Experimental Study ANIMAL AND HUMAN EXPERIMENTS RCT AND NON RCT

EXPERIMENTAL STUDY
ANIMAL AND HUMAN EXPERIMENTS
RCT AND NON RCT
CONFOUNDING
BIAS
BLINDING

1. Experimental Study Department of Community Medicine Dr Dy Patil Medical College And Research Centre-Pune DR SHEEZA SHAIKH

2. 2 Outline of the Presentation INTRODUCTION EPIDEMIOLOGICAL STUDY TYPES EXPERIMENTAL STUDY TYPES OF EXPERIMENTAL STUDY RCT AND ITS OTHER TYPES NON RCT SUMMARY

3. EPIDEMIOLOGY 3 The study of occurrence and distribution of health-related events, states and processes in specified populations including the study of determinants influencing such processes and the application of this knowledge to control relevant health problems ---JOHN M. LAST in 1988

4. 4 Observational Studies Experimental Studies Descriptive Study Analytical Study Cross-sectional Case-control Cohort Randomized Control Trials Field Trials Community Trials Individual Population Case report Case series Cross sectional survey Ecological study TYPES OF EPIDEMIOLOGICAL STUDIES

5. Experimental Study

6. BACKGROUND All who drink of treatment recover in short time , Except those whom it did not help , who will die, it is obvious, therefore, that it fails only in incurable cases. -Galen(129-C.199CE ) Galen gave one of his potions to a lot of patients : some recovered, some died. He thought that was evidence that the potion worked. The problem with Galen’s line of reasoning in that no experiment could disprove it. He could call any treatment superior by claiming that evidence against it doesn’t count. REFERENCE-GORDIS EPIDEMIOLOGY

7. 2.Unintentional Trial by Amboise Pare` In 1537,Ambroise Pare` conducted unplanned trials in the treatment of battle wounds. He used digestive made of yolks of eggs , oil of roses & turpentine due to lack of boiling oil which was standard treatment for war wounds during those days. He found that the digestive medicament worked better. 7

8. Experimental Study (ALSO KNOWN AS INTERVENTION STUDY) Best study design to prove causation. Here, investigator decides who will get the exposure and who will not . So under direct control of the investigator unlike other type prospective study where exposure is not dictated by the investigator. Epidemiologist takes some action, intervention or manipulation in contrast to descriptive studies where no action is taken but observation is done. 8

9. AIM 9 To provide scientific proof of etiological factors. To provide a method of measuring the effectiveness and efficiency of health services.

10. Types of EXPERIMENTAL STUDY 10 Animal Studies Human Studies Randomized Control Trial Non-Randomized Trial Clinical Trials Field Trial Risk Factor Trial Community Intervention Trial Health Services Evaluation Trial Cessation Experiment

11. Animal studies 11 Have played an important role in men’s quest of knowledge. Webster in United States & Topley , Wilson & Greenwood in England had carried out classical animal experiments of inducing epidemics in animals and studying herd immunity under laboratory conditions. Important applications of animal experiments have been in: Experimental reproduction of human diseases in animals Testing the efficacy of preventive & therapeutic measures. Completing the natural history of disease .

12. a)Experimental reproduction of human disease in animals to confirm aetiological hypothesis and to study the pathogenic phenomena or mechanism (b)Testing the efficacy of preventive and therapeutic measures such as vaccines and drugs, and (c)Completing the natural history of disease. For example, naturally occurring leprosy has been found in armadillos. Data obtained from studying these animals indicate that L epra bacilli might exist outside. This suggests that there are environmental or animal reservoirs where the bacteria can survive and potentially spread from. 12

13. 13 Advantages Limitations Can be bred in labs & can be manipulated easily. Rapid multiplication reduces the time of research . Not all human diseases can be reproduced in animals. Conclusions may not be strictly applicable to human being(e.g. WHO trial of typhoid vaccine in Yugoslavia,1950)

14. HUMAN studies 14 Since not all the diseases can be reproduced in animals, Human studies will always be needed. With Human Studies: Diseases etiology can be investigated. Evaluation of preventive and therapeutic measures can be done .

15. 15 Problems in application of experimental method for studying diseases in humans: So , always weight benefits of the experiment against risks involved . Ethical Considerations Logistics

16. Scottish surgeon named JAMES LIND (October 4, 1716 – July 13, 1794)

17. 17

18. Examples of History Planned trial on scurvy by James Lind in 1747: James Lind , a Scottish surgeon took 12 sailors suffering from scurvy & divided them into 6 pairs. He than assigned each pair to 6 different treatments for scurvy. • Two patients: A quart of cider • Two patients: 25 gutts tid Elixir vitrol • Two patients: Two spoonfuls vinegar • Two patients: Half pint sea water • Two patients: Two oranges and 1 lemon • Two patients: Nutmeg and Barley water tid

19. 19 Edward Jenner’s experiment with cowpox in 1796. Finlay & reeds experiments ( 1881-1900)-Mosquito borne nature of Yellow fever was elucidated. Goldberger’s Pellagra experiments,1915 Inducing pellagra by diets deficient in nicotinic acid. Providing evidence that pellagra is a nutritional deficiency disease and not an infectious disease.

20. Experimental studies (hypothesis testing ) 20

21. Experimental trials- Double blinding can be performed on in animal trial Ethical issues on animal is debatable Interim analysis can be done in experimental trial Experimental trials are longitudinal & prospective  Significance of clinical trials - Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat disease. 21

22. Natural Experiments – If experimental studies not possible then natural circumstances can be used in human population that mimic an experimental study John snow - cholera study is an experiment of natural experiment Study Researcher has no control over allocation of subjects Population that can be used- Mi grant population, religious group, population affected by nuclear disaster / natural disaster Used to study E ffects of intervention 22

23. Objectives of CLINICAL TRAILS Clinical trials are normally conducted to evaluate new forms of therapy or prevention methods such as --- • New drugs / treatment • New medical / health care technology • New organization/ delivery system of health care • New methods of primary prevention • New programs of screening or early detection 23

24. 24 TYPES OF EXPERIMENTAL STUDY

25. 1.RANDOMIZED CONTROL TRIAL(RCT) Defination - An epidemiological experiment in which subjects in a population are randomly allocated in to groups, usually called study and control groups to receive or not to receive an experimental, preventive or therapeutic procedures, or intervention. 25

26. -Gold standard for clinical research is RCT -A clinical trial is a planned experiment designed to assess the efficacy of prophylactic / diagnostic / therapeutic agents, devices, regimens, procedures etc. applied to human subjects -For new programs & therapies RCT is the best method of evaluation -Baseline characteristics of intervention are similar in both arms 26

27. -Baseline characteristics are comparable -Investigator bias is minimized by double blinding -Sample size required depends on the hypothesis & type of study -The dropouts from the trial are not excluded from the study - Intention to retreat analysis is done in RCT

28. Steps of RCT 29 1. Drawing up a protocol 2. Selecting reference population & experimental population 3. Randomization 4. Manipulation or intervention 5. Follow-up 6. Assessment of outcome Experimental group Control group

29. 1. DRAWING UP A PROTOCOL Specifies the aims & objectives of the study Size of the sample Question to be answered Selection criteria of study and control group Treatment to be applied- when, where & to whom Responsibilities of parties involved in the trials 30

30. 2. SELECTING REFERENCE POPULATION & EXPERIMENTAL POPULATION i . Reference or target population - It is the population to which the findings of the trial , if found successful, are expected to be applicable - May be geographically limited or limited to persons in specific age, sex, occupational or social groups ii. Experimental or study population Derived from the reference population Actual population that participates in the study It should be randomly chosen from the reference population • Purpose of control group in an experimental study is that it helps to eliminate alternative explanations for the results of the study 31

31. The participants must fulfill these three criteria: • They must give "informed consent? • They should be representative of the population. • They should be qualified or eligible for the trial. Eg : --For testing a new drug for the treatment of anemia participants should be anemic. --In the test of a new vaccine against whooping cough, participants already immune to the disease in question, are not qualifies 32

32. Inclusion Criteria: To specify who will be eligible to be included in the study, based on demographic and clinical characteristics . Exclusion Criteria: To define who will not be eligible to be included in the study. More the exclusion criteria More precise findings, and lesser requirement of sample size. More difficult to find subjects and generalizability will be restricted.

33. 3.RANDOMIZATION Statistical procedure by which the participants are allocated into groups called study & control groups to receive or not to receive the intervention Randomization is done while dividing patients into experimental group & reference group Randomization is the HEART OF RCT Best done by using a table of random numbers Random in randomization means equal & known chance Randomization is better than matching as it removes both confounding & bias - Both known & unknown confounding factors are distributed equally among 2 groups thus nullifying their effect where as matching only useful for known confounding factors  34

34. Purpose of randomization To equalize the effects of extraneous variables, thus guarding against bias Participants have equal & known chance of falling into either of the 2 groups To eliminate selection bias - It ensures that the investigator has no control over allocation to the participants to either study group or control group, hence it eliminates selection bias To ensure comparability of 2 groups To ensure that study groups are comparable on baseline characteristics To have similar prognostic factor among 2 groups Facilitates blinding of treatment Increase i nternal validity of study 35

35. Both groups should be alike with regards to certain variables that might affect the outcome of experiment 36

36. TYPES OF RANDOMIZATION SIMPLE RANDOM ALLOCATION RANDOMIZATION IN GROUPS OF TWO SYSTEMATIC ALLOCATION STRATIFIED ALLOCATION CLUSTER SAMPLING 37

37. 1.Simple Random Allocation • This is the most elementary form of randomization. • It is usually carried out using- -A random-number table or - A computerized random number generator. The Advantage of simple randomization is its ease. The Disadvantage is the possibility of an imbalance between the two groups at any one point specially if the sample size is small. 38

38. 2.Randomization in groups of Two • Also known as Block Randomization. • Block randomization reduces the risk that different numbers of people will be assigned to the Group A (Intervention) and Group B (Control). • At any time, if an even number of patients have been admitted into the study, exactly half would be assigned to Group A and half to Group B. • The order of assignment is randomized. • In randomly permuted blocks, there are several block sizes ( e.g , 4, 6, and 8), and the block size and specific order are chosen randomly at the beginning of each block 39

39. Advantage : • A balance in the number of cases assigned to A versus B at any point in the study (which could be valuable if the study needs to be stopped early) Disadvantages: With fixed blocks, predictability of the group assignment of patients being randomized late in the block by research staff. Can be reduced by using the method of randomly permuted blocks and blinding of research staff to the randomization process. 40

40. 3. Systematic Allocation • This method also ensures equal number of participants in experimental and control groups if even no. of participants take part in the study. • Here, first patient is randomly allocated to a group, next patient goes to alternate group automatically. Subsequent patients are allocated into groups alternatively. Being convenient and having statistical advantages makes this method desirable to use whenever possible. This can also be used for allocating study participants to three, four or more groups. 41

41. 4.Stratified randomization I deal to ensure similarity between experimental & control groups S tudy population is first stratified by each important variable & than randomization is done to treatment groups within each stratum. 42

42. Principle – Classify population into from Homogenecus subgroups (strata) Draw sample in each strata Combine results of all strata Advantage- More precise if variable associated with strata All subgroups represented, allowing separate conclusions abou t each of them Disadvantages Sampling error difficult to measure Loss of precision if small numbers sampled in individual strata Example of stratified sampling- Estimate vaccination coverage in a country One sample drawn in each region Estimates calculated for each stratum Each strata weighted to obtain estimate for country 43

43. 5. Cluster sampling Principle Random sample of groups ("clusters") of units All or proportion of units included selected clusters Advantages Simple: No list of units required Less travel/resources required Disadvantages Sampling error difficult to measures 44

44. 4. MANIPULATION OR INTERVENTION Deliberate application or removal of causal factor (e.g. drug, vaccine, habit etc.) 5. FOLLOW-UP Examination of the experimental & control group subjects at defined intervals of time with equal intensity, under the same given circumstances Loss of follow up is also know as Attrition S ome losses to follow up are inevitable due to factors,such as death, migration loss of interest 45

45. 6 . ASSESSMENT OF OUTCOME • Positive results - Reduced incidence or severity of disease • Negative results - Frequency of Side effects & complications 46

46. 47 presentation title

47. 1. Single blinding Participant is not aware whether he belongs to study group or control group Minimizes subject bias 2. Double blinding Neither the investigator nor the participant is aware of the group allocation & the treatment received Minimizes subject bias & investigator bias 3. Triple blinding Participant, Investigator & Analyzer (person analyzing the data) are all unaware of the two groups Minimizes- subject bias, investigator bias & analyzer bias 48 BLINDING

48. Blinding helps to eliminate • Co-intervention: participants use other therapy or change behavior or study staff, medical providers, family or friends treat participants differently • Biased outcome ascertainment: participants may report symptoms or outcomes differently or physicians or investigators may elicit symptoms or outcomes differently 49

49. Any systematic error in an epidemiological study, occurring during data collection, compilation, analysis & interpretation Arise from human errors of assessment of the outcome due to human element 50 BIAS

50. 51 1.Subject bias • Error introduced by study subjects • Example - participants who may subjectively feel better if knew they were receiving a new treatment a)Attention bias / HAWTHORNE EFFECT • Study subject may systematically alter their behaviour when they know they are being watched Seen in cohort study b)Memory / Recall bias Cases are more likely to remember exposure than controls It is a systematic distortion of retrospective study that can be eliminated by a prospective design 51

51. 2.Observer/ investigator bias • Investigator may be influenced if he knows beforehand that what therapy is given to which patient • Example- bias due to wrong interpretation of laboratory test BERKSONIAN bias- It is a type of selection bias It is due to different rates of admission to hospital due to different diseases 52

52. 3.Analyzer bias - Introduced by analyzer 4.Interviewer bias- Interviewer devotes more time with cases as compared to controls 5. Bias in evaluation - Investigator may subconsciously give a favorable report of the outcome of the trial Blinding, Randomization & Matching help to reduce bias. 53

53. Process of selecting controls in a such a way that they are similar to cases Matching is done to remove known confounding Matching eliminates confounding as it distributes known confounding factors equally in 2 groups Randomization is superior to both matching & blinding as it removes selection bias , whereas Matching removes only known confounding & Blinding removes bias only 54 MATCHING

54. TYPE 1.Caliper matching- Matching of two groups within specified distance of a variable (matching age to within 2 years) 2. Frequency matching- Similar Frequency variable are matched between 2 groups 3. Category matching- Matching study & control groups in broad categories (example-similar occupation) 4. Individual matching- Identifying individual subject for comparison resembling a study subject for matched variable 5.Pair matching- Pair of study & comparison subjects are made

55. Concurrent parallel study designs Comparison is made between 2 random groups One group exposed to specific treatment (experiment group) & the other group not exposed (reference group) Patient remains in the same group throughout the study duration 56 Types of RCT

56. 2.Crossover type of study designs • Each patient serves as his own control -Study group receives the treatment & control group receives the placebo -Patient in each group are taken off from their treatment or placebo to allow elimination of carry over effects -The two groups are now switched - Those who received treatment will receive placebo & those received placebo will now receive the treatment • Both groups acts as exposed as well as non exposed groups • Cases acts as their own controls • Helps in removing ethical concerns 57

57. 3 .Clinical trials • Concerned with evaluating therapeutic agents , mainly drugs • E.g.-trial of aspirin on cardiovascular mortality • Should be carried out before any new therapy is introduced 4 . Preventive trials • Trials of primary preventive measures • E.g.-trials of vaccines or chemoprophylactic drugs 5 . Risk factor trials • Investigator interrupts the usual sequence in the development of disease for those individuals who have risk factors of disease • E.g.- multiple risk factor intervention trial (MRFIT) in USA 58

58. 6 . Cessation experiments Attempt is made to evaluate the effect termination of habit or removal of agent & reduction of disease 7 . Trial of aetiological agents Aims to confirm or refuse an aetiological hypothesis E.g.-trial for retrolental fibroplasia as a cause of blindness 8 . Evaluation of health services • To assess the effectiveness & efficiency of health services • Also called Health Services Research Studies 59

59. Any factor viz associated with both exposure & outcome & has an independent effect in causation of outcome (so itself is a risk factor) Unequally distributed between study & control group Source of bias is interpretation 61 CONFOUNDER

60. Methods used to control confounding Randomization- most ideal method Matching- mostly useful in case control studies Restriction Stratification Statistical modeling Multivariate analysis • Example - A study revealed that lesser incidence of carcinoma colon in pure vegetarians than non vegetarians by which it was concluded that beta carotene is protective against cancer. This may not be true because the vegetarian subjects may be consuming high fibre diet which is protective against cancer 62

61. Phases in clinical trials and obJectives Clinical phase Units Purpose 1.Preclinical phase Lab experiments Animals Pre-testing 2.Clinical phase Phase 0 Healthy human volunteers Micro-dosing Phase I Healthy human volunteers Safety and non-toxicity profile Maximum tolerated dose of drug is given Phase II Patients Efficacy Maximum drug failure reported Phase III Patients Comparison with existing drugs It is an RCT, as comparison of new drug is done with old drug New drug is launched in market after phase III Phase IV Patients Long term and rare side effects Longest phase of trial Post marketing surveillence

62. Ethical Issues • Investigators are responsible to uphold ethical standards and guidelines. • Declaration of Helsinki, developed by the World Medical Association, this set of ethical principles guides medical researchers in conducting research on human subjects. • Some procedures for safeguarding human subjects include: Informed consent procedures. Procedures to safeguard confidentiality. Protocols to preserve safety and address adverse events Reporting study results. 64

63. Three issues of utmost importance: A patient must never be given a treatment that is known to be inferior. Patients must be fully informed about all the circumstances surrounding the treatments in the trial including possible adverse reactions and side effects they may experience. Patients who have entered a trial may withdraw at any time. 65

64. Run-in or Wash out • This is done for the effect of compliance. •Implementation of a run-in or wash out period prior to actual randomization: All participants receive either the active treatment or placebo for weeks or months before formal randomization to a treatment group Those who have difficulty adhering to study or having adverse effects to withdraw before randomization without affecting the validity of the study. 66

65. 67 presentation title NON-RandomiZED Trials 67 presentation title Also known as Quasi-Experimental Designs. It is a type of research in which the investigator manipulates the study factor but does not assign individual subjects randomly to the exposed & non- exposed groups. These are designed as: It is always not possible for ethical , administrative and other reasons to resort to a RCT. Some preventive measures apply only to groups or community-wide basis. When disease RCT require follow-up of thousands of people for a decade or more. As here randomization is not done . So, low comparability than RCT and chances of spurious results are high than RCT .

66. 68 presentation title NON-RandomiZED Trials 68 presentation title These studies may be of following types: Uncontrolled Trials Natural Experiments Before & after comparison studies With control Without control

67. 69 presentation title UNCONTROLLED Trials 69 presentation title There is no comparison group. Initially may be helpful in: Evaluating whether a specific therapy appears to have any value in a particular disease. To determine an appropriate dose. To investigate adverse reactions etc. Use of implied “ historical control” i.e., the experience of earlier untreated patients affected by the same disease .

68. 70 presentation title Historical controls 70 presentation title Advantages: When the disease is uniformly fatal and a new drug becomes available a decline in case fatality that parallels the use of the drug would suggest that the drug is having effect. Disadvantages: Data Records: We are comparing very meticulous system for data collection to the medical records for the historical controls. So, whether a true difference in outcome was there or not in doubted. Many things change over time (ancillary supportive therapy, living conditions, nutrition and lifestyles). Less likely to have clearly defined patient criteria.

69. 71 presentation title NATURAL EXPERIMENTS 71 presentation title When experimental studies are not possible in humans, Natural circumstances that "mimic" an experiment are identified. Example: Group of smokers and non-smokers (naturally separated). Other population groups involved include: migrants, religious or social groups etc. John Snow's discovery that cholera is a water borne disease was an outcome of a natural experiment.

70. 72 presentation title NATURAL EXPERIMENTS 72 presentation title When experimental studies are not possible in humans, Natural circumstances that "mimic" an experiment are identified. Example: Group of smokers and non-smokers (naturally separated). Other population groups involved include: migrants, religious or social groups etc. John Snow's discovery that cholera is a water borne disease was an outcome of a natural experiment.

71. 73 presentation title Before and after comparison studieS without control 73 presentation title Experiment serve as its own control. Incidence of disease before and after introduction of intervention is measured here. Standard for comparison: events which took place prior to use of new treatment or intervention. All group differences are virtually eliminated. Examples: Prevention of scurvy among sailors by James Lind (1750). Studies on transmission of cholera by John Snow (1854). Prevention of polio by Salk and Sabin.

72. 74 presentation title Before and after comparison studieS with control 74 presentation title In absence of control group, results of comparison may be misleading, Alternative is to utilize a "Natural control group" i.c. , the one provided by nature or natural circumstances. Example: Effect of seat belt legislation in one district on RTA related mortality, compared with the another district with no seat belt legislation.

73. 75 presentation title CTRI (CLINICAL TRIALS REGISTRY INDIA) 75 presentation title Health Condition of trial participants is now coded as per ICD-10 classification & must be chosen from the drop down list provided up to a maximum of 4 levels to the nearest diseases category possible. The mission of the CTRI is to ensure all clinical trials in India are registered before enrolling participants. This includes post-marketing surveillance studies, BA/BE studies, and clinical studies in PG theses.

74. 76 presentation title How to register 76 presentation title First login to CTRI website: www.ctri.nic.in Register here: obtain username and password New trial is then added using the CTRI registration : filling data set A reference number of the trial is given by CTRI CTRI checks the dataset and sends back trial modification : incomplete / inappropriate. A unique registration number is provided to the trial valid for submission of the study in any journal

75. The clinical trials are the only way for making a progress in medical science because, to invent new drugs, new therapies, new vaccines, new technologies or new interventions clinical trials are essential 77

76. REFERENCE

77. THANKS for LISTENING