Clinical trials facts and myths Why do clinical

Clinical trials - facts and myths! Why do clinical trials 2. How did it all start 3. Do we really need to do trials in India 4. SWOT Analysis reenanair@email. com 1.

Why do Clinical trials? Ø Academic Investigators / Caregivers ~ Increased ability to publish results ↑ professional stature, earlier promotion, ↑ salary ~ Desire to offer more therapeutic options to patients Ø Government Sponsors ~ Claims of success in advancing health care ~ Leverage for ↑ in government funding Ø Industry Sponsors ~ Company profits, ↑ value of stock options, promotion …. Wide Spread & Significant Conflicts of Interest

Clinical Trial Gains! l Gains for mankind l National gains l Institutional gains Departmental gains l Personal gains

How did it all start 1639 The surgeons Mate, by John Woodall The cures of scurvy 1753 Two sailors (2 X 6) 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 1900 s l If the sick are to reap the full benefit of recent progress in medicine, a more uniformly arduous and expensive medical education is demanded. l The AMA sought to eliminate schools that failed to adopt this rigorous brand of systematized, experiential medical education. l 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 l 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. l A “publish or perish” culture emerged in American universities and medical schools. l

Current (Cancer) Drug Development Pathway Hypothesis Clinical Commercialization Generation Candidate Development TRWG/CTWG Chem-Biol Cons $1200 MM NEXT pipeline Discovery Risk Cumulative Investment Phase 0/PD $500 -600 MM Target Validation Target/ Molecule Discovery Assay Pre-Clin. & Phase Development Lead Development I II Biological Optimization Char. Lead acteriz. Phase III Registration Global Launch Optimization Generation $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) 1 st/2 nd line treat (Adv) 1 st 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

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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? Ø 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 Ø 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 5 -FU+LEV n=81 LEV n=85 100 Control n=81 100 Surviving, % Cancer Intergroup Trial 80 - 80 60 - 40 - 20 - 0 0 0 5 -FU+LEV n=304 LEV n=310 Control n=315 1 2 3 4 5 6 Years from randomization 0 1 2 3 4 5 6 7 8 Years from randomization 9

8. Genetic make up also varies. This 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 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 0 2 8 10 12 14 16 Time (months) 4 6 8 10 12 14 16

9. Creating affordable treatments

Out of pocket expenditure results of a pilot study l 100 BPL patients interviewed l Mean expenditure was 72000 rupees before any cancer treatment was started. l Ranged 15000 to over 100000 l Two thirds (Rs. 50000 /USD 1000) were spent before reaching TMH. l 70% spend on multiple diagnostic imaging Tmh 2010 - survey 37

Outcome following adjuvant chemotherapy for pancreas cancer- recent trials 5 FU 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+ 5 FU 25% observation 0% No chemotherapy 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 5 FU in pancreas ESPAC-3 RCT JAMA 2010

Clinical Research in Cancer A SWOT ANALYSIS Speaking for myself!!

CLINICAL TRIALS

STRENGTHS l Very large patient pool l Untreated patients l High volume services l World class facilities l Good record keeping l Operating costs are low l English speaking l Research culture is improving

Lancet August 2010

WEAKNESS l Lack of formal training in clinical research l We give up easily (like our cricket team) – We also need foreign coaches l Very large (migrant) patient pool – Lost to follow up l High volume (overburdened) services l Cheap (untrained and incompetent) labor l Regulatory affairs personnel lack experience l Illiterate or vernacular speaking l Drop out and lost to follow up rates are high

No. Clinical trials

Types of Clinical trials

WEAKNESS l Few trials published in high impact journals l Still struggling with regulatory aspects of trials l Professional jealousy has crept in l Inter & Intra departmental bottlenecks l We do not collaborate [within TMC & out side] – Divide and rule hangover still exits l Less than 1% patients on clinical trials. l Routine care is starting to suffer l Education & training is loosing out

Opportunities l Training in trial methodology l Recognition and opinion leadership l Numerous trials help patients l Funding has increased l International exposure & network l HRD in clinical trials – Youngsters are getting opportunity

THREATS l Competitive enrollment – Many small groups enrolling l Cheaper than us options l Collaboration is higher l Competing trials l Professional rivalry l Failure to comply with regulators l Ethics/ Blacklisting l 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 l Mc. Kinsey had earlier projected that by 2011, over 3, 000 patients would be enrolled for clinical trials in India and 1, 500 to 2, 000 studies conducted here each year. l 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. l 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. l 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. l 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. l 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 l Do only those trials that are necessary l Have a portfolio of short and long term projects l Allocate time for each trial l Plan your act- Act your plan l Reinforce enthusiasm in your team l Reinforce competition among investigators by sending newsletters or holding investigator meets.

Winning in resource limited settings? AR Rahman’s Mantra s a e id / e r co s l a n i g i Or Passion/ Commitment Struggle/ Hard work Sel f im pro vem ent win t ’ n o d s r e uitt Q / e c n e i t Pa

So that every prospective idea does not become a retrospective study

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