http://bit.ly/bQKcGz This lecture was presented as part of the Drug Literature Evaluation course at Nova Southeastern University. Guided notes and an audience response system were used to augment to lecture. Context for my decision to share these slides can be found at the provided link.

1. Superiority,
Equivalence, and
Non-inferiority Trials:
A Gold Standard?
Kevin A. Clauson, Pharm.D.
Associate Professor
February 15, 2010

2. Objectives
• Review randomized controlled trial
design
• Preview elements of a journal club
• Examine purpose(s) of superiority,
non-inferiority and equivalence trials
• Assess non-inferiority trial design

3. Tr
ue
0%
Fa
l se
0%

4. How is data from a Likert Scale
classified?
1. Nominal
2. Ordinal
3. Interval
4. Ratio
0% 0% 0% 0%
tio
al
al
al
rv
in
in
Ra
m
te
d
Or
No
In

5. Randomized Controlled Trials
(Review)
• Randomization = allocation method where
all subjects have equal chance of study
group assignment
• Controls = placebo, active (comparator),
historical
• Blinding = reduce risk of observation bias
(single, double, triple)
AJR 2004;183(6):1539-44.

6. Randomized Controlled Trials
(Review)
• Method to determine if a cause-effect
(causal) relationship exists between
treatment and outcome
• Other designs can detect an association,
but can‟t rule out that an association was
caused by third factor
BMJ 1998;316:201.

7. What is the BEST design to
answer a clinical question?
1. Cross-sectional study
2. Meta-analysis
3. Epidemiological
analysis
4. Randomized 0% 0% 0% 0% 0%
controlled trial
is
ds
dy
is
.
ys
ys
t..
en
tu
5. It depends
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al
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lle
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iz
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Cr
om
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Ep
nd
Ra

8. While randomized, controlled
trials are capable of providing the
most robust evidence, they are
not always appropriate or
indicated
- Jacqueline Limpens
Paraphrased from http://laikaspoetnik.wordpress.com/

9. When would a RCT not be the
best choice?
1. The condition or
outcome is rare
2. The unit of
randomization is too
large
3. Ethical issues such 0% 0% 0% 0% 0%
as pain management
2
3
..
...
4. Answers 1 and 2 ...
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s2
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5. Answers 2 and 3
an
An
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ue
on
fr
ss
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nd
ica
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co
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Et
Th
Th

10. K-Type Questions
and the NAPLEX
I. Answer
II. Answer
III. Answer
A. I only
B. II only
C. I and II
D. II and III
E. I, II, and III

11. Effects of Coke on Sperm
Motility
45
40
35
30
25 Old Coke
20 New Coke
15 Diet Coke
10
5
0
Motility @ 1 min pH of Coke
N Engl J Med 1985;313(21):1351.

12. A Few Words About…

13. What has your experience been
with journal clubs so far?
1. I have presented a
journal club
2. I have only
observed a journal
club
0% 0% 0%
3. What is a journal
club?
b?
.
n.
..
c lu
a.
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nl
ha
ep
eo
W
av
av
Ih
Ih

14. Don’t be this guy

15. This is the really
important bit

16. Which of your course articles is
NOT a RCT?
1. Discontinuation of Drug
Therapy in Patients
with Atrial Fibrillation
2. Ginkgo biloba for
Preventing Cognitive
Decline in Older Adults
0% 0% 0%
3. Rituximab, B-
Lymphocyte Depletion,
...
...
...
ve
ug
yt
oc
and Preservation of
e
Dr
Pr
ph
of
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ym
fo
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ba
-L
Beta-Cell Function
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xim
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17. Superiority Trials
• Purpose
– To detect a difference between two drugs
• Goals
– Establish new drug is statistically superior to
active control (and/or placebo) [Easier]
– Establish new drug is clinically superior to
active control (and/or placebo) [Harder]

18. The consequence when a Type I error
occurs is that you mistakenly assume:
1. both treatments work.
2. neither treatment works.
3. there is a difference
between treatments.
4. there is no difference 0% 0% 0% 0%
between treatments.
.
k.
ks
...
or
...
or
be
e
sw
tw
c
en
ce
t
en
en
er
en
m
ff
tm
r
di
ffe
at
ea
e
no
di
tr
tr
a
is
er
th
is
e
ith
bo
er
re
ne
th
e
th

19. Null versus Alternative
Hypotheses
• H0 – no difference in
treatments
• H1 – there is a
difference in treatments
Errors
• Type I error (false )
• Type II error (false )

20. Superiority Trials
• If the active control is very effective
– it is difficult to demonstrate that a new drug is
more effective
• If active control is not very effective AND
the new drug is slightly better
– superiority can be established with a large
sample size

21. Superiority Trials
• New drug can only be superior to
active control if active control is also
effective in current trial

23. What can be concluded about the efficacy of
SJW in major depression from those results?
1. SJW doesn‟t work
2. SJW doesn‟t work as
well as sertraline
3. 1/3 of antidepressant
trials find an FDA-
approved comparator
doesn‟t work 0% 0% 0% 0%
4. You can only conclude
k
that you can‟t conclude
..
l ..
or
..
ria
th
el
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tt
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de
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sn
as
clu
ss
anything e
k
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or
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yc
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t id
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sn
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n
do
of
ca
3
u
W
1/
Yo
SJ

24. What did the
mainstream press
conclude about this
study based on their
„evaluation‟?

26. Is JAMA a reputable journal?
1. Yes
2. No
0% 0%
s
No
Ye

27. What if I told you that I could
cite a study in JAMA which
found that 2400 mg of
ibuprofen/day was used in a
patient population and ZERO
adverse reactions were
reported (not even GI)?

28. What
JAMA; 239 (1): 34-5 year?
• Ibuprofen in the treatment of acute
gouty arthritis [Abstract]
How many
patients?
___ patients with acute gouty arthritis
were treated with daily doses of 2,400 mg
of ibuprofen. All patients had rapid
improvement and complete resolution
with 72 hours; no adverse reactions were
reported. Ibuprofen may be an effective
alternative in the treatment of this
disorder.

29. Equivalence Trials
• Purpose: To confirm the
absence of a meaningful
difference between
treatments
• Equivalence is inferred
when ENTIRE confidence
interval falls exclusively
within equivalence margins
(between –Δ and Δ)

30. Non-inferiority Trials
• Purpose: To demonstrate that a new
drug is not worse than an active
comparator by more than a pre-specified
amount*
• NOT: That the two drugs are equivalent
• NOT: That the new drug is not inferior to
the active comparator
*non-inferiority margin, delta (Δ), 

32. Who is This?
1. Bizarro
2. Deadpool
3. DeadMan
4. Spiderman
5. Superman
0% 0% 0% 0% 0%
an
l
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an
an
oo
dM
rm
m
za
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r
Bi
pe
de
a
a
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i
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Sp

33. Non-inferiority Trials –
Null vs Alternative/Research
• Type I error –
“erroneous acceptance
of an inferior new
treatment”
Note the S is
reversed
• Type II error –
“erroneous rejection of a
truly non-inferior
treatment” JAMA 2006;295:1152-1160.

34. Non-inferiority
Null & Alternative
Hypotheses
• Null – no difference in treatments
[Desirable in non-inferiority]
• Alternative/Research – there is a
difference in treatments [Undesirable in
non-inferiority]

35. Erroneous acceptance of an inferior
new treatment in non-inferiority trial is:
1. Type I error. 50% 50%
2. Type II error.
.
r.
or
ro
rr
er
Ie
II
pe
pe
Ty
Ty

36. Non-inferiority Margin*
• Non-inferiority margin was traditionally
chosen as:
– The difference between the active
comparator and placebo in a previous trial
• Arbitrary choice and may NOT even
assure superiority over placebo
*delta (Δ), 

37. Non-inferiority Margin
• There is no single way to assess if non-
inferiority margin (Δ) is appropriate
• Margin (Δ) must be determined by
COMBINATION of statistical means and
clinical considerations
ˆ ˆ ~ ~
PrH 0 {ln(T / C )  1.96 tc  0.5[ln( P0 / C0 )  z(1 x ) / 2 cp 0 ]}
1.96 tc  0.5 z(1 x ) / 2 cp 0
 ( )
 tc  (0.5) 2  cp 0
2 2
DO NOT MEMORIZE 1.96  0.5 z(1 x ) / 2 f
 ( ),
1  (0.5) f 2
where
 cp 0
2
# of events in NI trial
f  2 
 tc # of events in historical trials

38. Non-inferiority – Design
• Trial design ideally incorporates a
placebo AND active comparator
• Presence of placebo allows to establish
superiority to placebo and thus
validate/establish internal validity (along
with non-inferiority to active drug)
European Medicines Agency 2005 http://bit.ly/aeNuST

39. Non-inferiority – Design
• Failure to include placebo can lead to
lack of internal validity in non-inferiority
trials, but is common
• Design flaws TEND TO BIAS RESULTS
towards a finding of equivalence
• Ethical issues
MJA 2009;190(6):326-330.

40. Non-inferiority – Design
• Compliance/adherence • Losses to follow-up
• Withdrawals • Missing data
• Inclusion/exclusion • Any deviation from
criteria protocol
Study must be even more closely
examined if assessments of any of the
above reveal inconsistencies

41. Non-inferiority trials established which drug as
1st line treatment for Dysphoric Social Attention
Consumption Deficit Anxiety Disorder?
1. Alprazolam
2. Avafynetyme
3. Eszopiclone
4. Zaleplon
5. Zolpidem
0% 0% 0% 0% 0%
m
n
em
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e
lo
on
m
la
ep
ty
d
zo
cl
pi
ne
pi
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zo
fy
p
Al
a
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Av

43. Non-inferiority – Comparator
• Active comparator (drug) should ideally
be widely used with established efficacy
via superiority trial and identical
indication
• Non-inferiority trial should mimic design
of superiority trial
– Primary variables, doses of comparator,
inclusion/exclusion criteria, etc.
Biometric Journal 2009;51(1):185-92.

44. Non-inferiority – Design
• Design should be implicitly stated in
protocol/methodology
• Lower bound of equivalence margin
should be clearly stated
• Margin determination should be
detailed and justified

45. Non-inferiority –
Method of data analysis
• Use of intent-to-treat (ITT) is generally
misunderstood and its role should be
examined carefully
– Does not confer same conservative
estimates in non-inferiority
Curr Control Trials Cardiovasc Med 2000;1(1):19–21.

46. Inference for Non-Inferiority
Delta Limits (95%) and Confidence Intervals
Non-inferiority shown
Non-inferiority shown
Non-inferiority not shown
Non-inferiority shown/
superiority issue*
- 0
Control Better Test Agent Better
Treatment Difference

47. T has a <10%
increase in risk
“NI”
C inferior by
at least 10%
T superior
increase in risk
T/C
T = Test Drug 1.0 =1.10 (NI margin)
C = Active Control
NI = non-inferiority Hung/Wang 2006

48. Non-inferiority – Conclusion
• Determination can be made from
observing a non-significant test result of
the null hypothesis
REMEMBER

49. Which design tries to prove a drug is
no worse than the comparator drug?
1. Superiority
2. Non-inferiority
3. Both
4. Neither
0% 0% 0% 0%
th
er
y
y
rit
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ith
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io
r io
Ne
r
pe
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in
Su
n-
No

50. Summary
• Superiority: detect a
difference between two drugs
• Equivalence: confirm absence
of significant difference
between two drugs
• Non-inferiority: show new
drug is not worse than active
by more than pre-specified
amount

51. Images
• http://a.abcnews.com/images/Business/ht_gold_pills_071221_ssh.jpg
• http://www.nabp.net/
• http://pimm.files.wordpress.com/2007/08/jc.jpg
• http://www.phdcomics.com/comics/archive.php?comicid=963
• http://www.null-hypothesis.co.uk
• http://dcscience.net/cumming-simpson-brown-cartoon2-vs.jpg
• http://www.redwiredesign.com/images/teva_01.png
• http://www.patentdocs.typepad.com/photos/uncategorized/2008/04/06/mylan.jpg
• https://www.roxane.com/tpPortal/framework/skins/rli/images/roxaneLogo.gif
• http://media.monster.com/xblabsx/joblogo.gif
• http://www.topnews.in/files/reddy-logo-300.jpg

52. Images
• http://www.havidol.com/elle.html
• http://www.havidol.com/understanding.html
• http://www.nature.com/nrd/journal/v5/n10/pdf/nrd2170.pdf
• http://www.rickcortes.com/bizarro.jpg
• http://www.flickr.com/photos/theflyingrat/2599301016/
• http://www.phdcomics.com/comics/archive.php?comicid=964
• http://www.standrews.austin.tx.us/library/Questioning.htm