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

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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!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!