Clinical trials

NACCMA Metanylysis
Forest plot P=.003
Survival Functions
1.1

1.0

.9

.8

.7
stgnw
.6
3.00

Cum Survival
.5
3.00-censored

.4 1.00

.3 1.00-censored
0 10 20 30 40 50 60 70

INTERPRETATION OS
Kaplan Meier
Phase III trial

Clinical trials
Multivariate analysis
Level of evidence

Bio-medical statistics
Sheh Rawat

NACCMA Metanalysis
Forest plot P=.003
Survival Functions
1.1

1.0

.9

.8

.7
stgnw
.6
3.00

Cum Survival
.5
3.00-censored

.4 1.00

.3 1.00-censored
0 10 20 30 40 50 60 70

OS
Kaplan Meier
Phase III trial

Clinical trials
Level of evidence

Dr Sheh Rawat

NACCMA Metanalysis
Forest plot P=.003
Survival Functions
1.1

Primary And secondary end points
1.0

.9

.8

.7
stgnw
.6
3.00

Cum Survival
.5
3.00-censored

.4 1.00

Informed consent .3 1.00-censored
0 10 20 30 40 50 60 70

OS
Kaplan Meier
Phase III trial

Randomisation Clinical trials
Level of evidence

Dr Sheh Rawat

NACCMA Metanalysis
Forest plot P=.003
Survival Functions
1.1

1.0

DNB:Diplomate in National Board .9

.8

.7
stgnw

DNB:Did Not Bat
.6
3.00

Cum Survival
.5
3.00-censored

.4 1.00

.3 1.00-censored
0 10 20 30 40 50 60 70

OS
Kaplan Meier
Phase III trial

Clinical trials
Level of evidence

Dr Sheh Rawat

Or did anyone
of you think it
was sunset?

Good Evening!

You can prove anything with
statistics.

So act with caution in interpreting,
and integrity while presenting data

An Overview
• Clinical trials and Levels of
evidence

• Definitions and terminology

• Collection of data and creating database

• How to analyze ?

• The need
• Types of trials
• Levels of evidence
• Eligibility criteria
• Informed consent
• Benefits and possible risks of participating in a clinical
trial
• Randomisaton/blind/double blind/multicentric
• Defining end points (primary and secondary)
• Statistical methods
• Interim analysis
• Publication

The need of clinical trials
• “Where the value of a treatment, new or
old, is doubtful, there may be a higher
moral obligation to test it critically than to
continue to prescribe it year-in-year-out
with the support merely of custom or
wishful thinking.”

FHK Green

Clinical trials are experiments to
determine the value of treatments.
• There are two key components to the
experimental approach.

• First, results rather than plausible
reasoning are required to support
conclusions.

• First, results rather than plausible reasoning are
required to support conclusions.
• Second, experiments should be prospectively
planned and conducted under controlled
conditions to provide definitive answers to well-
defined questions.

Types of Trials
• Prevention trials
• Screening trials
• Diagnostic trials study tests or
procedures that could be used to identify
cancer
• Treatment trials
• Quality-of-life (also called supportive
care) trials
• Genetics studies

Who sponsors clinical trials?
• The National Cancer Institute (NCI) and
other parts of the National Institutes of
Health (NIH),
• the Department of Defense,
• the Department of Veterans Affairs,
sponsor and conduct clinical trials

What are eligibility criteria, and why
are they important?

• Each study’s protocol has guidelines
for who can or cannot participate in the
study. These guidelines, called
eligibility criteria, describe
characteristics that must be shared by
all participants.

are they important?

• The criteria differ from study to study.
• They may include age, gender, medical
history, and current health status.
• Eligibility criteria for treatment studies
often require that patients have a
particular type and stage of cancer.

ERBITUX + RT in locally advanced SCCHN
Patient inclusion criteria

E
X • Measurable disease
• Pathologically demonstrated SCC of the oropharynx,
A hypopharynx, or larynx
M • Stage III or IV disease with an expected survival of

P >12 months
• Medically able to withstand a course of definitive RT
L • Karnofsky PS > 60%
E • No evidence of distant metastatic disease

Bonner et al. N Eng J Med 2006;354:567-578

are they important?

Enrolling participants with similar
characteristics helps to ensure that the
results of the trial will be due to what is
under study and not other factors.

are they important?

In this way, eligibility criteria help
researchers achieve accurate and
meaningful results.

are they important?

These criteria also minimize the risk of
a person’s condition becoming worse
by participating in the study.

What is informed consent?

Informed consent is a process by
which people learn the important facts
about a clinical trial to help them
decide whether to participate.


This information includes details about
what is involved, such as the purpose
of the study, the tests and other
procedures used in the study, and the
possible risks and benefits.


• In addition to talking with the doctor or
nurse, people receive a written consent
form explaining the study.
• People who agree to take part in the
study are asked to sign the informed
consent form.


However, signing the form does not
mean people must stay in the study.
People can leave the study at any time
—either before the study starts or at
any time during the study or the follow-
up period.


The informed consent process
continues throughout the study. If new
benefits, risks, or side effects are
discovered during the study, the
researchers must inform the
participants. They may be asked to
sign new consent forms if they want to
stay in the study.

Institutional Ethics Committee
(IEC)/Institutional Review
Board (IRB)

ETHICAL REVIEW PROCEEDURES

BASIC RESPONSIBILITIES

1) To protect the dignity,rights and well being of the potential
research participants
2) To ensure that universal ethical values and international
scientific standards are expressed in terms of local community
and customs
3) To assist in the development and the education of a research
community responsive to local health care requirements

COMPOSITION
1)Chairperson
2) 1-2 Basic Medical Scientists
3) 1-2 Clinicians from various institutes
4) One Legal expert or retired judge
5) One Social scientist/ Representative of non-governmental
voluntary agency
6) One Philosopher /Ethicist
7)One lay person from the community
8) Member Secretary

REVIEW PROCEDURES
The ethical review should be done through formal meetings and
should not resort to decisions through circulation of proposals

Where do clinical trials take place?
doctors’ offices
clinics

doctors’ offices
clinics

cancer centers
veterans’ and military
hospitals

community hospitals

Where do clinical trials take doctors’ offices
place?
clinics

cancer centers
veterans’ and military
hospitals
community hospitals

cities and towns across the country
and in other countries.

multicentrc


E
X
A
M
P
L
E

Clinical trials and Levels of
evidence
• Phase I: To define and to characterize the
new treatment to set the basis for later
investigations of efficacy and superiority.
eg. Establishment of MTD, toxicity profile,
anti tumor activity, basic clinical
pharmacology and recommendation of
doses for phase II studies.
• For non life threatening diseases:
Conducted on human volunteers,
• For life threatening diseases (cancer,
HIV): Conducted on patients.

ERBITUX + RT in locally
advanced SCCHN

E Phase I study of anti-epidermal growth factor
receptor antibody cetuximab in combination
X with radiation therapy in patients with
A advanced head and neck cancer
M
P Robert F, Ezekiel MP, Spencer SA, Meredith RF, Bonner JA,

L Khazaeli MB, Saleh MN, Carey D, LoBuglio AF,
Wheeler RH, Cooper MR, Waksal HW

E
Robert et al. J Clin Oncol 2001;19:3234-3243

advanced SCCHN Study design
Previously untreated patients with SCCHN,
stage III or IV, or recurrent, not resectable
for curative intent n=16
E
X ERBITUX initial dose (100, 200, 400, or
A 500 mg/m2) followed by 7 weekly maintenance
doses (100, 200, or 250 mg/m2)
M +
RT: conventional (70 Gy, 2 Gy / d) or
P hyperfractionated (76.8 Gy, 1.2 Gy bid)
L
Follow until disease progression
E
Robert et al. J Clin Oncol 2001;19:3234-3243

• The dose levels themselves are
commonly based on a modified Fibonacci
series. The second level is twice the
starting dose, the third level is 67%
greater than the second, the fourth level is
50% greater than the third, the fifth is 40%
greater than the fourth, and each
subsequent step is 33% greater than that
preceding it.

Traditional phase I trials have
three limitations:

• They sometimes expose too many
patients to subtherapeutic doses of the
new drug.
• The trials may take a long time to
complete.
• They provide very limited information
about interpatient variability and
cumulative toxicity.

accelerated titration designs -ph I
trials contd..
• New trial designs have been developed to
address these problems.
• One new class of designs, accelerated
titration designs, permit within-patient
dose escalation and use only one patient
per dose level until grade 2 or greater
toxicity is seen. Doses are titrated within
patients to achieve grade 2 toxicity.

accelerated titration designs -ph I
trials contd..
• Accelerated titration designs appear to be
effective in reducing the number of
patients who are undertreated, speeding
the completion of phase I trials, and
providing increased information.

evidence
• Phase II: used to screen new regimens for
activity and to decide which ones to be
tested further. Usually designed with 2 or
more stages of accrual, allowing early
stopping due to inactivity of the regimen.
• Phase III: Randomized trials where the
outcome is survival or, time until an
adverse event.

evidence
• Phase IV trials are conducted to
further evaluate the long-term safety
and effectiveness of a treatment.

• They usually take place after the
treatment has been approved for
standard use. Several hundred to
several thousand people may take
part in a phase IV study.

• These studies are less common than
phase I, II, or III trials.
• People who participate in a clinical trial work with
a research team. Team members may include
doctors, nurses, social workers, dietitians, and
other health professionals. The health care team
provides care, monitors participants’ health, and
offers specific instructions about the study.

What are some of the benefits of taking
part in a clinical trial?

• Participants have access to promising new
approaches that are often not available
outside the clinical trial setting.

• The approach being studied may be more
effective than the standard approach.

• Participants receive regular and careful
medical attention from a research team that
includes doctors and other health
professionals.


• Participants may be the first to benefit
from the new method under study.

• Results from the study may help others
in the future.

What are some of the possible risks
associated with taking part in a clinical trial?

associated with taking part in a clinical trial?

• New drugs or procedures under study are not
always better than the standard care to which
they are being compared.

• New treatments may have side effects or risks
that doctors do not expect or that are worse than
those resulting from standard care.

• Participants in randomized trials will not be able
to choose the approach they receive.

associated with taking part in a
clinical trial?

• Health insurance and managed care
providers may not cover all patient care
costs in a study.

• Participants may be required to make more
visits to the doctor than they would if they
were not in the clinical trial.

• The need
• Types of trials

• Eligibility criteria
• Informed consent
• Benefits and possible risks of participating in a clinical trial
• Levels of evidence
• Randomisaton/blind/double blind/multicentric
• Defining end points (primary and secondary)
• Statistical methods
• Interim analysis
• Publication

Clinical trials and Levels of evidence:
ASCO guidelines (JCO;17:1999)

• Level 1: Meta-analysis of multiple, well
designed, controlled studies. Randomized
trials- high powered ( low false+, low false
- errors) (Forest plot, L`Abbe plots-odds
ratio)
• Level II: At least 1 well designed
experimental study. Randomized Trials
having low power (hg false + and /or false
–ve errors)

Metaanalysis
• A metaanalysis is a quantitative summary
of research in a particular area.
• It is distinguished from the traditional
literature review by its emphasis on
quantifying results of individual studies
and combining results across studies.

Metaanalysis-Contd..
• Key components of this approach are:
• to include only randomized clinical trials,
• to include all relevant randomized clinical
trials that have been initiated, regardless
of whether they have been published,
• to exclude no randomized patients from
the analysis, and
• to assess therapeutic effectiveness based
on the average results pooled across trials

• Including all relevant randomized trials that
have been initiated in a geographic area (e.g.,
the world, or the Americas and Europe)
represents an attempt to avoid publication bias.
• Avoiding exclusion of any randomized patients
also functions to avoid bias.
• Assessing therapeutic effectiveness based on
average pooled results is an attempt to make
the evaluation on the totality of evidence rather
than on extreme isolated reports.

E
X
A
M
P
L
12% benefit in overall survival:
E

Metanalysis
• 1: Cochrane Database Syst Rev. 2004;(2):CD001774.
Neoadjuvant chemotherapy for locally advanced cervix E
cancer.Neoadjuvant Chemotherapy for Cervical Cancer
Meta-Analysis Collaboration (NACCCMA) X
• OBJECTIVES: This systematic review and individual
patient data (IPD) meta-analysis aimed to assess the
A
effect of neoadjuvant chemotherapy in two comparisons:
(1) neoadjuvant chemotherapy followed by radical
M
radiotherapy compared to the same radiotherapy NACT-RTP
alone; and RT
• (2) neoadjuvant chemotherapy followed by surgery AloneL
compared to radical radiotherapy alone.
NACT-SX
E
Eur J Cancer. 2003 Nov;39(17):2470-86.
RT Alone

Metanalysis (NACCCMA)
NACT-RT Vs RT Alone

• MAIN RESULTS: In the first comparison, we obtained data from 18 trials
and 2074 patients. When all trials were considered together, a high level of
statistical heterogeneity suggested that the results could not be combined
indiscriminately. A substantial amount of heterogeneity was explained by
E
•
separate analyses of groups of trials.
Trials using chemotherapy cycle lengths shorter than 14 days (HR = 0.83,
X
95% CI = 0.69 to 1.00, p = 0.046) or cisplatin dose intensities greater than
25 mg/m2 per week (HR = 0.91, 95% CI =0.78 to 1.05, p = 0.20) tended to
show an advantage for neo adjuvant chemotherapy on survival.
A
• In contrast, trials using cycle lengths longer than 14 days (HR =1.25, 95%
CI = 1.07 to 1.46, p = 0.005) or cisplatin dose intensities lower than25 M
mg/m2 per week (HR = 1.35, 95% CI = 1.11 to 1.14, p = 0.002) tended to

•
show a detrimental effect of neo adjuvant chemotherapy on survival.
In the second comparison, data from 5 trials and 872 patients were
P
obtained. The combined results from all trials (HR = 0.65, 95% CI = 0.53 to
0.80, p = 0.0004) indicate da highly significant reduction in the risk of death
with neo adjuvant chemotherapy, but there were some differences between
L
trials in their design and results.
E
NACT-Surgery Vs RT Alone

• In calculating average treatment effects, a
measure of difference in outcome
between treatments is calculated
separately for each trial. For example, an
estimate of the logarithm of the hazard
ratio can be computed for each trial. A
weighted average of these study-specific
differences then is computed, and the
statistical significance of this average is
evaluated.

Impact of Treatment on Mortality

E Study name Statistics for each study
Odds Lower Upper
Odds ratio and 95% CI

ratio limit limit
X Kelly, 1964 0.590 0.096 3.634
Hedrin, 1980 0.464 0.201 1.074
A Leigh, 1962
Novak, 1992
0.394
0.490
0.076
0.088
2.055
2.737

M
Saint, 1998 1.250 0.479 3.261
Pilbean, 1936 0.129 0.027 0.605
Day, 1960 0.313 0.054 1.805

P Kelly, 1966
Singh, 2000
0.429
0.718
0.070
0.237
2.620
2.179
Stewart, 1994 0.143 0.082 0.250
L 0.328 0.233 0.462
0.01 0.1 1 10 100

E Favours Tx Favours Pbo

Meta Analysis

the point estimate is represented by a square.

• This approach to metaanalysis requires
access to individual patient data for all
randomized patients in each trial. It also
requires collaboration of the leaders of all
the relevant trials and is very labor-
intensive. Nevertheless, it represents the
gold standard for metaanalysis
methodology.

• the metaanalysis may be useful for
answering important questions about a
class of treatments that the individual trials
cannot address reliably .

Metaanalysis is not an
alternative to properly
designed and sized
randomized clinical
trials.

advanced SCCHN Study design
Patients with measurable locally advanced SCCHN
(stratified by KPS;node+/0;T1-3/4; RT regimen)
E
Randomization
X
A RT RT as before +
once or twice daily or concomitant ERBITUX initial 400 mg/m2 2-h
M boost for 7 - 8 weeks infusion then 250 mg/m2 1-h infusion
weekly for at least 7 doses
P
L
E
Follow until disease
progression or up to 5 years


ERBITUX + RT for larynx preservation
Study design
Subgroup analysis

E Patients with stage III / IV SCC of larynx and hypopharynx
(stratified by KPS;node+/-;T1-3/4; radiation regimen)
X n=171

A n=78
Randomized
n=93
M
Radiotherapy Radiotherapy as before +
P once or twice daily or ERBITUX initial 400 mg/m2
concomitant boost for 6 - 2-h infusion then 250 mg/m2
L 7 weeks 1-h infusion weekly
E for at least 7 doses

Bonner et al. J Clin Oncol 2005;23(16S):Abstract 5533
Updated information presented at ASCO 2005

Randomisation-contd..
• There is generally differential bias in the
selection of patients to be treated resulting from
judgments by the physicians, self-selection by
the patients, and differences in referral patterns.
• There may be bias in treatment ineligibility rates.
Current patients sometimes are excluded from
analysis for not meeting eligibility criteria, not
receiving "adequate" treatment, refusing
treatment, or committing a major protocol
violation.
• The control group, on the other hand, generally
contains all the patients.

• There may be differences in the
distribution of known and unknown
prognostic factors between the controls
and the current treatment group.
• Often, there is inadequate information to
determine whether such differences are
present, and current known prognostic
factors may not have been measured for
the controls.

• Randomization does not ensure that the
study will include a representative sample
of all patients with the disease, but it does
help to ensure an unbiased evaluation of
the relative merits of the two treatments
for the types of patients entered.

At what point in time is
randomisation done?
• Randomization of a patient should be performed
after the patient has been found eligible and has
consented to participate in the trial and to accept
either of the randomized options.
• A truly random and nondecipherable
randomization procedure should be used and
implemented by calling a central randomization
office staffed by individuals who are independent
of participating physicians.

Power of a trial
• The probability of obtaining a statistically
significant result when the treatments differ in
effectiveness is called the power of the trial.
• As the sample size and extent of follow-up
increases, the power increases.
• The power depends critically, however, on the
size of the true difference in effectiveness of the
two treatments.
• Generally, one sizes the trial so that the power is
either .80 or .90 when the true difference in
effectiveness is the smallest size that is
considered medically important to detect.

Study name Statistics for each study Odds ratio and 95% CI
Odds Lower Upper
ratio limit limit
Kelly, 1964 0.590 0.096 3.634
Hedrin, 1980 0.464 0.201 1.074
Leigh, 1962 0.394 0.076 2.055
Novak, 1992 0.490 0.088 2.737
Saint, 1998 1.250 0.479 3.261
Pilbean, 1936 0.129 0.027 0.605
Day, 1960 0.313 0.054 1.805
Kelly, 1966 0.429 0.070 2.620
Singh, 2000 0.718 0.237 2.179
Stewart, 1994 0.143 0.082 0.250
0.328 0.233 0.462
0.01 0.1 1 10 100
Favours Tx Favours Pbo

the confidence interval (CI) for each
Meta Analysis

study is represented by a horizontal line

Odds Lower Upper
ratio limit limit
Kelly, 1964 0.590 0.096 3.634
Hedrin, 1980 0.464 0.201 1.074
Leigh, 1962 0.394 0.076 2.055
Novak, 1992 0.490 0.088 2.737
Saint, 1998 1.250 0.479 3.261
Pilbean, 1936 0.129 0.027 0.605
Day, 1960 0.313 0.054 1.805
Kelly, 1966 0.429 0.070 2.620
Singh, 2000 0.718 0.237 2.179
Stewart, 1994 0.143 0.082 0.250
0.328 0.233 0.462
0.01 0.1 1 10 100

Meta Analysis

the point estimate is represented by a square.

Odds Lower Upper
ratio limit limit
Kelly, 1964 0.590 0.096 3.634
Hedrin, 1980 0.464 0.201 1.074
Leigh, 1962 0.394 0.076 2.055
Novak, 1992 0.490 0.088 2.737
Saint, 1998 1.250 0.479 3.261
Pilbean, 1936 0.129 0.027 0.605
Day, 1960 0.313 0.054 1.805
Kelly, 1966 0.429 0.070 2.620
Singh, 2000 0.718 0.237 2.179
Stewart, 1994 0.143 0.082 0.250
0.328 0.233 0.462
0.01 0.1 1 10 100

Meta Analysis

The size of the square corresponds to the weight of the study in
the meta-analysis. ; this is the Mantel-Haenszel weight.

The confidence interval for
totals are represented by a
diamond shape. The pooled
estimate is marked with an unfilled diamond that
has an ascending dotted line from its upper
point. Confidence intervals of pooled estimates
are displayed as a horizontal line through the
diamond; this line might be contained within the
diamond if the confidence interval is narrow.

• The graph is a forest plot where the confidence
interval (CI) for each study is represented by a
horizontal line and the point estimate is
represented by a square. The size of the square
corresponds to the weight of the study in the
meta-analysis. The confidence interval for totals
are represented by a diamond shape. The scale
used on the graph depends on the statistical
method. Dichotomous data (except for risk
differences) are displayed on a logarithmic
scale. Continuous data and risk differences are
displayed on a linear scale.

How to interpret the Forest plot?

OR =
Intervention group Intervention group
1.0
does does
(no
better than control worse than control
effect

i. Probably a small study, with a wide confidence interval, crossing the line of no
effect (OR = 1). Unable to say if the intervention works
ii. Probably a small study, wide confidence interval , but does not cross OR = 1;
suggests intervention works but weak evidence
iii. Larger study, narrow confidence interval: but crosses OR = 1; no evidence
that intervention works
iv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggests
intervention works
v. Small study, wide confidence intervals, suggests intervention is detrimental
vi. Meta-analysis of all identified studies: suggests intervention works.

Clinical trials and Levels of evidence
ASCO guidelines (JCO;17:1999)

• Level III:
Well designed, quasi-experimental studies
such as non randomized, controlled,
single group. Pre-post, cohort, time or
matched case control series.
• Level IV: Well designed non experimental
studies.
• Level V: Case reports and clinical
examples.

What level of evidence is
“In my experience” ?

ERBITUX + RT in locally advanced SCCHN
Study endpoints

Primary endpoint
– locoregional control (absence of locoregional
disease progression at scheduled follow-up
visits)
– Secondary endpoints
– overall survival
– progression-free survival
– Safety (Mucositis, Dysphagia, Radiation
dermatitis, Weight-loss, Asthenia,
Xerostomia, Acne-like rash,Infusion reaction)


ERBITUX + RT in locally advanced SCCHN Patient and disease
characteristics
RT only ERBITUX + RT
Characteristics
% (n=213) % (n=211)
Gender: M / F 79 / 21 81 / 19
Median age 58 years 56 years
Karnofsky PS:
60 - 80% / 90 -
33 / 66 30 / 70
100%
Primary tumor site:
Oropharynx 63 56
Hypopharynx 13 17
Larynx 24 27
AJCC stage: III/IV 24 / 76 26 / 74
Tumor stage: T1-3 /
69 / 31 70 / 29
T4
Node stage: N0 / N+ 18 / 82 20 / 80


ERBITUX + RT improves locoregional control over RT alone in locally
advanced SCCHN (1)
ERBITUX + P value/
RT only
Efficacy RT *Hazard
% (n= 213) ratio
% (n= 211)
Median locoregional
14.9 24.4 0.005
control (months)
By site of primary
tumor (months):
Oropharynx 23.0 49.0 0.61*
Larynx 11.9 12.9 0.69*
Hypopharynx 10.3 12.5 0.92*
By disease stage
Stage III 16.2 38.9 0.69*
Stage IV 13.5 20.9 0.73*
Locoregional control
rate
2-year 41 50


advanced SCCHN (2)

Bonner et al. N Eng J Med
2006;354:567-578

advanced SCCHN (2)

Primary End
point

Bonner et al. N Eng J Med
2006;354:567-578

ERBITUX + RT prolongs survival over RT alone

in locally advanced SCCHN (1)

Efficacy RT only ERBITUX P value
% + RT
(n= 213) % (n=
211)
Median follow-
54 months 54 months
up
Median overall 29.3
49 months 0.03
survival months
Three-year
45 55 0.05
survival

ERBITUX + RT prolongs survival over RT alone in locally
advanced SCCHN (2)

Secondary
end point


ERBITUX does not increase acute RT-induced toxicity in locally advanced
SCCHN Yet another Secondary end
point

Selected or
RT only ERBITUX +
relevant grade 3-5
% RT
adverse events
(n=212) % (n=208)
reported
Mucositis 52 56
Dysphagia 30 26
Radiation
18 23
dermatitis
Weight loss 7 11
Asthenia 5 4
Xerostomia 3 5
Acne-like rash 1 17
Infusion reaction - 3

ERBITUX + RT for larynx
preservation

Improved preservation of larynx with the addition
of cetuximab to radiation for cancers of the larynx
and hypopharynx

Bonner J, Harari P, Giralt J, Baselga J, Shin DM, Cohen R,
Jassem J, Azarnia N, Molloy P, Ang K

Subgroup analysis of study by Bonner et al. J
Clin Oncol 2004;22(14S):Abstract 5507


ERBITUX + RT for larynx preservation Patient characteristics

Patient characteristics RT only ERBITUX+RT
% (n=78) % (n=93)
Median age (years) 61 59
Gender: M / F 79 / 21 80 / 20
Primary tumor site
Hypopharynx 35 39
Larynx 65 61
AJCC stage III / IV 28 / 72 38 / 62
ERBITUX treatment (n=91)
Median duration of treatment
8
(weeks)
Median number of infusions 8


ERBITUX + RT improves the rate of larynx preservation compared with RT

Efficacy RT only ERBITUX+RT
% (n=78) % (n=93)
Locoregional control:
Median (months) 12 16
One-year 49 60
Two-year 34 44
S
Overall survival: i
m
Two-year survival 48 50
i
Three-year survival 39 43
Laryngeal preservation: l
Two-year 80 a 90
Bonner et al. J Clin Oncol 2005;23(16S):Abstract 5533 87
Three-year 77 r
Updated information presented at ASCO
2005

ERBITUX + RT improves the rate of larynx preservation compared with RT

Efficacy RT only ERBITUX+RT
% (n=78) % (n=93)
Locoregional control:
One-year 49 60
Two-year 34 44
Overall survival:
Two-year survival 48 50
Three-year survival 39 43
Laryngeal preservation:
Two-year 80 90
Bonner et al. J Clin Oncol 2005;23(16S):Abstract 5533 87
Three-year 77
Updated information presented at ASCO
2005

ERBITUX + RT for larynx
preservation Conclusions

• The combination of ERBITUX
and RT improves laryngeal
preservation in patients with
laryngeal or hypopharyngeal
carcinomas compared with
RT alone

Definitions
• Mean, mode, median
• Statistical significance (P value)
• Variance, SD, SE and
• Confidence Interval
• Age-Adjusted Rate
• DFS, OS, Event, Censored cases
• Kaplan Meier/Life table methods
• Cox Regression
• Odds ratio (Forest and L`Abbe plots)

Definitions and terminology
• A discipline concerned with treatment of
numerical data derived from groups of
individuals
• To summarize our experience so that we
and other people can understand its
essential features.
• To use summary to make estimates or
predictions about what is likely to be the
case in other (perhaps future) situations.

• Descriptive : are methods used to
summarize or describe our observations.

• Inferential: Use of observations as a
basis for making estimates or predictions
(going beyond the fact).

Mean, mode, median
• Mean: The sum of all the observations divided by no. of
observations.
5,10,15,15,20,25,100,150,1000. Mean:

• Median: of a series of observations is the value of the
central or middle observation when all other
observations are listed in order from lowest to highest.
5,10,15,15,20,25,100,150,1000 Median:

• Mode: Most frequently occurring value in the series.
5,10,15,15,20,25,100,150,1000
• Mode:

Mean, mode, median
• Mean: The sum of all the observations divided by no. of
observations.
5,10,15,15,20,25,100,150,1000. Mean:148.5

• Median: of a series of observations is the value of the
central or middle observation when all other
observations are listed in order from lowest to highest.
5,10,15,15,20,25,100,150,1000 Median: 20

• Mode: Most frequently occurring value in the series.
5,10,15,15,20,25,100,150,1000
• Mode:15

Definitions and terminology:
Statistical significance
• If 2 means differ to more than twice the
value of SE of the difference, it is said to
be statistically significant i.e. more than is
likely to have arisen by chance (1 in
20=.05).
• An understanding of statistical significance
(p value ) requires understanding of terms
like Variance, Standard deviation, Std
error.

Definitions
• Mean, mode, median
• Statistical significance (P value)
• Variance, SD, SE and
• Confidence Interval
• Age-Adjusted Rate
• DFS, OS, Event, Censored cases
• Kaplan Meier/Life table methods
• Cox Regression

A crow was sitting on a tree, doing nothing all day.

A small rabbit saw the crow, and asked him,
"Can I also sit like you and do nothing all day
long?”
The crow answered: "Sure, why not.”

So, the rabbit sat on the ground below the
crow, and rested.

All of a sudden, a fox appeared,

Jumped on the rabbit... and ate it.

Moral of the story is….

To be sitting and doing nothing
you must be sitting very, very high up.

Variance, SD, SE and P value
20 observations of Deviation of each Square of each Deviation
Systolic BP in men observation from the from the mean
mean (128)
98 -30 900
160 +32 1024
136 +8 64
128 0 0
130 +2 4
114 -14 196
123 -5 25
134 +6 36
128 0 0
107 -21 441
123 -5 25

20 observations of Deviation of each Square of each Deviation
Systolic BP in men observation from the from the mean
mean (128)
125 -3 9
129 +1 1
132 +4 16
154 +26 676
115 -13 169
126 -2 4
132 +4 16
136 +8 64
130 +2 4
Sum 2560 0 3674
Mean Sq deviation=
3674/20=183.7

• Variance= mean squared deviation=183.7
Total no. 20 -1 (n-1)i.e.19=193.4

• Std. Deviation=Sq root of variance=13.91

• A large standard deviation means frequency
distribution is widely spread out from the mean.

• What is the Utility of Std Deviation?

It enables us to test whether the observed
diff. between 2 such means are more than
would be likely to have arisen by chance.

• Std. Error: of any statistical value is a
measure of the SD that that value would
show in taking repeated samples from the
same universe of observations. It shows
how much variation might be expected to
occur merely by chance. Std. Error of diff.
between 2 means=
• (S.D.1)2 + (S.D.2)2
• n1 n2

• Statistical significance: If 2 means differ
to more than twice the value of SE of the
difference, it is said to be statistically
significant i.e more than is likely to have
arisen by chance (1 in 20=.05).
• This calculation sets a standard of
judgment which is constant from one
person to another.

• A “ significant” answer does not prove
that the difference is real; “chance” is still
a possible explanation (though unlikely).
• A “ not significant” answer does not tell
us that Group A does not differ from group
B. It tells that “chance” may easily be a
reason for that difference.

• “ p value” does not give the reason for
significance or non significance.
• It is only by planning and foresight which
can ensure comparable groups of patients
and only in such circumstances can we
infer that the significant difference
between groups is more likely to be due to
the specific treatment than to any other
factor.

Confidence Interval

• A range of values that has a specified probability of
containing the estimated rate or trend of interest.
• The 95% (p-value = 0.05) and 99% (p-value = 0.01)
confidence intervals are the most commonly used.
• If an estimated annual percentage change (APC) is
-2.44 with a 95% confidence interval of (-2.83, -2.05),
then we are 95% confident that the actual APC is
between a decrease of -2.83% and a decrease of 2.05%.
Inversely, there is still a 5% chance that the actual APC
is not in the confidence interval (between the upper and
lower confidence limits)

• Confidence intervals are generally much more
informative than are significance levels. A
confidence interval for the size of the treatment
difference provides a range of effects consistent
with the data. The significance level tells nothing
about the size of the treatment effect because it
depends on the sample size. However, it is the
size of the treatment effect, as communicated by
a confidence interval, that should be used in
weighing the costs and benefits of clinical
decision making.

survivals
• Disease free survival (DFS,PFS).
• Overall Survival (OS): calculated from
date of registration or start of treatment.
• Cause specific survivals.
• Systems available: BMDP,SAS,SPSS
• Methods: Life table, Kaplan Meier, Cox
regression.

“Event” Vital status
• DFS
• Recurrence, lost to f/up with disease

• OS
• Death, lost to F/up with disease, status
unknown (worst case scenario),etc.

Vital status
• Alive;tumor free;no recurrence
• Alive;tumor free;after recurrence
• Alive with persistent, recurrent, or metastatic
disease
• Alive with primary tumor
• Dead;tumor free
• Dead with cancer
• Unknown;lost to follow up
• Completeness of follow up is crucial in any study
of survival time to exclude bias in data

Kaplan Meier curve
Survival Functions
1.1

1.0

.9

.8

.7
stgnw
.6
3.00
Cum Survival

.5
3.00-censored

.4 1.00

.3 1.00-censored
0 10 20 30 40 50 60 70

OS

Kaplan Meier curve
Survival Functions
1.1

1.0

.9

.8 Life table method
.7
stgnw
.6
3.00
Cum Survival

.5
3.00-censored

.4 1.00

.3 1.00-censored
0 10 20 30 40 50 60 70

OS

Kaplan Meier method
• This kind of data usually includes some
censored cases. Censored cases are cases
for which the second event isn’t recorded (for
example, people still alive disease free at the
end of the study).

Kaplan Meier method
• The Kaplan-Meier procedure is a method
of estimating time-to-event models in the
presence of censored cases.
• It is based on estimating conditional
probabilities at each time point when an
event occurs and taking the product limit
of those probabilities to estimate the
survival rate at each point in time.

• Censored cases can happen for several
reasons:

reasons:
1.for some cases, the event simply doesn’t occur
before the end of the study;

reasons:
2.for other cases, we lose track of their status
sometime before the end of the study;

reasons:
3.still other cases may be unable to continue for
reasons unrelated to the study

reasons:
3.still other cases may be unable to continue for
reasons unrelated to the study
Collectively, such cases are known as
censored cases, and they make this kind of
study inappropriate for traditional techniques
such as t tests or linear regression.

A wife is a wife,

No matter, who the hell you are!!

Cox Regression
• Like Life Tables and Kaplan-Meier survival
analysis, Cox Regression is a method for
modeling time-to-event data in the
presence of censored cases.
• However, Cox Regression allows you to
include predictor variables (covariates) in
your models, allowing you to assess the
impact of multiple covariates in the
same model.

Intention-to-Treat Analysis

• One of the important principles in the analysis of
phase III trials is called the intention-to-treat
principle.
• This indicates that all randomized patients
should be included in the primary analysis of the
trial. For cancer trials, this has often been
interpreted to mean all "eligible" randomized
patients. Because eligibility requirements
sometimes are vague and unverifiable by an
external auditor, excluding "ineligible" patients
can itself result in bias.

Intention-to-Treat Analysis-contd..

• However, excluding patients from analysis
because of treatment deviations, early death, or
patient withdrawal can severely distort the
results.
• Often, excluded patients have poorer outcomes
than do those who are not excluded.
• Investigators frequently rationalize that the poor
outcome experienced by a patient was due to
lack of compliance to treatment, but the direction
of causality may be the reverse.

Intention-to-Treat Analysis –
contd..
• In randomized trials, there may be poorer
compliance in one treatment group than the
other, or the reasons for poor compliance may
differ.
• Excluding patients, or analyzing them separately
(which is equivalent to excluding them), for
reasons other than eligibility is generally
considered unacceptable.
• The intention-to-treat analysis with all eligible
randomized patients should be the primary
analysis.

Intention-to-Treat Analysis –
contd..
• If the conclusions of a study depend on
exclusions, then these conclusions are
suspect.
• The treatment plan should be viewed as a
policy to be evaluated.
• The treatment intended cannot be
delivered uniformly to all patients, but all
eligible patients should generally be
evaluable in phase III trials.

Interim analysis
• It has become standard in multicenter clinical
trials to have a data-monitoring committee
review interim results, rather than having the
monitoring done by participating physicians.
• This approach helps to protect patients by
having interim results carefully evaluated by an
experienced group of individuals and helps to
protect the study from damage that ensues from
misinterpretation of interim results.

Interim analysis-contd..
• Generally, interim outcome information is
available to only the data-monitoring committee.
• The study leaders are not part of the data-
monitoring committee, because they may have a
perceived conflict of interest in continuing the
trial.
• The data-monitoring committee determines
when results are mature and should be
released.
• These procedures are used only for phase III
trials.

What happens when a clinical trial
is over?
• the researchers look carefully at the data
before making decisions about the
meaning of the findings and further
testing.
• After a phase I or II trial, the researchers
decide whether to move on to the next
phase, or stop testing the agent or
intervention because it was not safe or
effective.

is over?

The results of clinical trials are often
published in peer-reviewed, scientific
journals.

is over?
• Peer review is a process by which experts
review the report before it is published to make
sure the analysis and conclusions are sound.
• If the results are particularly important, they may
be featured by the media and discussed at
scientific meetings before they are published.
• Once a new approach has been proven safe and
effective in a clinical trial, it may become
standard practice.

Publication bias
• An additional factor to consider is that of
publication bias, which denotes the
preference of journals to publish positive
rather than negative results. A negative
result may not be published at all,
particularly from a small trial. If it is
published, it is likely to appear in a less
widely read journal than it would if the
result were positive.

• Publication bias
These observations emphasize that results in
the medical literature often cannot be
accepted at face value.

Publication bias
• It is essential to recognize that "positive"
results need confirmation, particularly
positive results of small studies, before
they can be believed and applied to the
general population.

Where can people find more
information about clinical trials?
• People also have the option of searching for
clinical trials on their own. The clinical trials
page of the NCI's Web site, located at
http://www.cancer.gov/clinicaltrials/ on the
Internet,
• Another resource is the NIH's
ClinicalTrials.gov Web site. ClinicalTrials.gov
lists clinical trials sponsored by the NIH,
other Federal agencies, and the
pharmaceutical industry for a wide range of
diseases, including cancer and other
conditions. This site can be found at
http://clinicaltrials.gov/ on the Internet.

Thankyou

This happens only in india

How to tabulate &
collect in what form?
• Strings Status DFS
1:Residual
(Names)
2:LFU with disease
3:LFU without disease
• Numericals 4 :disease Free

(Sex, types of protocols,
Status OS
stage, race,etc.)
1:Dead due to disease
2:LFU with disease
3:LFU without disease
4:Alive with disease
5:Alive disease free
6:dead other cause

Hands on SPSS
• Understanding variables.

• Entering the data.

• Analysis of data.

Conclusion
• It is a means of coming to
conclusions in the face of
uncertainty

“Act with caution”
You can prove anything with statistics.

There are lies, dammed lies, and
statistics.
Figures don’t lie, but liars use figures.

Act with Integrity.

A little bird was flying south for the winter.

It was so cold, the bird froze and fell to the ground in a large field.

While it was lying there, a
cow came by
and dropped some dung
on it.

As the frozen bird lay there in the pile of cow dung, it began to
realise how warm it was. The dung was actually thawing him out!
PURR.... He lay there all warm and happy, and soon began to sing for joy.
A passing cat heard the bird singing and came to investigate.

Following the sound, the cat discovered the bird under the pile of cow
dung, and promptly dug him out and ate him!

The morals of this story are:

1) Not everyone who drops shit on
you is your enemy.
2) Not everyone who gets you out of
shit is your friend.
3) And when you're in deep shit,
keep your mouth shut

Don’t ask me 2oo many ?s.
I’m not a statistician

Thank you. Have a nice day

Clinical trials

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