Clinical Trials:A Story, A Science, A Career

Dr. Bhaswat S. ChakrabortySr. VP & Chair, Science Core Committee, R&D

Cadila Pharmaceuticals Ltd.

Presented at GFSU on July 30, 2012

History of Clinical Trials

http://fcit.coedu.usf.edu/holocaust/gallery2/77021.htm

The Nazi Medical War Crimes

• “Medical experiments” were performed on thousands of concentration camp prisoners

• Included deadly studies and tortures such as injecting people with gasoline and live viruses, immersing people in ice water, and forcing people to ingest poisons

War Crimes Tribunal at Nuremberg

• Indictments:– Conspiracy to commit crimes against peace– Planning, initiating and waging wars of

aggression– War-Crimes– Crimes against humanity

War Crimes Trial at Nuremberg

In his closing remarks Robert Jackson, the U.S. Chief Prosecutor issued the following warning:

“….. If we cannot eliminate the causes and prevent the repetition of these barbaric events, it is not an irresponsible prophecy to say that this twentieth century may yet succeed in bringing the doom of civilization”

The Nuremberg Trial• December 1946

– 23 physicians and administrators– for their willing participation in the systematic torture,

mutilation, and killing of prisoners in experiments– Despite the arguments of the German physicians that the

experiments were medically justified, the Nuremberg Military Tribunals condemned the experiments as “crimes against humanity”

– 16 were found guilty and imprisoned– 7 were sentenced to death

• August 1947 verdict– A section called “Permissible Medical Experiments.” This section

became known as the Nuremberg Code

1. The voluntary consent of the human subject is absolutely essential.  This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonable to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment.

The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.   2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.  3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment.  4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.  5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.

Directives for Human ExperimentationNUREMBERG CODE

6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.  7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.  8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.  9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. 

10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject._____________________

Reprinted from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2, pp. 181-182.. Washington, D.C.: U.S. Government Printing Office, 1949.

Directives for Human ExperimentationNUREMBERG CODE

The Tuskegee Syphilis Study

The Tuskegee Syphilis Study

The Tuskegee Syphilis Study• 1932-72, More than 400 black men with syphilis &

about 200 men without syphilis– recruited without informed consent– misinformed that some of the procedures (e.g., spinal

taps) were actually “special free treatment”

• 1940s, Penicillin found to be effective in syphilis– the study continued, however, and the men were neither

informed nor treated with the antibiotic

• 1972, Congress established regulation for human research

• 1997, President Clinton apologized

Jewish Chronic Disease Hospital Study

Jewish Chronic Disease Hospital Study

• 1963, New York City's Jewish Chronic Disease Hospital– studies to develop information on the nature of the human transplant

rejection process– involved the injection of live cancer cells into patients who were hospitalized

with various chronic debilitating diseases

• Researchers said that consent had been given orally, but was not documented– felt that documentation was unnecessary– because much more dangerous medical procedures are undertaken without

the use of consent forms– would frighten the patients unnecessarily– good cause

• Researchers were found guilty of fraud, deceit and unprofessional conduct

Positive Stories in Drug Discovery & Clinical Trials

Dr. Y. Subbarao, 1940’s;Discovery of the role of Phosphocreatine and ATP in muscular activitySynthesis of Folic AcidSynthesis of MethotrexateDiscovery of Diethylcarbamazine

Dr. Upendranath Brahmachari, 1920’s;Discovery of ureastibamine (antimonial compound for treatment of kala azar)

Sir Alexander Fleming, 1950’s; Penicillin Sir James W. Black, 1960’s; Propranolol

Dr. Jerome Horwitz, 1960’s; Zidovudine Dr. Akira Endo, 1970’s; Mevastatin

Dr. Napoleone Ferrara, 1990’s; Bevacizumab

Science of Clinical Trials

The Science & Art of Clinical Trials

Global Pharmaceutical Market

• The global pharmaceutical market research has been done by many companies– All indicate a significant growth of pharma market

in 2010-2011. – The forecasting indicates pharmaceutical market

growth of about 4 - 6% in 2010-2011. – >$850 Billion– Expected to grow at a 4 - 7% compound annual

growth rate (CAGR) through 2013. – >$975 billion by 2013

Global Top 20 Pharmaceutical Companies

Rank Company Revenue in $ Million(2010)

01 Johnson & Johnson 61,897

02 Pfizer 50,009

03 Abbott 30,764

04 Merck & Co. 27,428

05 Eli Lilly & Co. 21,836

06 Bristol-Myers Squibb 21,634

07 Amgen 14,642

08 Gilead Sciences 7,011

09 Mylan 5,093

10 Genzyme 4,516

Indian Pharmaceutical Market• 3rd largest (after US and European) generic market in volume,

14th in value– India currently holds only ~2% share, but it has been growing at

approximately 10% per year

– India is a leader in generic drugs and active pharmaceutical ingredients (API)

– Now seeking to become a major player in outsourced clinical research as well as contract manufacturing and research

– There are ~100 U.S. FDA-approved manufacturing facilities in India, more than in any other country outside the U.S

– In 2010, almost 30% of all Abbreviated New Drug Applications (ANDA) to the FDA have been filed by Indian companies

– India’s share of the global generics market is ~33% now

Top 10 Pharmaceuticals in India, as of 2010Rank Company Revenue 2010

(Rs crore)Revenue 2010 (Rs billion)

1 Cipla 4,198.96 41.989

2 Ranbaxy (Taken over by Daiichi Sankyo in 2008) 4,162.25 41.622

3 Dr. Reddy's Laboratories 3,763.72 37.637

4 Sun Pharmaceutical 2,463.59 24.635

5 Lupin Ltd 2,215.52 22.15

6 Aurobindo Pharma 2,081.19 20.801

7 GlaxoSmithKline Pharmaceuticals Ltd 1,773.41 17.734

8 Cadila Healthcare 1,613 16.13

9 Aventis Pharma Limited 983.80 9.838

10 Ipca Laboratories 980.44 9.8044

Growth in Indian Domestic MarketRe

venu

e in

US$

Bill

ion

Dynamic Continuum of Drug Discovery

Clinical Research• Clinical research is a branch of medical science that determines the

safety and effectiveness of – Medications– Medical devices (including surgicals)– Diagnostic products and treatment regimens intended for human use.

• These may be used for prevention, treatment, diagnosis or for relieving symptoms of a disease

• Ethical research, overseen and regulated by local and other pertinent Government authorities

• Regulators and Ethics committees review the research prior to conduct as well as after completion of a study

• Clinical research is often understood by four phases of Clinical Trials (Phase I – IV)

Global Clinical Research Environment Today

• Large, multinational clinical trials preferred over smaller, locally-sponsored trials– Pressures on pharmaceutical and biotech companies – Budget and resource constraints

• The goal is to increase access to treatment of naïve subjects by enlisting sites outside of major markets, and to drive cost savings through economies of scale.

• After a steep learning curve in the 1990’s, now reaping benefits of large, multinational studies while minimizing the problems: – Hardware and IT infrastructure harmony– Support in multiple languages– Responding to regulators’ queries from several countries arriving at the same

time

• Better & successful management of large, multinational clinical studies

Largest Registry of Clinical Trials• ClinicalTrials.gov (www.clinicaltrials.gov) is a registry and

results database of federally and privately supported clinical trials conducted in the United States and around the world.

– currently contains 113,598 trials

– sponsored by the National Institutes of Health, other federal agencies, and private industry

– Studies listed in the database are conducted in 176 countries

– 24 categories of diseases

– gives you information about a trial's purpose, who may participate, locations, and contact phone numbers

– receives over 50 million page views per month 65,000 visitors daily

Map of All Studies in ClinicalTrials.gov

What is a Clinical Trial (CT)?• Biomedical or health-related research

studies in human beings that follow a pre-defined protocol

• Clinical Trials mean both interventional and observational types of studies– Interventional studies are those in

which the research subjects are assigned by the investigator to a treatment or other intervention, and their outcomes are measured

– Observational studies are those in which individuals are observed and their outcomes are measured by the investigators

Different Types of CTs• Treatment trials test experimental treatments, new combinations of drugs, or

new approaches to surgery or radiation therapy

• Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vaccines, vitamins, minerals, or lifestyle changes

• Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition

• Screening trials test the best way to detect certain diseases or health conditions

• Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.

Different Phases of CT• Clinical trials are conducted in phases. The trials at each phase have

a different purpose and help scientists answer different questions:– In Phase I trials, researchers test an experimental drug or treatment in a

small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

– In Phase II trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

– In Phase III trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely.

– In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

Participation in Clinical Trials• Participants in clinical trials can play a more active role in their own health

care, gain access to new research treatments before they are widely available, and help others by contributing to medical research

• All clinical trials have guidelines about who can participate– Inclusion/exclusion criteria

– The factors that allow someone to participate in a clinical trial are called "inclusion criteria"

– Those disallow someone from participating are called "exclusion criteria“

– These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions

– A participant must qualify for the study by I/E

– Some studies need patients with illnesses, while others need healthy participants

– I/E not used to reject people personally

What are the Benefits & Risks of Participating in a Clinical Trial?

• Benefits– Clinical trials that are well-designed and well-executed are the

best approach for eligible participants to play an active role in their own health care

– Gain access to new research treatments before they are widely available

– Obtain expert medical care at leading health care facilities during the trial

– Help others by contributing to medical research.

• Risks – There are risks to clinical trials. There may be unpleasant, serious

or even life-threatening side effects to experimental treatment

– The experimental treatment may not be effective for the participant

– The protocol may require more of their time and attention than would a non-protocol treatment, including trips to the study site, more treatments, hospital stays or complex dosage requirements

What Happens During a CT?• Depends on the kind of trial being conducted

– The clinical trial team includes doctors and nurses as well as social workers and other health care professionals

– They check the health of the participant at the beginning of the trial, give specific instructions for participating in the trial

– They also monitor the participant carefully during the trial, and stay in touch after the trial is completed

– Some CTs involve more tests and doctor visits than the participant would normally have for an illness or condition

– For all types of CTs, the participant works with a research team– A CT is most successful when the protocol is carefully followed and

there is frequent contact with the research staff

Career in Clinical Trials & Research

Opportunities

United States

Western Europe Rest of world

1997 86% 9% 5%

1999 80% 9% 12%

2001 77% 10% 13%

2003 70% 11% 19%

2005 62% 13% 25%

2007 57% 14% 29%

The Rise of Trial Outsourcing% of PIs in a Country/Region

•Source: Tufts Center for the Study of Drug Development analysis of FDA data

Multi-centric CTs in India• India is said to participate in 7% of global Phase III

and 3.2% of Phase II trials.• 2.5% of global market.• Today, most of the big pharmaceutical companies

are conducting multi-centric trials in India• All leading global CROs have also set up services in

India • India has about 30 established major international

CROs and nearly 100 CROs of reasonable size that are currently involved in conducting clinical trials in the country.

Opportunities for Capacity (Continuous) Development

Ethics Capacity• Ethics Committees, ethical guidelines and norms, and IRBs

ensure compliance with established ethical guidelines and good practices.

• Ethics committees need data to evaluate ethical conduct of a study.

• Critical issues: conflict of interest, cultural specificities in obtaining informed consent from vulnerable population, safety etc.

• Meaningful trials• Subject’s independent decision• Punitive measures and/or legal liability• Training of ethics committee members, accreditation of these

committees and the development of stringent guideline.

Regulatory Capacity• Currently a portion of the required capacity is existing

but slow• Main focus: regulatory capacity of monitoring, oversight,

enforcement , review and approval of trials • An innovative structure with “consultants” may be more

is being sought out• A definition of conflict of interest in the Indian context

for these consultants is also being looked into• Complemented by required legislative changes• Credible CROs for the conduct of need based trials• Certification for principal investigators

Expertise• Development of world-class expertise is an outcome of this

growth in clinical trials• involves knowledge transfer from abroad and local expertise

building

• Quality control and joint trials with reputed global players• Partnerships between public and private sector and with

international organizations• Guidelines and standards of learning• Human and other resource planning for clinical trials of the

future (e.g., biotech therapies, molecular diagnostics and molecular epidemiology)

Data Management Capacity

• Case report forms (CRFs) design • Database design • Database programming • 21 CFR part 11 compliant validation process • Loading, reconciliation and integration of external data • Medical coding • Status reporting • Forms management• Data entry and cleaning• Data locking• Statistical analysis• Report generation

Data Capture (1)

No

Yes

CRF

Manual data

Electronic data

Raw data

A

Electronic data to be combined?

Raw data (Manual)

Get approval

A

Data Capture (2)

Real time query

Are the queries answered?

Yes

No

Data cleaning1. Detecting & diagnosing errors2. Editing incorrect data3. Integrated data passage4. Outlier determination5. Robust estimation of analytical parameters

Clean data

Approval required

Can this data be locked?

Yes

NoRepeat Observation/

Omission

Locked data B

B

Data Capture (3)

Locked Clean Data

Statistical analysis required?

Yes

No

SAS Data SetsStatistical Data AnalysisTests of HypothesesCohort Analyses

ResultsReport

Data Summary, Charts/Graphs

CT Professional Personnel• Principal & co-investigators• Clinical (medical ) investigators• Regulatory and Ethics Submissions / Feasibility Specialists • Clinical Trial Assistant (CTA) / Clinical Trial Coordinator (CTC) • Clinical Research Associates (CRA) – from entry level trainee to senior

level jobs • Clinical Project Manager (CPM), Clinical Study Managers, Clinical Trial

Managers (CTM) • Clinical Contract Associate / Manager • Clinical Operations Managers • Clinical Research Scientist, Clinical Research Manager • Clinical Program Managers • Clinical Associate Director, Clinical Directors• Bioanalysts• Biostatisticians• Trial Managers• Top management• ……..

Concluding Remarks

• CT is a Huge Industry approaching 20 Bn USD• Ousourcing is the trend• India has terrific attractiveness as the outsourcing

destination• Several areas for capacity building and expertise

building• Team players are required• International Multicentre RCTs are increasing• Welcome to a career of Clinical Trialist

Thank you Very Much