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Clinical trials - facts and myths!
1.
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Why do clinical trials
How did it all start
Do we really need to do trials in India
SWOT Analysis
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Why do Clinical trials?
 Academic Investigators / Caregivers
~ Increased ability to publish results
↑ professional stature, earlier promotion, ↑ salary
~ Desire to offer more therapeutic options to patients
 Government Sponsors
~ Claims of success in advancing health care
~ Leverage for ↑ in government funding
 Industry Sponsors
~ Company profits, ↑ value of stock options, promotion
….Wide Spread & Significant Conflicts of Interest
Clinical Trial Gains!

Gains for mankind

National gains

Institutional gains
Departmental gains

Personal gains
How did it all start
1639
The surgeons Mate, by John Woodall
The cures of scurvy
1753
Two sailors (2X6) allocated to each of:
a quart of cider daily
25 gutts of elixir vitriol thrice daily
2 spoonfuls of vinegar thrice daily
half a pint of sea water daily
two oranges and a lemon daily
the bigness of a nutmeg thrice daily
Diet was constant
1795
Approved in all ships
The Flexner Report - the Standardization
of American Medical Education 1900s

If the sick are to reap the full benefit of recent
progress in medicine, a more uniformly arduous
and expensive medical education is demanded.

The AMA sought to eliminate schools that failed
to adopt this rigorous brand of systematized,
experiential medical education.

Editors of JAMA declared, “It is to be hoped that
with higher standards universally applied their
number will soon be adequately reduced, and
that only the fittest will survive,”
American Medical Education –
100 Years after the Flexner Report


Flexner envisioned a clinical phase of
education in academically oriented hospitals,
where thoughtful clinicians would pursue
research stimulated by the questions that
arose in the course of patient care and teach
their students to do the same.
In academic hospitals, research quickly
outstripped teaching in importance.
 A “publish or perish” culture emerged in
American universities and medical schools.
Current (Cancer) Drug Development Pathway
Hypothesis
Clinical
Commercialization
Generation
Candidate Development
TRWG/CTWG
Chem-Biol Cons
$1200 MM
NEXT
pipeline
Discovery
Cumulative
Investment
Risk
Phase 0/PD
$500-600 MM
Target
Validation
Target/
Molecule
Discovery
Assay
Pre-Clin.
&
Phase Phase
Development Lead
Development
I
II
Biological
Optimization
CharLead
acteriz.
Generation
Phase
III
Registration
Global Global
Launch Optimization
$200-300 MM
$20-60 MM
Risk
Cumulative Investment
Time: 6-8 Years
Time
: 12-15 Years
Therapeutic development - Oncology
Phase I
Aim
Phase II
Pharmacology
Activity
1-25
9-50
Sample
Patient
Methods
refractory to
all treatment*
Fibonacci,
CRM*…
refractory to
conventional
Gehan,
Simon,…
Phase III
Efficacy
(Cost Benefit)
Phase I
Strategy
(post/
marketing)
X
200 - 1000 (Adv)
1000 - > 5000 (Adj)
1st/2nd line treat (Adv)
1st line treatment (Adj)
Randomized simple,
Stratified, Factorial,
or cross-over….
* May be different with targeted therapy
X
X
Examples of (Cancer)Research Priorities
Compare management strategies for localized
cancer on survival, recurrence, side effects,
quality of life, and costs
Compare imaging technologies in diagnosing,
staging, and monitoring patients with cancer
including PET, MRI, and CT
Compare genetic and biomarker testing and usual
care in preventing and treating breast, colorectal,
prostate, lung, and ovarian cancer, and possibly
other clinical conditions
1. Disease (Cancer) burden
Liver, Breast & Cervix Cancer burden
13
Health education improves survival
3-year survival improved from 26.6% to 44.0%
14
2. Natural history varies
3. Needs of our populations vary
Expansion of cancer care and control in countries of low
and middle income: a call to action.
Paul Farmer, MD, et al. Lancet August 2010
Can We Apply - What We Know?
Breast
Cancer
5-yr
Relative
Survival
If breast cancer survival
rates were uniformly as
high as the best in the
world, 100,000 fewer
women would die of
breast cancer each year
in the developing world.
“Do-Know Gap”
}
4. Co-morbidity varies
Variations in macro-nutrients
The percentage of
women who are too thin
is particularly high in
Bihar (45%),
Chhattisgarh, and
Jharkhand (43% each).
Malnutrition levels are
lowest in Delhi, Punjab,
and several of the small
northeastern states.
The percentage of
women who are
overweight or obese is
highest in Punjab (30%),
followed by Kerala (28%)
and Delhi (26%)
Variations in micro-nutrients
5. Infections are very common
and the bugs are different
6. PK/PD can also vary.
Toxicity and effectiveness varies
7. Tumor response varies
Hypothesis generation
observational data vs confirmation by clinical research
Mega doses of Vitamin C:
What is the effect on duration of survival in preterminal cancer patients?
 Nobel Laureate Linus Pauling: Loch
Lomanside, Scotland Cameron, Pauling.
Proc Natl Acad Sci 1976; 1978
Median Survival:
50 vs. 210 days;
38 vs. 293 days
 Mayo Clinic sponsored randomized trial
Moertel, Fleming, Creagan et. al. NEJM 1985; 312: 137-141
An Illustration of Exploratory Analyses:
Surgical Adjuvant Therapy
of Colorectal Cancer
5-FU and Levamisole
R
Levamisole
Control
Surgical Adjuvant Therapy: Colorectal Cancer
NCCTG Trial
Cancer Intergroup Trial
5-FU+LEV n=81
LEV
n=85 100 Control
n=81
100 -
80 -
80 60 -
60 -
40 -
40 -
20 -
20 -
0
0
0
5-FU+LEV n=304
LEV
n=310
Control
n=315
1
2
3
4
5
Years from randomization
6
0
1
2
3
4
5
6
7
Years from randomization
8
9
8. Genetic make up also variesThis is going to be important in
the era of personalized medicine
NATURE| Vol 461|24 September 2009
Allele frequency differences between groups in India are larger than in Europe
Gefitinib by smoking history and ethnicity
Proportion without treatment failure
1.0
Never smoked (n=375)
Ever smoked (n=1317)
p<0.0001
p=0.071
0.8
0.6
Gefitinib
Placebo
0.4
0.2
0.0
0
1.0
2
4
6
8 10 12 14 16
0
2
4
6
8 10 12 14 16
Asian ethnicity (n=342)
Non-Asian ethnicity (n=1350)
p=0.008
p=0.020
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8 10 12 14 16
0 2
Time (months)
4
6
8 10 12 14 16
9. Creating affordable treatments
Out of pocket expenditure
results of a pilot study

100 BPL patients interviewed

Mean expenditure was 72000 rupees before
any cancer treatment was started.

Ranged 15000 to over 100000

Two thirds (Rs. 50000 /USD1000) were spent
before reaching TMH.

70% spend on multiple diagnostic imaging
Tmh 2010- survey
37
Outcome following adjuvant chemotherapy for
pancreas cancer- recent trials
5FU costs 5% of Gemcitabine
CONKO-001:
Disease-Free Survival
ESPAC-1: Survival
75%
100%
50%
Survival (%)
Cumulative Disease Free Survival
100%
gemcitabine
25%
75%
50%
LV+ 5FU
25%
observation
No chemotherapy
0%
0%
0
12
24
36 48
Months
60
72
84
Oettle H, et al. J Am Med Assoc.2007;297:267-77.
Assoc.
0
12
24
36
Months
48
60
Neoptolemos JP, et al. NEJM. 2004;350:1200-10.
72
Adjuvant head to head Gem or
5FU in pancreas ESPAC-3 RCT
JAMA 2010
Clinical Research in Cancer
A SWOT ANALYSIS
Speaking for myself!!
CLINICAL TRIALS
Investigator
1989 – 1998
Sponsored
1995 – 1998
Designed
8
5*
Conducted
5
5
Analyzed
4
5*
Abstracts
2
5*
Publications
1
4*
Multicentric*
STRENGTHS

Very large patient pool

Untreated patients

High volume services

World class facilities

Good record keeping

Operating costs are low

English speaking

Research culture is improving
Lancet August 2010
WEAKNESS

Lack of formal training in clinical research

We give up easily (like our cricket team)
– We also need foreign coaches

Very large (migrant) patient pool
– Lost to follow up

High volume (overburdened) services

Cheap (untrained and incompetent) labor

Regulatory affairs personnel lack experience

Illiterate or vernacular speaking

Drop out and lost to follow up rates are high
No. Clinical trials
Types of Clinical trials
WEAKNESS

Few trials published in high impact journals

Still struggling with regulatory aspects of trials

Professional jealousy has crept in

Inter & Intra departmental bottlenecks

We do not collaborate [within TMC & out side]
– Divide and rule hangover still exits

Less than 1% patients on clinical trials.

Routine care is starting to suffer

Education & training is loosing out
Opportunities

Training in trial methodology

Recognition and opinion leadership

Numerous trials help patients

Funding has increased

International exposure & network

HRD in clinical trials
– Youngsters are getting opportunity
THREATS

Competitive enrollment
– Many small groups enrolling

Cheaper than us options

Collaboration is higher

Competing trials

Professional rivalry

Failure to comply with regulators

Ethics/ Blacklisting

Move away from core competence
When a great profession and the forces of
capitalism interact, drama is likely to result.
Clinical trials losing the plot in India

McKinsey had earlier projected that by 2011, over 3,00,000 patients would be
enrolled for clinical trials in India and 1,500 to 2,000 studies conducted here each
year.

As against this, the Indian clinical trial industry did only 240-260 trials from MNCs
and another 180-200 trials of domestic companies last year.

Recession, regulatory issues, lack of laws, concerns on data protection, skill sets,
infrastructure and delay in approvals are among the many reasons given by sector
experts for the decline.

If a trial is approved in the US within a month, it takes six to eight weeks for the apex
drug regulator, Drug Controller General of India, to respond. Normally 12-16 weeks
are needed to get approval for a trial.

Not only the trial sites: quality and infrastructure of CROs are another area of
concern. Of the 120-plus CROs, only about 20 comply with the global benchmark
ICH- GCP.

DCGI had, a few days earlier, come out with a comprehensive clinical trial inspection
programme, with specific guidelines and checklists to make trial regulations more
stringent and uniform. At present, trials are based on guidelines brought out by the
Indian Council of Medical Research and the office of DCGI. India had amended
Schedule Y of the Drugs and Cosmetics Act in 2005 to create a conducive
environment for doing trials in India, but specific laws are yet to be in place to
effectively regulate trials in the country.
SUMMARY

Do only those trials that are necessary

Have a portfolio of short and long term projects
 Allocate
time for each trial

Plan your act- Act your plan

Reinforce enthusiasm in your team

Reinforce competition among investigators by
sending newsletters or holding investigator meets.
Winning in resource limited settings?
AR Rahman’s Mantra
Struggle/ Hard work
Passion/ Commitment
So that every prospective idea
does not
become a retrospective study
Thank You!