Clinical trials - facts and myths!
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Transcript of Clinical trials - facts and myths!
Clinical trials - facts and myths!Clinical trials - facts and myths!
1. Why do clinical trials2. How did it all start3. Do we really need to do trials in India4. SWOT Analysis
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!Clinical Trial Gains!Gains for mankind
National gains
Institutional gains Departmental gains
Personal gains
16391639The surgeons Mate, by John WoodallThe surgeons Mate, by John WoodallThe cures of scurvyThe cures of scurvy
17531753Two sailors (2X6) allocated to each of:Two sailors (2X6) allocated to each of:
a quart of a quart of cidercider daily daily25 gutts of 25 gutts of elixir vitriolelixir vitriol thrice daily thrice daily2 spoonfuls of 2 spoonfuls of vinegarvinegar thrice daily thrice dailyhalf a pint of half a pint of sea watersea water daily dailytwo oranges and a lemontwo oranges and a lemon daily dailythe bigness of a the bigness of a nutmegnutmeg thrice daily thrice dailyDiet was constantDiet was constant
17951795Approved in all shipsApproved in all ships
How did it all startHow did it all start
The Flexner Report - the StandardizationThe Flexner Report - the Standardizationof American Medical Education 1900sof American Medical Education 1900s
If the sick are to reap the full benefit of recent If the sick are to reap the full benefit of recent progress in medicine, a more uniformly arduous progress in medicine, a more uniformly arduous and expensive medical education is demanded.and expensive medical education is demanded.
The AMA sought to eliminate schools that failed The AMA sought to eliminate schools that failed to adopt this rigorous brand of systematized, to adopt this rigorous brand of systematized, experiential medical education.experiential medical education.
Editors of JAMA declared, “It is to be hoped that Editors of JAMA declared, “It is to be hoped that with higher standards universally applied their with higher standards universally applied their number will soon be adequately reduced, and that number will soon be adequately reduced, and that only the fittest will survive,”only the fittest will survive,”
American Medical Education –American Medical Education –100 Years after the Flexner Report100 Years after the Flexner Report
Flexner envisioned a clinical phase of Flexner envisioned a clinical phase of education in academically oriented hospitals, education in academically oriented hospitals, where thoughtful clinicians would pursue where thoughtful clinicians would pursue research stimulated by the questions that research stimulated by the questions that arose in the course of patient care and teach arose in the course of patient care and teach their students to do the same. their students to do the same.
In academic hospitals, research quickly In academic hospitals, research quickly outstripped teaching in importance.outstripped teaching in importance.
A “publish or perish” culture emerged in A “publish or perish” culture emerged in American universities and medical schools.American universities and medical schools.
ClinicalCandidate Development
HypothesisGeneration
Risk
Cumulative InvestmentRisk
CumulativeInvestment
$20-60 MM
$200-300 MM
$500-600 MM
$1200 MM
Time: 12-15 Years
Pre-Clin.Development
PhaseI
PhaseII
PhaseIII
Regis-tration
GlobalLaunch
GlobalOptimization
Commercialization
LeadOptimization
Target Validation
AssayDevelopment
LeadGeneration
Time: 6-8 Years
TRWG/CTWGTRWG/CTWG
Phase 0/PDPhase 0/PD
NEXTNEXTpipelinepipeline
Chem-Biol ConsChem-Biol Cons
Target/MoleculeDiscovery&BiologicalChar-acteriz.
Discovery
Current (Cancer) Drug Development Pathway
Therapeutic development - OncologyTherapeutic development - Oncology Phase I Phase II Phase III Phase IAim Pharmacology Activity Efficacy Strategy
(Cost Benefit) (post/ marketing)Sample 1-25 9-50 200 - 1000 (Adv) X
1000 - > 5000 (Adj)Patient refractory to refractory to 1st/2nd line treat (Adv) X
all treatment* conventional 1st line treatment (Adj)
Methods Fibonacci, Gehan, Randomized simple, X CRM*… Simon,… Stratified, Factorial,
or cross-over….
* May be different with targeted therapy
Examples of (Cancer)Research Priorities
1. Disease (Cancer) burden1. Disease (Cancer) burden
Liver, Breast & Cervix Cancer burdenLiver, Breast & Cervix Cancer burden
13
Health education improves survivalHealth education improves survival
14
3-year survival improved from 26.6% to 44.0%3-year survival improved from 26.6% to 44.0%
2. Natural history varies2. Natural history varies
3. Needs of our populations vary3. 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
}
BreastCancer
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.
Can We Apply - What We Know?
“Do-Know Gap”
4. Co-morbidity varies4. Co-morbidity varies
The percentage of The percentage of women who are too thin women who are too thin is particularly high in is particularly high in Bihar (45%), Bihar (45%), Chhattisgarh, and Chhattisgarh, and Jharkhand (43% each). Jharkhand (43% each).
Malnutrition levels are Malnutrition levels are lowest in Delhi, Punjab, lowest in Delhi, Punjab, and several of the small and several of the small northeastern states.northeastern states.
The percentage of The percentage of women who are women who are overweight or obese is overweight or obese is highest in Punjab (30%), highest in Punjab (30%), followed by Kerala (28%) followed by Kerala (28%) and Delhi (26%)and Delhi (26%)
Variations in macro-nutrients
Variations in micro-nutrients
5. Infections are very common 5. Infections are very common and the bugs are differentand the bugs are different
6. PK/PD can also vary. 6. PK/PD can also vary. Toxicity and effectiveness variesToxicity and effectiveness varies
7. Tumor response varies7. 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 pre-terminal 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 Therapyof Colorectal Cancer
5-FU and Levamisole
Levamisole
Control
R
Surgical Adjuvant Therapy: Colorectal CancerS
urv i
v ing
, %
0 1 2 3 4 5 6
100 -
80 -
60 -
40 -
20 -
0
Years from randomization
NCCTG Trial Cancer Intergroup Trial
0 1 2 3 4 5 6 7 8 9
100 -
80 -
60 -
40 -
20 -
0
Years from randomization
5-FU+LEV n=81LEV n=85Control n=81
5-FU+LEV n=304LEV n=310Control n=315
8. Genetic make up also varies- 8. Genetic make up also varies- This is going to be important in This is going to be important in
the era of personalized medicinethe era of personalized medicine
Allele frequency differences between groups in India are larger than in EuropeAllele frequency differences between groups in India are larger than in Europe
NATURE| Vol 461|24 September 2009NATURE| Vol 461|24 September 2009
Gefitinib by smoking history and ethnicityGefitinib by smoking history and ethnicity
0 2 4 6 8 10 12 14 16
Pro
porti
on w
ithou
t tre
atm
ent f
ailu
re
Never smoked (n=375)p<0.0001
Ever smoked (n=1317)p=0.071
Asian ethnicity (n=342)p=0.008
Non-Asian ethnicity (n=1350)p=0.020
GefitinibPlacebo
Time (months)
0 2 4 6 8 10 12 14 160.0
1.00.80.60.40.2
0 2 4 6 8 10 12 14 160 2 4 6 8 10 12 14 160.0
1.00.80.60.40.2
9. Creating affordable treatments9. Creating affordable treatments
Out of pocket expenditureOut of pocket expenditureresults of a pilot studyresults 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- survey37
ESPAC-1: SurvivalCONKO-001: Disease-Free Survival
Oettle H, et al. J Am Med Assoc.
Outcome following adjuvant chemotherapy for Outcome following adjuvant chemotherapy for pancreas cancer- recent trialspancreas cancer- recent trials
Neoptolemos JP, et al. NEJM. 2004;350:1200-10.Oettle H, et al. J Am Med Assoc.2007;297:267-77.
Months
Cum
ulat
ive
Dis
ease
Fre
e Su
rviv
al
100%
75%
50%
25%
0%0
100%
75%
50%
25%
0%12 24 36 48 60 72
LV+ 5FU
No chemotherapy
Months
Surv
ival
(%)
847260483624120
observation
gemcitabine
5FU costs 5% of Gemcitabine5FU costs 5% of Gemcitabine
Adjuvant head to head Gem or Adjuvant head to head Gem or 5FU in pancreas ESPAC-3 RCT 5FU in pancreas ESPAC-3 RCT
JAMA 2010JAMA 2010
Clinical Research in CancerClinical Research in Cancer
A SWOT ANALYSISA SWOT ANALYSIS
Speaking for myself!!Speaking for myself!!
Investigator 1989 – 1998
Sponsored 1995 – 1998
Designed 8 5* Conducted 5 5 Analyzed 4 5* Abstracts 2 5*
Publications
1 4*
Multicentric*
CLINICAL TRIALSCLINICAL TRIALS
STRENGTHSSTRENGTHS 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
WEAKNESSWEAKNESS 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 trialsNo. Clinical trials
Types of Clinical trialsTypes of Clinical trials
WEAKNESSWEAKNESS 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 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
THREATSTHREATS 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 When a great profession and the forces of capitalism interact, drama is likely to result.capitalism interact, drama is likely to result.
Clinical trials losing the plot in IndiaClinical 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.
SUMMARYSUMMARY
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.
Patience/ Quitters don’t winPatience/ Quitters don’t win
Struggle/ Hard workStruggle/ Hard work
Self improvement
Self improvement
Original score/ideas
Original score/ideas
Passion/ CommitmentPassion/ Commitment
Winning in resource limited settings?Winning in resource limited settings?AR Rahman’s MantraAR Rahman’s Mantra
So that every prospective idea So that every prospective idea does not does not
become a retrospective studybecome a retrospective study
Thank You!Thank You!