Epidemiology
Clinical Trials
23.10.2014
Outline
• Basic principles
• Biases
• Ethics- GCP
• Statistical analysis
• Ethics
Well-designed clinical research
Methodology
Ethics
What is a clinical trial?
•
Prospective study comparing the effect and
value of intervention(s) (against a control) in
human subjects (Comparative)
• Alternative definition- experimental study in
humans in which the investigator determines
the exposure/intervention
‫אלגוריתם לסיווג סוגי מחקר בבני אדם‬
!!‫היום‬
Surveys
Case Reports
Case Series
Ecological
study
Early phases of clinical research
Pre-clinical studies
• Pre-clinical studies involve in vitro and in vivo
experiments
Phase 0 – FDA 2006
• “first-in-human” trials also known as human microdosing
studies
• designed to speed up development of promising drugs or
imaging agents
• administration of single subtherapeutic doses of study
drug to a small number of subjects (10 to 15) to gather
preliminary data on pharmacokinetics and
pharmacodynamics
• give no data on safety or efficacy, being by definition a
dose too low to cause any therapeutic effect.
Phase I - clinical trial new drug
• Objective: dose finding for future trials
• Participants:
– in cancer trials, usually patients with
advanced, resistant disease
– in benign disease -healthy volunteers
(paid)
Phase I - clinical trial
• Start with low dose (1/10 of LD50 most
sensitive species)
• Dose increased in pre-planned steps
until dose-limiting toxicity (DLT)
occurs in >1/3
• Cohorts of 3-6 patients treated at each
level
Phase I - clinical trial
Usually  6 patients at “recommended
dose”
to Phase II studies
NB:
- useful for toxicity and pharmacokinetics
- not designed to test efficacy/biologic effect
- sample size insufficient for comparative
questions
Phase II - clinical trial
• Outcome of interest: response (shorter term
outcomes)
• Target group: most likely to show
favorable response but no effective
therapy available. Good performance
status, minimal prior therapy
• Eligibility: patients with specific
diagnosis, no internal control group
(sometimes randomized)
Phase II - clinical trial
• Response does not translate necessarily to
patient benefit
• Concluding about treatment effectiveness is
erroneous
• High response rates in Phase II do not
translate into improved survival in Phase III
• In some diseases response is difficult to
measure (no measurable disease)
Phase III clinical trial
• Randomized controlled clinical trial with
sufficient sample size and long enough
follow-up to determine treatment effect
• Often multicentered
• Frequently sponsored by pharmaceutical
company or clinical trials consortium
• Often administered by CRO
• $$$$$$$$
Phase IV Clinical Trial
• Post - marketing surveillance for side effects,
tolerability, new indications
• Often drug is provided for a limited time at
no cost so that the company can collect the
required information
• Rare complications of drugs may only
become apparent years after clinical trials
(Ticlopidine – TTP, Eprex-PRCA)
The unpredictable course of disease: the natural
history of systemic lupus erythematosus in a
patient observed before the advent of
immunosuppressive drugs
The unpredictable course of disease: the natural
history of systemic lupus erythematosus in a
patient observed before the advent of
immunosuppressive drugs
The unpredictable course of disease: the natural
history of systemic lupus erythematosus in a
patient observed before the advent of
immunosuppressive drugs
Total effects of treatment are the sum of
spontaneous improvement, nonspecific responses
and the effects of specific treatments
The structure of a clinical trial
Experimental
Intervention
Outcome
Improved
Not improved
Population
of patients
with the
condition
SAMPLE
ALLOCATION
Improved
Not improved
Comparison
Intervention
Types of clinical trials: Parallel placebo
controlled with composite outcome/endponts
Crossover trial
Most efficient and valid method of
using patient as his own control
Factorial design: Can answer n
questions
Randomization scheme for the PHS (physicians’ health study)
Willing and eligible
22,000
Active Aspirin
11,000
Active carotene
5,500
Carotene placebo
5,500
Aspirin placebo
11,000
Active carotene
5,500
Carotene placebo
5,500
Clinical trials of equivalence
Basic principles underlying confidence interval approach to
equivalence/non-inferiority
Garrett, Statist. Med. 2003
Clinical trials principles
1. Informed consent
2. Randomization
3. Blinding/masking - especially important for “soft”
outcomes
- single
- double
- “triple”
4. Objective, and equal assessment of outcomes
5. Monitoring committees and stopping rules
Randomization
1. Guarantees equal probability of
receiving control/experimental
treatment to all participants (removes
investigator bias)
2. Protects against imbalances in known
and unknown confounders
3. Provides basis for
statistical analysis
Did the randomization work?
Table 1
Stratified randomization: patients are first divided into strata
(1-3) according to one or more prognostic factors and then
randomized separately within each stratum into treatment
(T) and control(C) groups
Can’t always trust
that randomization
will result in
balance
Bias in clinical trials
• Internal and external validity
Location of potential bias in a randomized
controlled trial
Location of potential bias in a
randomized controlled trial
Internal Validity
Unblinded trials
(“open label”)
Both participant and investigator know
which intervention participant has been
assigned
- surgery
- devices
- lifestyle modification
Advantages: Simpler, cheaper, more
“comfortable” for investigator knowing
patient assignment
BIAS is the problem
Bias in unblinded trials
• Bias of expectation (participant and
investigator)
• Bias of reporting side effects (participant)
• Bias of reporting adverse events
• Increased withdrawal in placebo or control
group
Double blind trials
• Neither the investigator nor the participant
know treatment assignment
• usually trials of drug efficacy (Sham
treatments)
• double blind assessments of interventions
previously tested in single blind fashion may
yield different conclusions
• function of investigators must be taken over
by others- monitoring toxicity and benefit
Blinding
• If pill – same color, sheen, texture, taste,
smell
• Same side effects?
• If injection – same color, length of
infusion, same care and fuss
• Sham procedures, sham surgery
Intention to treat analysis
Drop out
Population
of patients
with the
condition
Cross over
Drop out
Analysis
according
to treatment
assigned
Analysis by “intention to treat”
• Should always be primary analysis
• factors such as co-intervention,
compliance, loss to follow-up may all
be associated with the outcome (or the
treatment effect)
• proper strategy is to:
a) randomize close to time of 1st treatment
b) minimize these during the trial
c) analyze according to treatment assignment
Explanatory analysis
Drop out
Population
of patients
with the
condition
Cross over
Drop out
Analysis
according to
treatment
received
RCT – importance of Intention to treat
Five-Year
Mortality
Drug
Poor-Adherence
Good Adherence
NEJM 1980;303:1038
JAMA 1993;270:742
RCT- importance of intention to treat
Five-Year
Mortality
Placebo
Poor-Adherence
Good Adherence
NEJM
1980;303:1038
Location of potential problems of external
validity in a randomized controlled trial
External Validity
Sampling for a clinical trial: the Coronary Artery Surgery
Study (CASS)
Circulation 68, 1983:939-950
% of patients remaining
100
Potentially eligible
Seen at one of participating centers
Suspected coronary artery disease
Coronary angiogram
72
67
Exclusions
Normal or minimally diseased
Coronary arteries
No operable vessels
30
Severe angina
29
Severe L. main coronary stenosis
13
Randomizable (after other exclusions)
5
Randomized
Efficacy and effectiveness
-
+
Internal
validity
Efficacy trial
Does receiving treatment
work under ideal conditions?
Non-compliance
+
Less selected patients
Less selected clinicians
Costs
Impracticality etc…
Generalizability
+
-
Effectiveness
trial
Does offering treatment help
under ordinary circumstances?
Effectiveness of treatment
Efficacy: an intervention is efficacious if
it does more good than harm in
patients who use it.
Effective: an intervention is effective if it
does more good than harm in those
patients to whom it is offered.
Major Disadvantage of RCTs:
Selectivity
But…SHEP study
Of 447,921 (100%) identified
31,960 (7.1%) met initial criteria
4,736 (1.06%)
randomized
.
.
Comorbidity: General Pop
vs. Subgroup
Men, gen’l pop
%
of Pop
% of
Pop
DM
CVD
CHF
MI
Angina
Wom., gen’l pop
SHEP pop
Messerli et al, Arch Int Med, 1999
How to measure effect in clinical
trials
The analysis of clinical trials
Sackett BMJ 1994;309:755-6
Qualitative result:
Treatment A is better than treatment B
Statistical result: p < 0.05
Quantitative result:
Risk ratio (Risk A: Risk B)
(1-Risk ratio) x 100 = “relative risk reduction”
Risk A - Risk B = “absolute risk reduction”
1/absolute risk reduction = NNT = number needed
to treat to prevent 1 event”
Naming the erroneous conclusions
form a clinical trial
The true state of affairs
Drug A is better Drug A is no better
than drug B
than drug B
Drug A is better
than drug B
TP
Correct
(1- = power)
Conclusion
drawn from
a clinical
trial
FP
Type I error
(risk of making this
error = =the P
value!)
w x
y
Drug A is no
better than drug
B
Type II error (risk
of making this
error=)
FN
z
Correct
TN
Meta-analysis: effect of antihypertensive
drugs on patients with moderate to severe
hypertension: five year follow up
Treatment A = active antihypertensive drugs
1800 strokes among 15,000 patients
randomized
Risk = 1800 / 15,000 = 0.12
Treatment B = placebo or no active
treatment
3000 strokes in 15,000 patients
randomized
Risk = 3000 / 15,000 = 0.20
Risk ratio = 0.12 / 0.20 = 0.6
Relative risk reduction = (1-0.6)x100 = 40%
Absolute risk reduction = 0.20 - 0.12 = 0.08
NNT = 1/ 0.08 = 13
13 patients must be treated for five years to
prevent one stroke
Treatment of hypertension: changing definition
of recommended treatment level over time
What if trial done on mild hypertensives?
Treatment A = active antihypertensive drugs
135 strokes among 15,000 patients randomized
Risk = 135 / 15,000 = 0.009
Treatment B = placebo or no active treatment
225 strokes in 15,000 patients randomized
Risk = 225 / 15,000 = 0.015
What if trial done on mild
hypertensives?
Risk ratio = 0.009/0.015 = 0.6
Relative risk reduction = (1-0.6)x100 = 40%
Absolute risk reduction=0.015=-0.009=0.006
NNT=1/0.006 = 167
167 patients must be treated for 5 years to
prevent one stroke
The effect of different baseline risks and
relative risk reductions on the number
needed to treat
Baseline
(with no
treatment)
Relative risk reduction on treatment
50%
40%
30%
25%
20%
15%
10%
.9
.6
.3
2
3
7
3
4
8
4
6
11
4
7
13
6
8
17
7
11
22
11
17
33
.2
.1
.05
10
20
40
13
25
50
17
33
67
20
40
80
25
50
100
33
67
133
50
100
200
.01
.005
.001
200
400
2000
250
500
2500
333
667
3333
400
800
4000
500
1000
5000
667
1333
6667
1000
2000
10000
Reducing mortality from colo-rectal cancer by
screening for fecal occult blood
Mandel NEJM 1993;328:1365-71
Assignment A = annual screening x 13 years
Mortality 5.88 per 1000
Assignment B = biennial screening 13 years
Mortality 8.33 per 1000
Assignment C = control group
Mortality 8.83 per 1000
Risk ratio = A/C = 5.88/8.83 = 0.66
Relative risk reduction = (1-0.66) x 100 = 34%
Abs.risk reduction = 0.00883 - 0.00588 = 0.00295
NNT = 1/0.00295 = 339
339 healthy people need to be screened yearly for 13
years to prevent one death from colo-rectal cancer
Clinical Trials
• Have made a huge impact on health
• There are now 75 trials, and 11 systematic
reviews of trials published per day and a
plateau in growth has not yet been
reached.
• They are a problematic tool
• PEOPLE ARE NOT MICE
THEY CANNOT BE CONTROLLED
Part two
Ethics in clinical trials
‫דרישות אתיות‬
ETHICAL REQUIREMENTS
Emanuel et al. JAMA 2000;283:2801-11
‫או מדעי‬/‫ערך חברתי ו‬
SOCIAL &/OR SCIENTIFIC VALUE
‫תוקף מדעי‬
SCIENTIFIC VALIDITY
‫בחירה הוגנת של משתתפים‬
FAIR SUBJECT SELECTION
‫ תועלת חיובי‬-‫יחס סיכון‬
FAVORABLE RISK-BENEFIT RATIO
‫בקרה בלתי תלויה‬
INDEPENDENT REVIEW
‫הסכמה מדעת‬
INFORMED CONSENT
‫כבוד למשתתפים הפוטנציאלים והמגויסים‬
RESPECT FOR POTENTIAL & ENROLLED SUBJECTS
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Ethical issues in clinical trials
1. Equipoise
2. Timing (“Enroll the first patient” Chalmers)
3. Inadequate sample size
4. Selective enrollment of patients
5. Violation of eligibility criteria
Ethical issues in clinical trials (cont.)
6. Violation of randomization
7. Placebo/sham ethical?
8. Change in doctor/patient relations
9. Fraud in execution or analysis
10. Data dredging/selective presentation
of results
Macon County Study
• 1929 -- Julius Rosenwald fund
asks US public health service
(PHS) for assistance in developing
health programs for southern
blacks (fund establishes a medical
division to complement its
educational activities)
• PHS suggests demonstration
treatment program for syphilis.
Official Apology 1997
Equipoise B.
Freedman
NEJM 1987;317:141-5
“a state of genuine uncertainty regarding the
comparative merits of treatments A and B for
population P.
Disturbed by:
- prior prejudice/thoughts about treatment
- preparation of research proposal
- preliminary or interim results of trial
Informed consent
• Practical expression of autonomous choice
• Modifications of consent required in 1/4 of
protocols
Ingredients - participants must:
1) have legal capacity to consent
2) be sufficiently free that consent is truly
voluntary
3) be given adequate information
4) understand information well enough to make
enlightened decisions
Death of A Research Volunteer
• Johns Hopkins University Asthma Study
• 24 year old lab technician -volunteer
• died of pulmonary complications of
inhaled drug
• after methacholine challenge given
hexamethonium
• pulmonary complications (rare) described
in pre-1966 literature- not in informed
consent
• drug not FDA approved
“Not quite as random as I pretended
Lancet 1996;347:70
Most people are uncomfortable with
the idea that important decisions
should hang on chance
• hold envelope up to light
• change schedule
• open bottles
‫‪Violation of randomization‬‬
‫יחידת הלב ‪ -‬ע”כ‬
‫‪ .I‬לפני ‪ 3‬שנים בערך השתתפה היחידה במחקר גוסטו‪ .‬במסגרתו‬
‫נבדקה יעילות של ‪ T.P.A‬לעומת ‪-S.T.K‬סטרפטוקינז בטיפול‬
‫בחולים עם ‪ .Acute MI‬באחד המקרים התקבל חולה בן ‪ 78‬עם‬
‫‪ Acute MI‬שהסכים להשתתף במחקר וחתם‪ .‬נפתחה הערכה‬
‫שהוא אמור לקבל לאחר תיאום עם מרכז הרנדומיזציה והתברר‬
‫שיש לו ערכה ‪( S.T.K‬נא לציין ש‪ T.P.A -‬היא תרופה מאוד‬
‫יקרה‪ .‬ביחידה שמורה רק מנה אחת ואפשר להשתמש בה רק‬
‫לאחר תיאום ואישור מההנהלה)‪ .‬זה לא מצא חן בעיני הרופא‬
‫המטפל כי הוא קיווה שיהיה ‪ T.P.A‬לכן הוא פתח ערכה אחרת‬
‫והתחיל לחפש ‪ , T.P.A‬פתח עוד ערכה עד שמצא‪ .‬שהתברר‬
‫המעשה למרכזי המחקר נפסלה היחידה ככלל והורדה מכל‬
‫המחקר שבמקביל רץ בהרבה יחידות באירופה וארה”ב‪.‬‬
Fraud and clinical trials
•
•
•
•
•
•
falsification of data
entry of ineligible participants
phantom participants (Ruben, Bezwoda)
randomization procedure violation
protocol violations
publication fraud
What is Misconduct?
FDA’s Focus
• Deliberate or repeated noncompliance with the
regulations can be considered misconduct, but is a
secondary focus compared to falsification of data.
• Research misconduct does not include honest error
or honest differences of opinion.
Fakery
• Baystate Medical Center in Springfield, Massachusetts, asked several
anesthesiology journals to retract 21 drug studies published 1996-2008 by
anesthesiologist Scott S. Reuben, M.D., a pioneer in the area of multimodal
analgesia.
•
The studies were funded by Pfizer, Merck, and Wyeth. Reuben was also paid by
Pfizer as a speaker to promote its products .Raymond F. Kerins Jr., a Pfizer
spokesman: "It is very disappointing to learn about Dr. Scott Reuben's alleged
actions".
• Reuben is suspected of falsifying some of his data, including the names of patients
and co-authors. Evan Ekman, MD, an orthopedic surgeon in Columbia, S.C., told
Anesthesiology News that his name was forged on two of the retracted papers.
• Dr. Hal Jenson, Baystate's chief academic officer,
said that the investigation of Reuben's work found that
in many cases "there was no clinical trial because
there were no patients".
Falsification of Data
• Falsification of data includes creating,
altering, recording, or omitting data in
such a way that the data do not
represent what actually occurred.
The Misconduct Scale
• Innocent Ignorance- misconduct of the
uninformed kind
– Noncompliance based on lack of
understanding the regulatory
consequences of an action. The act itself is
usually intentional but the noncompliance
is unintentional, not usually done to
deliberately deceive
The Misconduct Scale
• Surprising Sloppiness- misconduct of the lazy
kind
– Consent forms inadvertently not obtained from
subjects
– Blood pressures rounded to the nearest 5mm
– Data estimated rather than actually measured
– Data inaccurately transcribed or recorded
– Protocol ignored or shortcuts taken
The Misconduct Scale
• Surprising Sloppiness- misconduct of the lazy
kind
– Noncompliance due to inaction, inattention to
detail, inadequate staff, lack of supervision. The
act itself may be intentional or unintentional, the
noncompliance is unintentional and usually
repeated
The Misconduct Scale
• Malicious Malfeasance- Misconduct of the
sleazy kind
– Usually noncompliance due to deliberate action to
deceive or mislead includes The “F” Word:
Falsification
Detecting and Handling Research
Misconduct
• The Fiddes Case
• Background: shortage of research patients
• Dr. Robert Fiddes turned his “sleepy” medical practice Whittier.Ca
into major clinical research org.
• Another study on an antibiotic required that patients have a certain
type of bacteria growing in their ear. No problem for Fiddes. He
bought the bacteria from a commercial supplier and shipped them to
testing labs, saying they had come from his patients' ears.”
• If patient didn’t have the condition – he bought urine from
someone who did
• 1997 found guilty – 15 month prison sentence
‫‪Israel –role of Helsinki committee‬‬
‫• הועדה פועלת על‪-‬סמך נוהל לניסויים רפואיים בבני אדם‪,‬‬
‫בהתאם לתקנות בריאות העם (ניסויים רפואיים בבני‬
‫אדם‪ ,‬התשמ”א‪ ,1980 ,‬על תוספותיהן ותיקוניהן ‪,)1999‬‬
‫ומיישמת את עקרונות הצהרת הלסינקי‪.‬‬
‫• הוועדה דנה בהצעות מחקר לניסויים קליניים בבני אדם‬
‫ומאשרת אותן‪ ,‬וכן דנה בהצעות מחקר בתחום החברתי‬
‫(פסיכולוגיה‪ ,‬רפואה חברתית ובקשות הכוללות שאלונים)‪.‬‬
‫• ועדת הלסינקי המוסדית‪ ,‬פועלת על‪-‬פי הוראות נוהל‬
‫משרד הבריאות והוראות הנוהל ההרמוני הבינלאומי‪,‬‬
‫העדכני‪ ,‬להליכים קלינים נאותים (‪.)ICH-GCP‬‬
‫ממשרד הבריאות נמסר‪" :‬בעקבות בדיקת מבקר המדינה‬
‫בנושא ניסויים רפואיים שבוצעו בבית החולים הרצפלד וקפלן‪,‬‬
‫‪2011‬‬
‫ואיכות לבדיקת הנושא‪.‬‬
‫מונתה בתאריך ‪ 28.6.05‬ועדת בקרה‬
‫החלטת משרד הבריאות‪:‬קובלנה‬
‫"בעקבות פרסום ממצאי מבקר המדינה וכן בעקבות דוח ועדת הבקרה‬
‫ממחנה‬
‫• המוות של הרבנית ברטה ויזל (‪ ,)84‬ניצולת שואה‬
‫והאיכות פתחה משטרת ישראל בחקירה פלילית בנושא‪ ,‬שהסתיימה‬
‫המזעזעת‪.‬‬
‫הפרשה‬
‫לחשיפת‬
‫זה שהביא‬
‫בית‪ ,‬היה‬
‫אושוויץ‬
‫ההשמדה‬
‫היא מכונה בקובלנה‪,‬‬
‫הרצפלד"‪ ,‬כך‬
‫הגריאטרי‬
‫החולים‬
‫פרשת‬
‫"‬
‫לאחרונה‪.‬‬
‫בתה‪ ,‬אחות‬
‫בטוב‪.‬‬
‫שלא‬
‫לאחר‬
‫בקפלן‬
‫‪2004‬‬
‫ויזל אושפזה ב‪-‬‬
‫המדינה‪.‬‬
‫חשה מבקר‬
‫‪ 2004‬למשרד‬
‫בתחילת‬
‫שהגיעה‬
‫בעקבות תלונה‬
‫נולדה‬
‫הניסויים‬
‫הפיקוחמ"על‬
‫כיכשל‬
‫בניסוייםשל‬
‫שנגלתה‪,‬‬
‫התמונה‬
‫"‬
‫בחולים‬
‫קפלן"‬
‫רופאים‬
‫שלידי‬
‫מערכתי על‪-‬‬
‫הנעשים‬
‫חוקיים‬
‫לא‬
‫גילתהעסקה‬
‫לנוכח התלונה‬
‫באמה ניסוי‬
‫מבצעים‬
‫האשפוז‬
‫במהלך‬
‫במקרה‬
‫במקצועה‪,‬‬
‫הפרקליטות‪.‬‬
‫להפסיקלעיון‬
‫המקרה הועבר‬
‫הסכמתם לניסויים‬
‫לתת‬
‫כשירים‬
‫שחלקם לא‬
‫מבוגרים‪,‬‬
‫כהונת‬
‫את‬
‫הבריאות‪ .‬דאז‬
‫משרד‬
‫השתן“ל‬
‫מנכ‬
‫החליט‬
‫החולים ‪-‬‬
‫של בבית‬
‫מכן היא‬
‫לאחר‬
‫ימים‬
‫ארבעה‬
‫‪.‬‬
‫הבטן‬
‫דרך‬
‫שלפוחית‬
‫דיקור‬
‫בתום חקירה ארוכה החליטה הפרקליטות לסגור את התיק מאחר שהיה קושי לקבוע אם‬
‫פלילית‪.‬המרכזיים‬
‫החברים‬
‫את‬
‫קפלן ולהחליף‬
‫החולים‬
‫ועדת הלסינקי של בית‬
‫שהניסויעבירה‬
‫היטבבפרשה הזאת‬
‫ידעהשנעשתה‬
‫אפשר להוכיח‬
‫הרצפלדשהוא‬
‫משום‬
‫‪,‬‬
‫חוקי‬
‫אינו‬
‫הבת‬
‫מזיהום‪.‬‬
‫נפטרה‬
‫החולים‬
‫בבית‬
‫מחקרים‬
‫נעצרו‬
‫ממושכת‬
‫תקופה‬
‫ובמשך‬
‫‪,‬‬
‫בהרכבה‬
‫הפרקליטות המליצה למשרד הבריאות להעמיד את החשודים לדין משמעתי‪,‬‬
‫אמה‬
‫כי‬
‫העובדה‬
‫לאור‬
‫במיוחד‬
‫אמה‬
‫של‬
‫הסכמתה‬
‫אדםר"‪.‬‬
‫קליניים‬
‫ניסויים‬
‫בביתבביצוע‬
‫ליקויים‬
‫משמעתית‪" -‬בעניין‬
‫הגשת‬
‫ללאהחליט‬
‫נעשה וזה‬
‫בבני‪ -,‬ד“‬
‫בנוסף‬
‫קפלן‪.‬‬
‫החולים‬
‫המחקר‬
‫קובלנהבקשות‬
‫על כל‬
‫פיקוחעלצמוד‬
‫והוטל‬
‫עבודתו‪.‬מאחותה בתקופת שהותה באושוויץ‪ ,‬כדי‬
‫שהופרדה‬
‫תאומהסיים את‬
‫הייתהשמואל לוי‬
‫שלא תילקח לניסויים הזוועתיים של יוזף מנגלה‪ .‬לפני כל ביקור‬
‫נכתבו‬
‫כולה‪,‬‬
‫אומרת מהפרשה‬
‫הייתהמערכתיים‬
‫הופקו לקחים‬
‫בבית"פרט לכך‪,‬‬
‫נהליםעליי‪ .‬אל‬
‫ילמדו‬
‫שלא‬
‫לילדיה‪" :‬‬
‫החולים היא‬
‫מעודכנים והוגבר הפיקוח על הניסויים הרפואיים בכל בתי‬
‫בישראל‪ .‬עליי ניסויים"‪.‬‬
‫להם לעשות‬
‫תיתנו‬
‫החולים‬
‫מבית החולים הרצפלד‪ ,‬שירותי בריאות כללית‪ ,‬והרופאים המעורבים‬
‫בפרשה ומועסקים עדיין בכללית‬
Clinical trials registration
What and why?
September 2004
A Statement from the International
Committee of Medical Journal Editors
• “In return for the altruism and trust that make
clinical research possible, the research
enterprise has an obligation to conduct
research ethically and to report it honestly”
• Concealing the presence of trials is
dishonest!
• Concealing the original purpose of the trial is
also dishonest!
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Analysis of discrepancies between
protocol and publication (Denmark and
Canada) have shown..
• Publication bias is a real issue
– Negative studies less likely to be published,
especially by pharma
• So is selective reporting of results
– Statistically significant results more likely to
be reported
– Secondary outcomes and subgroup analyses
presented as primary outcome
Trial Registration
Pros
•
•
•
•
Enhanced public confidence
All volunteers for medical
research will contribute to
improving human health
Decrease publication bias
Decrease selective presentation
of results and inappropriate
subgroup comparisons
Cons
• Bureaucratic
delays
• Gives an
advantage to the
competition
Student’s role in research ethics
•
•
•
•
Be aware of guidelines
Be alert-‫ראש גדול‬
Be honest
Don’t do anything that makes you
uncomfortable
• Don’t chase the magic p value
• Discuss authorship early