experimental study -DR SHUHAIB

2. EXPERIMENTAL EPIDEMOLOGY

3. contents
• INTROUCTION
• HISTORY
• STEPS IN RANDOMIZED CONTROL 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.
TYPES OF RCT

4. INTRODUCTION
• Evidence Based medicine.
• Hypothesis testing research studies (Experimental
studies) are those where the researcher tests the
hypotheses of causal relationships between variables.

5. CHARACTERISTICS
• Experimental research is defined as “OBSERVATIONS
UNDER CONTROLLED CONDITIONS”.
• In experimental design the researcher is active agent
rather than a passive observer.
• Experimental designs are concerned with examination of
the effect of an independent variable on dependent
variable, where the independent variable is manipulated
through treatment or intervention(s).

6. History
• As early as 1510 unintentional trial conducted by AMBROISE
PARE , a leading figure in surgery then .

7. FIRST PLANNED TRIAL BY JAMES LIND IN 1747
• He examined twelve patients with scurvy on board the
Salisbury at sea.
• The cases had similar findings, they stayed in one place
and had one common diet.

8. • 1943: The First Double blind Controlled Trial - Patulin for
Common Cold
• 1946 First Randomized Curative Trial - The Randomized
Controlled Trial Of Streptomycin

9. STEPS IN RCT
1. Drawing up a protocol.
2. Selecting reference and experimental populations.
3. Randomization.
4. Manipulation or intervention.
5. Follow-up.
6. Assessment of outcome.

10. DRAWING UP A PROTOCOL
• aims and objectives of the study,
• questions to be answered,
• criteria for the selection of study and control groups,
• size of the sample,
• the procedures for allocation of subjects into study and control
groups,

11. • treatments to be applied - when and where and how to
what kind of patients,
• standardization of working procedures and
• schedules as well as responsibilities of the parties
involved in the trial.

12. SELECTING REFERENCE AND
EXPERIMENTAL POPULATIONS
a) Reference or target population
It is the population to which the findings of the trial, if found
successful, are expected to be applicable.
• Whole population
• Geographically limited
• Age or sex
• Occupation or social group

13. (b) Experimental or study population
The study population is derived from the reference
population
It should be randomly chosen from the reference population
The participants or volunters must fulfil the following three
criteria

14. RANDOMIZATION
• Randomization is the "heart" of a control trial
• Is a statistical procedure by which the participants are
allocated into groups usually called "study“ and "control"
groups, to receive or not to receive
⮚An experimental
⮚Preventive or therapeutic procedure,
⮚Manoeuvre or intervention

15. • Randomization ensures that the investigator has no
control over allocation of participants to either study or
control group, thus eliminating what is known as
"selection bias“
• It is crucial that both the groups should be alike with
regard to certain variables or characteristics that might
affect the outcome of the experiment (e.g., age, sex).

16. MANIPULATION
• The next step is to intervene or manipulate the study
(experimental) group by the deliberate application or
withdrawal or reduction of the suspected causal factor
(e.g,, this may be a drug, vaccine, dietary component, a
habit, etc) as laid down in the protocol.

17. FOLLOW UP
• This implies examination of the experimental and control
group subjects at defined intervals of time, in a standard
manner, with equal intensity, under the same given
circumstances. in the same time frame till final
assessment of outcome.
• The follow-up may be short or may require many years
depending upon the study undertaken.
• Attrition 🡪It may be mentioned that some losses to
follow-up are inevitable due to factors, such as death,
migration and loss of interest

18. ASSESSMENT
• The final step is assessment of the outcome of the trial in
terms of :

20. In order to reduce these problems , a technique known as
“blinding” is adopted , which will ensure that the outcome is
assessed objectively

21. THANKYOU

22. TYPES OF RCT
• Clinical trials
• Preventive trials
• Risk factor trial
• Cessation trial
• Trial of etiological agent
• Evaluation of health services

23. CLINICAL TRIAL
• Concerned with evaluating therapeutic agents, mainly
drugs.
• Many ethical , administrative and technical problems are
involved in the conduct of clinical trials – nevertheless ,
they are a powerful tool and should be carried out before
any new therapy.

24. PRE – CLINICAL STUDIES
• Before starting clinical trials on drugs, extensive pre-
clinical studies are conducted.
• Pre-clinical studies involve in vitro studies and trials
on animal populations in order to obtain preliminary
efficacy and pharmacokinetic information and to
assist in decisions regarding further development of
the test compound.
24

25. • Cell studies: These are often the first tests done
when looking at a new form of treatment.
Researchers look for effects of the new treatment on
cells on a laboratory dish or in a test tube.
• Animal studies: Treatments that appear promising
in cell studies are next tested on animals. This gives
the researchers an idea of how safe the new
treatment is in a living organism.
25

26. PHASE 0
• Phase 0 is a recent designation for exploratory, first-
in-human trials conducted in accordance with the
United States Food and Drug Administration's (FDA)
2006 Guidance on Exploratory Investigational New
Drug (IND) Studies.
• Phase 0 trials are also known as human micro dosing
studies
26

27. Distinctive features of Phase 0
• Primary goal:- Pharmacodynamic and Pharmacokinetic
particularly oral bioavailability and half-life of the drug.
• Dose: it is 1/100th of therapeutic dose.
• Subjects: 10-15 healthy volunteers.
• A Phase 0 study gives no data on safety or efficacy, being
by definition a dose too low to cause any therapeutic
effect.

28. PHASE I
• Phase I trials are the first stage of testing in human
subjects. Normally, a small group of 20–100 healthy
volunteers will be recruited.
• Phase I trials also normally include dose-ranging,
also called dose escalation studies, so that the best
and safest dose can be found and to discover the
point at which a compound is too poisonous to
administer
28

29. Distinctive features of Phase 1
⮚Primary goal: To assess the safety (pharmacovigilance),
tolerability, pharmacokinetics, and pharmacodynamis of a
drug.
⮚These trials are often conducted in an inpatient clinic,
where the subject can be observed by full-time staff.
⮚Phase I trials most often include healthy volunteers.
⮚Volunteers are paid an inconvenience fee for their time
spent in the volunteer centre. Pay depends on length of
participation

30. PHASE II
• Once a dose or range of doses is determined, the
next goal is to evaluate whether the drug has any
biological activity or effect. Phase II trials are
performed on larger groups (100-300) and are
designed to assess how well the drug works, as well
as to continue Phase I safety assessments.
30

31. Types of Phase 2

32. Distinctive features of phase 2a
• Primary goal: To determine the therapeutic efficacy.
• Trial design: Comparison with baseline status. Open
level or single/ double-blind.
• Dose escalation.
• Parallel dose response.

33. Distinctive features of Phase 2b
⮚Pivotal studies.
⮚Objectives: Focus on aspects of phase 2a trial.
Blinding.
Placebo or other concurrent control.
Crossover treatments.
Multicenter.
⮚Subjects: similar to phase 2a.
⮚Trial design: Single or double blinded.
⮚ Conducted at multiple sites

34. PHASE 3
• Phase III studies are randomized controlled multicenter
trials on large patient groups (300–3,000 or more
depending upon the disease/medical condition studied)
and are aimed at being the definitive assessment of how
effective the drug is, in comparison with current 'gold
standard' treatment.

35. Types of Phase 3
Phase 3b: Phase III trials
will continue while the
regulatory submission is
pending at the appropriate
regulatory agency. This
allows patients to continue
to receive possibly
lifesaving drugs until the
drug can be obtained by
purchase. i.e.
Antiretroviral,
Anticancer etc.
⮚Peri-approval studies.

36. PHASE IV
• Although it has been customary to approve drugs or
devices for general use following successful phase
III trials.
• Phase IV trials involve the post-launch safety
surveillance and ongoing technical support of a
drug.
• Such adverse effects detected by Phase IV trials
may result in the withdrawal or restriction of a drug.
36

37. 2. PREVENTIVE TRIALS
• It implies trials of primary preventive measures,
to prevent or eliminate disease on an
experimental basis. The most frequently
occurring preventive trials are of vaccines and
chemo-prophylactic drugs.
37

38. 3. RISK FACTOR TRIAL
• A type of preventive trial is the trial of risk
factors in which the investigator intervenes to
interrupt the usual sequence in the development
of disease for those individuals who have ‘risk
factor’ for developing the disease.
• Examples are: cholesterol and coronary heart
disease, smoking and lung cancer, sugar intake
and dental caries, etc. 38

39. 4. CESSATION EXPERIMENTS
• Here, an attempt is made to evaluate the
termination of a habit (or removal of a suspected
agent) which is considered to be causally related
to the disease.
• A good example is that of smoking and lung
cancer.
39

40. 5. TRIAL OF ETIOLOGICAL AGENTS
• One of the aims of experimental epidemiology is
to confirm or refute an etiological hypothesis.
Since most diseases are disabling, unpleasant or
fatal in humans, these experiments are therefore
rarely possible.
40

41. 6. EVALUATION OF HEALTH SERVICES:
• Randomized controlled trials have been extended to
assess the effectiveness and efficacy of health services.
Often, choices have to be made between alternative
policies of health care delivery.
• The necessity of choice arises from the fact that resources
are limited, and priorities must be set for the
implementation of a large number of activities.
41

42. 7. COMMUNITY INTERVENTION TRIALS
(CITs)
• CITs are usually carried out in hospitals or
clinics, and are usually directed at a patient group
with specific health conditions.
• A classical example would be that of testing a
vaccine. Some communities will be randomly
assigned to receive the vaccine, while other will
just have a placebo. The major difference here is
that the randomization is done on communities
rather than individuals. 42

43. Thankyou

44. EXPERIMENTAL RESEARCH DESIGN
• PRE EXPERIMENTAL DESIGN
• QUASI EXPERIMENTAL DESIGN &
• TRUE EXPERIMENTAL DESIGN
• Basic principles of experimental designs
• - Prof R. A. Fisher

45. 1.PRE-EXPERIMENTAL DESIGNS
• Pre-experimental designs are the weakest designs
• They lack one or more charecterstic of true experimrntal
design.
• Hence there is no control for internal validity

46. 1.ONE-SHOT CASE STUDY DESIGN
• A treatment is given to one group
• No control for any of the internal validity

47. 2.BEFORE AND AFTER WITHOUT
CONTROL DESIGN
• In this single test group or area is selected and the dependant
variable is measured before and after the treatment.
Treatment effect = Y-X
47
Level of
phenomenon
before
treatment
Level of
phenomenon
after treatment
Treatment
introduced

48. 3.STATIC GROUP COMPARISON
DESIGN
• There will be a comparison group who does not receive the
treatment
TREATME
NT
EXP
GROUP
CONTRO
L GRP
POST
TEST
POST
TEST

49. QUASI EXPERIMENTAL DESIGN
• Where true experimental designs are not possible.
• Stronger than pre experimental designs
• Donot involve the use of randomization and control

50. 1.INTERRUPTED TIME SERIES DESIGN
• O1 O2 O3 O4 X O2 O3 O4 O5
POSTTEST
PRETEST
PRETEST
POSTTEST
PRETEST
POSTTEST
TREAT
MENT

51. 2.EQUIVALENT TIME SAMPLE DESIGN
TREAT
MENT 1
POSTTEST
1
TREAT
MENT 2
POSTTEST
2
TREAT
MENT 1
POSTTEST
1
TREAT
MENT 2
POSTTEST
2

52. 3.NON EQUIVALENT CONTROL GROUP
DESIGN
POST
TEST
POSTTEST
POSTTEST
EXP GROUP
CONTROL
GRP
TREATMET
PRE
TEST
PRE
TEST

53. 2.TRUE EXPERIMENTAL DESIGNS
• In true experimental designs the researchers have
complete control over the extraneous variables and can
predict confidently that the observed effect on the
dependent variable is only due to the manipulation of
independent variable.

54. TYPES OF TRUE EXPERIMENTAL
DESIGNS
• 1. POST TEST ONLY DESIGN.
• 2. PRETEST-POST-TEST-ONLY DESIGN.
• 3. SOLOMON FOUR GROUP DESIGN.
• 4. COMPLETELY RANDOMIZED DESIGN
. TWO-GROUP SIMPLE RANDOMIZED DESIGN
RANDOM REPLICATIGNION DESIGN
RANDOMIZED BLOCK DESIGN
CROSS OVER DESIGN.
• 5. LATIN SQUARE DESIGN
• 6 . FACTORIAL DESIGN

55. 1.POST TEST ONLY CONTROL DESIGN
RANDOM
ASSIGNMENT
EXP
GROUP
CONTRO
L GRP
TREATME
NT
POST
TEST
POST
TEST

56. 2.PRETEST –POST TEST ONLY DESIGN
RANDOM
ASSIGNMET
EXP GROUP
CONTROL
GRP
TREATME
NT
POST
TEST
POST
TEST
PRE
TEST
PRE
TEST

57. 3.SOLOMON FOUR GROUP DESIGN
RANDOM
ASSIGNMENT
Exp grp I
Exp grp
II
Cont grp
I
Cont grp
II
Pre test
Pre test
Treatment
Treatment
Post
test
Post
test
Post
test
Post
test

58. 4.COMPLETELY RANDOMIZED DESIGN
• Involves the principle of replication and randomization.
• Simplest possible design and used when experimental
areas are homogeneous.
1. TWO-GROUP SIMPLE RANDOMIZED DESIGN
2. RANDOM REPLICATIGNION DESIGN
3. RANDOMIZED BLOCK DESIGN
4. CROSSOVER DESIGN

59. TWO-GROUP SIMPLE RANDOMIZED DESIGN
59
POPULATION
RANDOMLY SELECTED
SAMPLE
RANDOMLY ASSIGNED
EXPERIMENTAL
GROUP
CONTROL
GROUP
TREATMENT B TREATMENT A

60. RANDOM REPLICATION DESIGN

61. RANDOMIZED BLOCK DESIGN

62. 5.LATIN SQUARE DESIGN
1 2 3 4
1
2
3
4

63. 6.FACTORIAL DESIGN
• Used in experiments where the effects of varying more
than one factor are to be determined.

64. SIMPLE FACTORIAL OR TWO-FACTOR
FACTORIAL DESIGN
64

65. COMPLEX FACTORIAL OR MULTI-FACTOR
FACTORIAL DESIGN
65

66. THREATS TO INTERAL VALIDITY
• Internal validity exists if the observed effects of the
independent variable on the dependent variable are real not
caused by the extraneous factors.

67. HISTORY
• A history effect threatens internal validity when events
occur between the pretest and posttest of a research study
that could effect participants in such a way as to impact
the dependent variable.
MATURATION
• A maturation effect occurs when there are changes seen in
subjects because of the time that has elapsed since the
study began and which maynot be the result of any
program effects.
• Eg. School exercise programe, school oral health
intervention programme.

68. TESTING
• While conducting a pretest, the participants will be ready
to perform good in posttest
INSTRUMENTATION
• The instruments used to collect data in a study can cause
threats to internal validity when measurments are not
accurate or procedures are not standardized.

69. SELECTION BIAS
• Anytime individuals are selected in a nonrandom manner,
selection bias may be present, which may reduce internal
validity.
SELECTION MATURATION EFFECT
• It actually combines a selection bias with a maturation
threat this occurs when using intact groups that vary in
their maturation level.
• Pretesting or prescreening groups on maturity level is a
way to avoid this threat to internal validity.

70. STATISTICAL REGRESSION
• Statistical regression concerns occur when participants are
selected on the basis of their extremely high and low
scores.
ATTRTION OR MORTALITY
• It is common to lose participants over the course of a
study.
• participants may die, poor health status,may move to
different areas.
Eg smoking sessation programme

71. HAWTHORNE EFFECT
• Participants behaviour will change when they know that
they are invoved in a study.
• This phenomenon was first observed in hawthorne plant
of the westrn electric company in chicago.
• Control group also has to get similar kind of attention.
PLACEBO EFFECT
• A placebo effect is caused by participants expectataions
rather than by any provided treatment.
• Blinding can be done to overcome this.

72. DIFFUSION OF TREATMENT
• A diffusion effect occurs when the treatment being
applied to one group spills over or contaminates another
group.
• Occurs when the two groups are working or living
togather.
• To overcome this control group can be selected from
different city or different community.

73. IMPLEMENTATION
• The individual or individuals who is responsible for
implementing the experimental treatment inadvertantly
introduce inequality or bias in the study.
• There are two types of implementation errors.
• 1. If there are multiple people providing the treatment.
• 2. If the individual favours one group than the other.

74. THREATS TO EXTERNAL VALIDITY
• External validity is concerned with the ability to
generalize study results to other groups and settings
beyond those in the current experiment.

75. SELECTION TREATMENT
INTRACTION
• This threat concerns the ability of a researcher to
generalize the results of a study beyond the groups
involved in the study.

76. SETTING TRATMENT INTERACTION
• This threat concerns the extent to which the
environmental conditions or setting under which an
experimental study was conducted can be duplicated in
other setting.

77. HISTORY TRATMENT INTERACTION
• This threat develops when the researcher tries to
generalize findings to past and furure situations.

78. INTERNATIONAL REGULATORY
ORGANIZATIONS
Good clinical practice (GCP)
• Good Clinical Practice (GCP) is an international ethical
and scientific standard for conducting biomedical and
behavioral research involving human participants.
• This standard ensures the rights, safety, well-being, and
confidentiality of trial participants and the data collected
in clinical trials, as well as the reported results of clinical
trials, are credible and accurate.

79. International Council on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for
Human Use (ICH)
• The International Council on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for
Human Use (ICH) is a project that brings together the
regulatory authorities of Europe, Japan and the United
States and experts from the pharmaceutical industry in the
three regions to discuss scientific and technical aspects of
pharmaceutical product registration.
ICH guidelines have been adopted as law in several
countries

80. REGULATIONS IN INDIA
• Regulations are mechanisms to ensure that the quality and
integrity of data collected in clinical trials is maintained
and also to ensure that the rights, safety and welfare of
research participants are protected.

81. TYPES OF REGULATORY MECHANISMS
• Law: A rule of conduct enforced by a controlling
authority e.g., Drugs and Cosmetics Act 1940 and Rules
1945.
• Regulation: An interpretation of how to implement a law
schedule e.g., Y schedule is the Indian regulation for
clinical research issued by CDSCO, headed by DCGI,
FDA Bhawan, Delhi.
• Guideline: An interpretation of the regulations which has
no legal binding and may not be universally accepted. It
is accepted as Industry Standards e.g., Indian Council of
Medical Research [ICMR] guidelines, Indian GCP
guidelines.

82. THE DRUGS & COSMETICS ACT, 1940
• It contains powers for regulating and ensuring quality,
safety and efficacy of drugs and clinical trials and the
necessary rules, procedures and guidelines have been
framed under the Drugs and Cosmetics Rules, 1945.
Rules for conducting clinical trials in India are prescribed
under Rule-122DA, 122DAA, 122DAB, 122DAC,
122DD, 122E and Schedule Y to the Drug and Cosmetics
Rules, 1945

83. The different rules for regulation of clinical trials
are as follows
• Permission to conduct clinical trial (Rule 122 DA)
• Definition of Clinical trials (Rule 122 DAA)
• Compensation in case of trial-related injury or death (Rule 122
DAB)
• Conditions of Clinical Trial permission & Inspection (Rule 122
DAC)
• Registration of Ethics Committee (Rule 122 DD)
• Definitions of New Drugs (Rule 122 E)

84. THE CENTRAL DRUGS STANDARD CONTROL
ORGANIZATION (CDSCO )
• The Central Drugs Standard Control Organization
(CDSCO) is the Central Drug Authority for discharging
functions assigned to the Central Government under the
Drugs and Cosmetics Act..
Major functions of CDSCO:
• Regulatory control over the import of drugs,
• Approval of new drugs and clinical trials,
• Meetings of Drugs Consultative Committee (DCC) and
Drugs Technical Advisory Board (DTAB),
• Approval of certain licences as Central Licence
Approving Authority

85. Prerequisites of conducting a clinical trial in
India
• Permission from the Drugs Controller General, India
(DCGI).
• Approval from respective Ethics Committee where the
study is planned.
• Mandatory registration on the ICMR maintained website

86. The Clinical Trials Registry- India (CTRI),
• The Clinical Trials Registry- India (CTRI), hosted at the
ICMR National Institute of Medical Statistics (NIMS), is
a free and online public record system for registration of
clinical trials being conducted in India that was launched
on 20th July 2007 (www.ctri.nic.in).
• Initiated as a voluntary measure, since 15th June 2009,
trial registration in the CTRI has been made mandatory
by the Drugs Controller General (India) (DCGI)

87. • Any researcher who plans to conduct a trial involving
human participants, of any intervention such as
• drugs,
• surgical procedures,
• preventive measures,
• lifestyle modifications,
• devices,
• educational or behavioral treatment,
• rehabilitation strategies
• as well as trials being conducted in the purview of the
Department of AYUSH
expected to register the trial in the CTRI before enrollment
of the first participant..

88. • Trial registration involves public declaration and
identification of trial investigators, sponsors,
interventions, patient population etc before the enrollment
of the first patient.
• Submission of Ethics approval and DCGI approval (if
applicable) is essential for trial registration in the CTRI

89. REPORTING OF CLINICAL TRIAL
• Randomised controlled trials, when appropriately
designed, conducted, and reported, represent the gold
standard in evaluating healthcare interventions.
• Flaws in the design, conduct, analysis, and reporting of
randomised trials can cause the effect of an intervention
to be underestimated or overestimated.
• To improve the quality of reporting of clinical trial
various scales and checklists are available.

96. CONSORT
• Consort (consolidated standards of reporting trials)
encompasses various initiatives developed by the consort
group to alleviate the problems arising from inadequate
reporting of randomized controlled trials.

97. HISTORY
Concurrently, and
independently, another
group of experts, the
Asilomar Working Group
California, USA, and were
working on a similar
mandate.
1993, 30 experts - medical
journal editors, clinical
trialists, epidemiologists, and
methodologists - met in
Ottawa, Canada
SORT
1995 representatives from both these groups met in
Chicago, USA, with the aim of merging the best of
the SORT and Asilomar proposals into a single,
coherent evidence-based recommendation

101. The Cochrane Collaboration’s tool for assessing risk
of bias in randomised trials
Principles for assessing risk of bias
1. Do not use quality scales
2. Focus on internal validity
3. Assess the risk of bias in trial results, not the quality of
reporting or methodological problems that are not
directly related to risk of bias
4. Assessments of risk of bias require judgment
5. Choose domains to be assessed based on a combination
of theoretical and empirical considerations
6. Focus on risk of bias in the data as represented in the
review rather than as originally reported
7. Report outcome specific evaluations of risk of bias

102. The risk of bias tool covers six domains of bias:
•
Bias domain Source of bias
Selection bias Random sequence generation
Allocation concealmentd
Performance bias, Blinding of participants and personnel
Detection bias Blinding of outcome assessment
Attrition bias Incomplete outcome data
Reporting bias, Selective reporting
Other bias Anything else, ideally prespecifie

104. CONCLUSION
• Since the Scurvy trial, clinical trials have evolved into a
standardized procedure, focusing on scientific assessment
of efficacy and guarding the patient safety.
• Eventhough the exponential growth in the field of
RCT,there is ample evidence that many trials are
methodologically weak and increasing evidence that
deficiencies translate into biased findings of systematic
reviews.
• The assessment of the methodological quality of
controlled trials and the conduct of sensitivity analyses
should therefore be considered routine procedures in
systematic reviews and metaanalysis

105. REFERENCES
• Park K. Textbook of Preventive and Social Medicine.22nd ed,
Banarasidas Bhanot publishers; 2007,75-81
• Kothari CR. Research methodology methods and
techniques.2nd ed, New age international publishers;2005,40-
50.
• WHO.health research methodolgy: A guide for training
research methods;2nd ed,2001,55-70
• Leon Gordis. Epidemiology; 3rd ed.,Elsevier Saunders
pubishers;2004,115-130

106. • Bhatt A. Evolution of Clinical Research: A History Before and
Beyond James Lind. Perspect Clin Res. 2010 Jan-Mar; 1(1): 6–
10.
• J. Sanmukhani and C. B. Tripathi. Ethics in Clinical Research:
The Indian Perspective. Indian J Pharm Sci. 2011 Mar-
Apr; 73(2): 125–130.
• Cochran and Cox.Completely Randomized Designs Adapted
from Experimental Designs, 2nd ed., (1957)
• Dan Nettleton. A Discussion of Statistical Methods for Design
and Analysis of Microarray Experiments for Plant Scientists.
Plant Cell. 2006 September; 18(9): 2112–2121.

107. • Oxman AD, Guyatt GH: Guidelines for reading literature
reviews. Can Med Assoc J 138:697-703, 1988
• Wood L, Egger M, Gluud LL, Schulz K, Jüni P, Altman DG,
et al. Empirical evidence of bias in treatment effect estimatesin
controlled trials with different interventions and outcomes:
metaepidemiological study. BMJ2008;336:6015