a planned trial. Lind became interested in scurvy, which killed thousands of British seamen each year. He was intrigued by the story of a sailor who had developed scurvy and had been put ashore on an isolated island where he subsisted on a diet of grasses and then recovered from the scurvy. • تجربه لیند 12 دریانورد بیمار از کشتی Salisbury با ویژگی های نسبتا مشابه و واجد آسکوربوت برای مطالعه انتخاب شدند. به دو تای آنها روزانه یک پیمانه آب سیب و دو تای دیگر روزانه 25 پیمانه محلول زاج، دو تای دیگر روزانه دو قاشق سرکه ، دو نفر آب دریا، و دو تای دیگر میوه جوز و دو تای دیگر از لیمو استفاده کردند. نتایج خارق العاده بود و کسانی که از لیمو استفاده کرده بودند در پایان روز ششم از بیماری رهایی یافتند و بقیه گروهها همچنان علایم بیماری را با خود داشتند.

9. قوانين ابن سينا براي آزمون و استفاده تجربي از داروها980–1037 1-داروي تحت بررسي بايد خالص و بدون تاثير معکوس گرفتن از سرما يا گرما باشد. مواد خارجي نبايد ذات و جوهره آن را تغيير دهند. مواد خارجي نبايد به آن ناخالصي اضافه کنند. 2-دارو، تنها بايد براي يک نوع بيماري آزمايش شود و اگر فردي، بيش از يک مشکل دارد که هر کدام درمان‌هاي متفاوتي را مي‌طلبد و درمان‌ها نيز هر کدام مخالف يکديگر هستند، نمي‌توان مطمئن بود که داروي مورد آزمايش روي کدام يک از شرايط بيمار موثر بوده است. 3-داروها بايد در شرايط متفاوت و متناقض بيماري خاص هم آزمايش شوند و اگر در هر شرايطي موثر بودند، پس نمي‌توان گفت عملکرد دارو براي يک حالت خاص موثر بوده است. 4-توانايي دارو بايد متناسب با شدت بيماري باشد. به عنوان مثال بهتر است دارو در مقادير کم آزمايش شود و به تدريج مقدار آن اضافه شود تا اثرات آن شناخته و از بروز عوارض جانبي ناخواسته پيشگيري شود.

10. قوانين ابن سينا براي آزمون و استفاده تجربي از داروها980–1037 5-زماني که اثر درماني يک دارو ظاهر مي‌شود، بايد در نظر گرفته شود که اگر دارو بلافاصله عمل ‌کند، مشخص است که اين اثر متعلق به داروست و دارو تاثير مثبتي روي خودش دارد. اگر اثر دارو، با تاخير ظاهر شود و اثر درماني آن بعدا ديده شود يا اگر دارو يک اثري پس از اولين مصرف نشان دهد و بعدتر، به روش مخالفي عمل نمايد، پس در اينجا براي شناخت قدرت و اثر درست و حقيقي دارو با مشکل مواجه مي‌شويم. 6-دارو بايد براي بررسي اثر ادامه‌دار يا براي يک زمان طولاني تحت نظر باشد تا مشخص شود که اثرات آن واقعي است يا نه، سپس بايد به صورت ممتد يا در موارد متعددي برسي شود. 7-به منظور شناسايي قدرت و اثر يک دارو، بايد در ابتدا روي انسان امتحان شده و سپس در مورد آن قضاوت شود. اغلب امکان آزمايش دارو روي حيوانات وجود دارد که بر آن اساس نيز نتيجه‌گيري مي‌شود، اما شايد اثرات ديده شده از آن در انسان فرق کند. به طور مثال، يک گياه ريشه‌اي هندي که داراي اثرات سمي کشنده در انسان است، روي سار، هيچ اثر نامناسبي ندارد.»ابن سينا اين قوانين را با اين جمله به اتمام مي‌رساند: «رعايت قوانين بالا براي شناسايي قدرت داروها از راه آزمايش، الزامي است

11. امریکا= 144392 بریتانیا= 34864 آلمان= 32110 کانادا= 19683 فرانسه= 21185 سوئد= 13556 ژاپن= 26098 ایران = 2954 مقاله ترکیه = 8755 مکزیک= 2643 مصر = 1640 عربستان سعودی= 818 مالزی= 547 کویت= 237 تعداد کارآزمایی های بالینی منتشر شده بر اساس ایندکس مدیکوس از 1966 تا 2013 کل موارد در جهان= 627815 مقاله

12. Schematic representation of some stages involved when planning a clinical trial

13. Why RCTs are done? • As they provide better evidence of the effect or the outcome that cannot be obtained with any other observational method. • The variation is minimized and bias is controlled, hence more valid and their results speak truth.

14. What are its Objectives? • They determine whether experimental treatments or trials are safe and effective under controlled environment. • Observation trails address health issues in large groups of people in natural settings.

15. When they are done? • When the laboratory and animal studies yield the most promoting results of the intervention, those results are tested by clinical trials. • When the margin of the expected benefit or the outcome of an intervention is doubtful or very narrow (10-30%) only. • When the margin is large, obvious and beyond doubt, it will be unnecessary to conduct clinical trials.

16. the parts of a good clinical question: • First, define precisely whom the question is about (i.e. ask ‘How would I describe a group of patients similar to this one?’). • Next, define which maneuver you are considering in this patient or population (e.g. a drug treatment), and, if necessary, a comparison maneuver (e.g. placebo or current standard therapy). • Finally, define the desired (or undesired) outcome (e.g. reduced mortality, better quality of life, (QoL) overall cost savings to the health service and so on).

17. Thinking about Clinical Trials

18. Disadvantages of RCTs: Low generalizability. Experimental conditions are so tightly controlled that resemblance to real-world conditions is low. • RCTs commonly over-estimate effectiveness • RCTs may be better at rankingthe efficacy of different treatments rather than realistically estimating their effectiveness. • Costly and difficult to perform. • Not ethical or practical in many situations

19. What are its types? • Treatment trials • Prevention trials • Diagnostic trials • Screening trials • Quality of life trials

20. Treatment trials They test • New treatments • New combination of drugs • New approches to Surgery • New radiation therapy

21. Prevention Trials • They try to find better ways to prevent disease in people and to prevent disease occurrence using • Medicines • Vaccines • Vitamins • Minerals • Lifestyle changes

22. Diagnostic Trials • To find better tests for diagnosis of a disease • To find better procedures for diagnosis of a disease

23. Screening trials • To find out the best way to detect certain diseases or conditions

24. Lifestyle trails • Also called Supportive care trials • Often employed for the chronically ill patients • They explore the ways to improve the quality of life

25. DESIGN OF A RANDOMIZED TRIAL

26. DESIGN OF A RANDOMIZED CLINICAL TRIAL

27. Target population andsample • Sample size (Alpha & Beta errors, Effect size) • Selection criteria • Inclusion criteria • Exclusion criteria • Sampling • Convenience samples • Probability samples • Simple Random Sample • Stratified Random Sample • Cluster Random Sample • Systematic Random Sample R.C. T Topics:

28. Random Allocation • Choosing an accessible population • Measurement Scales (Continuous, Ordinal, or Categorical measurement) • Intention to Treat • Compliance and Noncompliance • Precision of Measurements R.C. T Topics (continue):

29. There are three primary justifications forthe use of this method of allocation 1. In principle at least, it ensures that the groups to be given the different treatments are comparable. 2. The allocation to treatment is unknown at the time of entry to the trial. 3. There is a statistically sound estimate of error available for the comparison of the two treatment groups.

30. Standardizing the measurement methods e.g. variation in blood pressure measurement due to variable rate of cuff deflation (faster than 2mm Hg/sec or slower) Training the observers/raters e.g. variation in BP due to variable observer technique (applying and calculation of KAPPA) Refining the instruments e.g. variation in BP due to the digit performance Automating the instruments e.g. variation in BP due to variable observer technique Repetition the measurement e.g. use mean of two or more BP measurements Strategies for enhancing precision:

31. Accuracy AND Quality Control Controlling of Observer Bias, Subject Bias, Instrument Bias Confounding variables and control of them Randomization Blinding What are the main outcome variables? Applying the interventions Monitoring the outcomes (Who will monitor, how often to monitor, how to monitor) Follow-up (Procedure, Duration or length, Maximizing follow-up, Minimizing the loose of follow-up) Analyzing the results

32. Bias in Clinical trials 1. Selection bias/Volunteer Bias 2. Allocation bias 3. Assessment bias 4. Publication bias 5. Attrition bias 6. Stopping rules

33. Selection Bias Selection bias can occur when the decision to enter a patient to an RCT is influenced by knowledge of which treatment the patient will receive when entered. In a well-run RCT selection bias should not occur, because the patient will be formally entered into the study before the treatment is chosen.

34. Allocation Bias • Patients have many factors that can affect the outcome of their therapy, regardless of the treatment group they are allocated. • These prognostic factors might be, for example: whether the tumor is advanced or not; whether initial disease control was good; higher or lower natural levels of immunity; whether or not a patient can walk (ambulatory status).

35. Assessment Bias At the end of the trial, and often during its course, observations are made on a variety of outcome variables. Many of these will be entirely objective, such as whether a patient has died or the Concentration of hemoglobin in the blood. Other variables are less objective: the proportion of the body covered with plaques of psoriasis is usually assessed by a dermatologist using various rules of thumb; blood pressure (systolic) is usually measured by reducing the pressure in the cuff of a sphygmomanometer until the sound of a pulse can be heard in an artery of the arm. Other variables, such as measures of quality of life, though clinically very important, are necessarily highly subjective.

36. Publication Bias • The ultimate aim of an RCT is to influence medical practice. This is generally done by publishing a report of the results of the trial in a medical journal. • Papers reporting positive findings are more likely to be published than those that do not.

37. Attrition bias Attrition bias refers to systematic differences between groups in withdrawals from a study. Withdrawals from the study lead to incomplete outcome data. There are two reasons for withdrawals or incomplete outcome data in clinical trials. Exclusions refer to situations in which some participants are omitted from reports of analyses, despite outcome data being available to the trials . Attrition refers to situations in which outcome data are not available.

38. Stopping Rules • Once a trial has been started, how will it stop? • A crude possibility that is clearly unsatisfactory when assessing the “by-chance” outcomes of a trial is to keep analyzing the data as the trial continues and stop when a promising result has been obtained. • This would obviously induce a bias.

39. Feasibility of Masking • Ethics: The double-masking procedure should not result in any harm or undue risk to a patient • Practicality: It may be impossible to mask some treatments • Avoidance of bias:Masked studies require extra effort (manufacturing look-alike pills, setting up coding systems, etc.) • Compromise: Sometimes partial masking, e.g., independent masked evaluators, can be sufficient to reduce bias in treatment comparison • Although masked trials require extra effort, sometimes they are the only way to obtain an objective answer to a clinical question

40. Any Question? Thank you for your attention

41. لطفا برای هرکدام از انواع کارآزمایی های زیر دو عنوان یا هدف تحقیقاتی تعیین کنید: Treatment trials Prevention trials Diagnostic trials Screening trials Quality of life trials Excercise

42. Exercise It has recently become apparent that various disorders of the stomach are due to infection with a bacterium Helicobacter pylori (H. pylori). Thus, for example, stomach ulcers are now treated with a short course of antibiotics that eradicate the H. pylori. The presence of H. pylori in a person’s gut can be detected with reasonable certainty by analyzing a sample of the patient’s breath. In a general practice, there are many patients suffering from stomach problems for which, despite much investigation, no cause could be found (dyspepsia of unknown origin). These patients are treated by giving tablets T to reduce the amount of acid secreted by the stomach: they take these tablets permanently. It was decided to run a trial to see if giving antibiotics to eradicate H. pylori was preferable to a maintenance dose of T. The outcome would be the amount of indigestion remedy (a simple antacid) used by the patient in the year that the trial would last. It is proposed to randomize patients to two groups, one receiving T for the whole year and the other receiving antibiotics for the first three weeks of the year. In the group randomized to receive the antibiotics, it was suggested that the breath test should be administered and the antibiotic given only to those who gave a positive test. Those patients given antibiotics could then be compared with those given tablets. Explain why this would give a biased comparison and suggest alternatives that would be unbiased.

43. The comparison is biased because we are not comparing groups formed by randomization. The groups to receive antibiotics or T were comparable when randomized, but patients in the antibiotic group who did not test positive for H. pylori were excluded. It is at least plausible that these individuals may be less seriously diseased, so we are leaving a group of such patients in the T group but excluding them from the antibiotic group, thereby biasing the comparison. Four possible alternatives are as follows:• Perform the breath test before randomization and only randomize those with a positive breath test. All patients receiving antibiotics are compared with all patients receiving T and the comparison is unbiased. This is probably the best option but has the disadvantage that entry to the trial depends on the results of a test that is not 100% accurate; some patients with H. pylori will test negative and not be offered a treatment that would help.• Randomize patients before the breath test and give antibiotics to all randomized to that group, regardless of the outcome of the breath test. Again, comparison of the groups receiving antibiotics and T would be as formed by randomization and therefore comparable. The disadvantage is that antibiotics would be given to patients in whom there is no infection; antibiotic treatment can lead to problems and the doctor may feel he needs some evidence of infection before exposing a patient to such a risk, however small. • Perform the test as described in the question, but compare all those randomized to antibiotics with all those randomized to T , regardless of whether or not they actually received antibiotics. Again, this would be unbiased because we are comparing groups as formed by randomization. However, the trial would need to decide what treatment should be offered to those randomized to antibiotics who had negative breath tests. If they were given T , then the trial would be less powerful than it might have been because of the presence of a proportion of identically treated patients in both groups.• Perform the trial as in the question but perform the breath test in the T group too, and then compare only those with positive breath tests. Although this is probably far better than the suggestion in the question, the groups being compared (allocated to antibiotics and then found to have positive breath test vs. allocated to T and then found to have positive breath test) have not been formed solely by randomization, so this comparison cannot be claimed to be unbiased.

44. پایگاه پاورپوینت فارسیwww.txtzoom.comبانک اطلاعات هوشمند اسلاید