INDIA AS A SITE FOR

CONDUCTING CLINICAL
TRIALS

Submitted by:

Ravinder Rana
B.PHARMA (FINAL YEAR)
GYAN VIHAR SCHOOL OF PHARMACY
JAIPUR
ph.ravinder@gmail.com
 DECLARATION

Certified that this Research Study in My Original Work and

that I have not taken or borrowed any material from other’s
work nor have I presented this partly or fully to any other
Institution/College/University. I have complied with all the
formalities prescribed in this regard.

Date: 01/01/2010
Ravinder Rana
 CONTENTS
ABBREVIATION I

CHAPTER-I 1

INTRODUCTION

CHAPTER – II 4

THE PHARMACEUTICAL INDUSTRY SCENE

CHAPTER – III 8

AN INTRODUCTION OF CLINICAL TRIALS

CHAPTER – IV 22

INDIA AS A SIGHT FOR CONDUCTING CLINICAL TRIALS

CHAPTER – V 62

LINKS TO GENERAL INFORMATION ON CLINICAL TRIALS

CHAPTER – VII 76

FUTURE OF CLINICAL TRIALS IN INDIA

CHAPTER – VIII 77

CONCLUSION

BIBLIOGRAPHY 78
 ABBREVIATION

AUC - Area under the Curve

CFR - Code of Federal Regulations
CRO’s - Contract Research Organizations
CTRA - Clinical Trial Regulatory Affairs
EC - Ethics Committee
ERB - Ethical Review Board
FDA - Food and Drug Administration
FDC - Fixed Dose Combinations
GCP - Good Clinical Practice
IND - Investigational New Drug
IRB - Institutional Review Board
MNC’s - Multinational Companies
NDA - New Drug Application
QC - Quality Control
CHAPTER-I
INTRODUCTION
India is fast emerging as an attractive destination for conducting global clinical trials due
to availability of vast pool of patients and also well-trained medical professionals and
sophisticated technological infrastructure.

The clinical research outsourcing market in India was valued at Rs 3.1 billion in 2005 and
is expected to grow to Rs 13.2 billion by 2010. Most of the US and European nations are
outsourcing clinical trials to India

The pharmaceutical industry is research and development driven, given that company
growth and viability are dependent on the discovery of new drug molecules.
Pharmaceutical company survival depends on recovering costs and attaining the profit
target necessary to meet investors' expectations.

Unlike their global counterparts, the Indian pharmaceutical market--estimated at 400

billion Indian rupees (US $8 billion) in 2001--is in a business climate of token R&D
investment. India was, until recently, protected from global product patent laws. The
upside in Indian pharmaceutical history is its self-reliant, independent, international-
standard manufacturing base.

A CII study predicts that the clinical trials market will grow to $200 million by 2007 and
anywhere between $500 million and $1 billion by 2010,.

Global consultancy McKinsey also estimates that by 2010, India will grow to $1.5-2
billion, "Increased globalization has brought about fundamental changes in the way
clinical trials are conducted here. Increased awareness of Good Clinical Practices
requirements, stronger international acceptability of research done in India has brought
favorable changes in the attitude of clinicians in India towards participation in clinical
trials.

Today, there are nearly 100 players, who are involved in several outsourcing business
related to clinical research in India. They include Pfizer, Novartis, Eli Lilly, Dr Reddy's,
Ranbaxy, Dabur, Merk and Astra Zeneca.

The fact that entire education in modern medicine in India is in English, is an added
attraction? All source documents, hospital papers, lab reports, clinical notes are generally
written and printed in English, avoiding need of translation as in China or Japan for
auditors from the west, those in the field. The trials are going on in diverse areas. The
highest number of studies have been done in infection and oncology areas in the last few
areas.

However, there are several trials also being carried out in psychiatry, neurology,
cardiology, gastroenterology, endocrinology, dermatology, respiratory and ophthalmic
areas, "India's experience in clinical trials, while most of them are for USFDA and
European submission, suggest that the quality of the data is acceptable to meet the global
standards

"The success of clinical research in India is entirely dependent on the availability of

sufficiently high-end, skilled personnel to work on trials for the global sponsors.

Being an emerging business of the last decade, today we lack matured and trained clinical
research professionals with more than 10-15 years of industry experience.”

The Drug Development Process

Bringing a new drug or medical device to market can take 20 years and cost as much as
$1 billion. Research, product development, and clinical trials involve not only the
sponsor's staff, but regulators, physicians, academic researchers, and patients.
Throughout the process, information systems managers must maintain the flow of data
between researchers and sponsors, as well as to the world's regulatory bodies. Experts in
health economics and other fields analyze the market into which the product will be
introduced. Specialists in preclinical evaluation, clinical trial design and implementation,
and biologics production all play significant roles.

This lengthy, expensive, and complex process is broken into several stages. The first,
called pre-clinical research, lasts one to three years and tests the drug in animals. If these
tests indicate the product is safe, human clinical trials begin.

• During Phase I of human trials, the drug is tested on perhaps 20 to 80 healthy

individuals. These tests determine the drug's basic safety and pharmacological
data. Phase I lasts an average of six months to one year.

• Phase II involves testing with around 100 or 200 patients who suffer from the
disease or condition the drug is meant to address. Phase II usually lasts between
one and two years.

• Phase III is broken into two segments: Phase III a trials test the drug with
several hundred to several thousand subjects to verify efficacy and safety on a
 larger scale. Generally lasting two to three years, Phase IIIa focuses on regulatory
issues and is conducted at a variety of sites.

Once Phase IIIa is complete, the drug's sponsor submits all pre-clinical,
pharmacologic, efficacy, and safety data to local regulatory agencies. Information on
the drug's composition and plans for producing, packaging, and labeling are also
included. The resulting regulatory review can take up to 30 months to complete,
sometimes more, depending on the country and type of drug.

Meanwhile, Phase IIIb trials begin. Involving a large number of patients, Phase IIIb
focuses on issues such as cost-effectiveness and efficacy compared with approved
drugs in the same therapeutic class or that are used to treat the same disease.

• After the product has received regulatory approval, Phase IV trials begin. These
address the safety and efficacy of uses beyond the drug's original application, test
different dosage strengths and formulations – for example, a sustained release
capsule or a flavored solution for children – or confirm extra-clinical benefits
such as cost-effectiveness or improved quality of life. Phase IV trials also collect
and analyze long-term safety data on patients treated in normal practice.
CHAPTER - II
THE PHARMACEUTICAL INDUSTRY SCENE
There are over 20,000 registered pharmaceutical manufacturers in India. The fragmented
but highly entrepreneurial Indian pharmaceutical industry has grown independently due
to friendly process-patenting regulations and low-cost manufacturing structure. Exports
have been rising at about 30% cumulative annual growth rate over the last 5 years. There
is a shift in export profile from low-value bulk drugs toward value-added formulations.

Intense competition, high volumes, and low prices characterize this highly regulated
industry. The Drug Pricing Control Order (DPCO) has severely affected the profitability
of the industry, and innovation has suffered due to lack of reinvestment of cash surpluses
into R&D. However, the government has been relaxing controls slowly but progressively.
The span of control of DPCO has come down from 90% in the 1980s to 50% in 1995 and
is likely to be further reduced as per the latest proposed changes.

The domestic pharmaceuticals industry output is expected to exceed 260 billion Indian
rupees (US $5.2 billion) in fiscal year 2002, which accounts for 1.3% of the global
pharmaceutical sector. Of this, bulk drugs will account for 21% and formulations the
remaining 79%. In FY 2001, imports were 20 billion Indian rupees and exports were 87
billion Indian rupees. The leading 250 pharmaceutical companies control 70% of the
market, with market leader Ranbaxy Laboratories Ltd. having nearly 7% of the market
share

Trends in Clinical Trials

The stage is set for Indian clinical trials to begin receiving global clinical research
revenue after 2005. The outsourcing of clinical trials from developed countries is
expected to double after 2005. The pull factors are cost-effective trials, with data transfer
to developed countries being legitimized by the World Trade Organization ( WTO),
patient numbers, disease profile, and availability of highly adaptable internationally
trained investigators who have no language barriers.

The downside includes cultural resistance to Good Clinical Practice (GCP), clinical
research process real-time compliance, inadequate information systems leading to
unpredictable project milestones, a "no clock" application process in the regulatory
machinery, and inconsistent time frames for export/import of clinical trial materials at the
border.

In November 2001, the Drug Controller of India met with representatives from
pharmaceutical companies, study sites, and clinical research organizations to discuss the
issues. Pertinent clinical trial problems were identified and solutions sought. Investment
in information technology and human resource training that would raise the country's
clinical research standards to an international level within a short time frame were
proposed.

The Government's Role and the Impact of Globalization

The government of India plays a significant role in fuelling R&D growth in the country.
In May 2000, it announced an increase in R&D expenditure from 2% of the budget to 5%
by 2005. It also targeted the development of an R&D plan with an annual outlay of 15
billion Indian rupees from the industry by year 2005. The outlay in FY 2000 was 3.2
billion Indian rupees.

Presently, India recognizes only process patents. However, with the imposition of WTO
rules by 2005, product patenting will be implemented. This will lead to a widening of the
market for indigenous drugs, as they will have the authenticity of internationally
recognized product patents. Product patent protection will encourage multinational
companies to import technology into India to develop new products. These developments
will bring about increased opportunities for clinical trials of biotech and medicinal
products.
The product patent regime is expected to open India's door to global multinational
corporations (MNCs). The game plan for Indian companies will be to partner with MNCs
on R&D. The external pharmaceutical companies will then have access to the Indian
patient population, market, and clinical trial subjects with an unmatched volume, disease
profile, and therapy-naïve status. Such is the impact of globalization on clinical research
in India.

New Career Opportunities and Workforce Development

The WTO-imposed patent law will bring about new employment opportunities in clinical
research. These opportunities encompass job designations such as clinical research
coordinator/monitor, clinical research physician, and clinical research associate.

Joint venture partnerships will set the trend for the medical/R&D departments of Indian
registered pharmaceutical companies to be spearheaded by global R&D directed from
developed countries. Hence, employment opportunities will be wide open for European
and American clinical research physicians and clinical research associates willing to
relocate to India, as well as Indian citizens with overseas experience.

The central referral research laboratory concept will flourish, providing yet another area
of new employment prospects. There will be additional needs for scientists (Ph.D. and
medical) with bench experience to maintain the anticipated mushrooming of central
clinical trial laboratories.

Clinical research education in India will require some adaptation to groom top-notch
clinical research physicians and clinical research associates for the industry. It is almost
certain that Indian registered MNCs will be introducing plans for clinical research
courses in partnership with domestic educational institutions.

Indian Pharmaceutical and Healthcare Industries

As a key destination for manufacturing and outsourcing, India boasts a pharmaceutical

industry that is growing at a fast rate of 9% per year. Many multinational corporations as
well as Indian pharmaceutical companies continue to market drugs and tap into the
country’s skilled technical talent and resource base to conduct clinical trials and perform
research and development.

Spurred by increasing purchasing power, economic liberalization and impending

recognition of product patents, India’s pharmaceutical industry is currently making
unprecedented investments in new molecule drug development. In addition, the country’s
maturing healthcare system continues to expand its coverage, services, and spending in
the public and private sectors, providing a huge market for pharmaceutical products,
sophisticated medical diagnostics, and medical devices.
This report includes a comprehensive view of the pharmaceutical and healthcare
industries, with an in-depth analysis of pharmaceutical manufacturing. It assesses
regulatory policy factors, changing economic factors, and market forces driving growth
in both industries. Case studies are used to illustrate analyses and to highlight the revenue
opportunities for drug manufacturers and healthcare service providers.

For a thorough analysis of the opportunities in India, this report:

- Presents an overview of India’s population, history, geography, politics,

infrastructure, economy, and healthcare situation.

- Incorporates primary data from interviews with 20 industry thought leaders about
emerging growth opportunities, the advantages of pharmaceutical manufacturing in India,
and the effects of ongoing regulatory and political change

- Includes 15 key company profiles of major players

- Identifies major growth areas and opportunities in the pharmaceutical and

healthcare industries, especially for foreign investors

- Provides case studies that illustrate successful approaches to manufacturing,

healthcare service implementation, and current regulatory challenges
CHAPTER - III
AN INTRODUCTION OF CLINICAL TRIALS
Clinical study, Clinical trial, and Clinical protocol mean the same thing-a scientific study
of how a new medicine or treatment works in people. Through clinical studies, doctors
find new and better ways to prevent, detect, diagnose, control, and treat illnesses. Many
new medicines and treatments are found to be helpful and safe in test tubes and in
animals. They must also prove safe and effective in humans before doctors can prescribe
them. This testing in humans is permitted only if that person volunteers for participation
and understands the risks and benefits of taking part in a study. This informed consent to
participate must be based on the volunteer’s understanding of what is involved in the
study, including potential risks and benefits. Volunteers may leave a study at any time.

A clinical trial is a research study done to evaluate new treatments in people. Carefully
conducted clinical trials are the fastest way to find new treatments that work in people.
Each study is designed to learn about a potential treatment and its effects on people.
Before a new treatment is tried in people, it is carefully studied in the laboratory. The
treatments with the most promising laboratory results are moved into clinical trials.
Clinical trials help us find out if a promising new treatment is safe and effective. During a
trial, more and more information is gained about a new treatment, its risks, and how well
it may or may not work. A clinical trial is a research study in human volunteers to answer
specific health questions. Carefully conducted clinical trials are the safest and fastest way
to find treatments that work in people, and new ways to improve health. There are
different kinds of clinical trials, including those to study:

* Prevention options
* New treatments or new ways to use existing treatments
* New screening and diagnostic techniques
* Options for improving the quality of life for people who have serious medical
conditions Clinical trials are conducted according to a plan called a protocol. The
protocol describes what types of patients may enter the study, schedules of tests and
procedures, drugs, dosages, and length of study, as well as the outcomes that will be
measured. Each person participating in the study must agree to the rules set out by the
protocol.

TYPES OF CLINICAL TRIALS

* Treatment trials test treatments for a specific disease or condition.
* Supportive care trials, also called quality-of-life trials, study ways of making sick
people more comfortable and giving them a better quality of life.
* Prevention trials study ways to reduce the chance that people who are healthy, but
may be at risk for a disease, will develop the disease.
* Early detection or screening trials study new ways of finding diseases or conditions
in people who are at risk, before they have any signs or symptoms.
* Diagnostic trials test new ways to identify, more accurately and earlier, whether
people have diseases and conditions.

IMPORTANCE OF CLINICAL TRIALS

Many clinical trials are done to see if a new drug or device is safe and effective for
people to use. Clinical trials are also done for other reasons. Some compare existing
treatments to determine which is better. The current, approved treatments are called the
i·standard treatments.lﾝ³ Sometimes clinical trials are used to study different ways to use
the standard treatments so they will be more effective, easier to use, and/or decrease side
effects. Sometimes, studies are done to learn how to best use the treatment in a different
population, such as children, in whom the treatment was not previously tested.

For most trials, researchers, doctors, and other health professionals administer the clinical
trials according to strict rules set by the Food and Drug Administration (FDA). FDA sets
the rules to make sure that people who agree to be in studies are treated as safely as
possible. People volunteer to take part in clinical trials for many reasons. First is the hope
that by participating in a trial, they will benefit in some way. There is always a chance
that a new treatment will be disappointing. However, based on laboratory results, the
researchers have reason to believe that the new treatment will be as good as, or better
than, current treatments. Participants in clinical trials may be the first to benefit from a
new treatment. Often people volunteer because they want to contribute to a research
effort that may help others.

Prior to conducting a clinical trial the following are needed :

• Protocol
• CRF (Case Report Form)
• Informed consent form
• Investigator’s brochure
• Regulatory approvals (Phase I, II, III)
• Ethics Committee approvals
• Documentation formats for monitoring

The actual clinical trial involves the following personnel Clinical/ Biometrics/Study
site personnel
 • Investigator/s (at the site where subjects are actually given the study
drug)
• Site coordinator
• Clinician (responsible for the trial from the sponsor’s end)
• Project manager
• Clinical Research associate
• Data Manager
• Programmer
• Statistician
• Medical writer

For clinical trials using paper CRF’s the scanning/indexing personnel scan the data
into an imaging system and data entry personnel enter the data in the project
database.

The data passes through the following steps before it is compiled in the form of a
clinical study report.
• Data transcribed onto paper case report forms/ electronic data capture
systems at the site.
• Scanning/Indexing into imaging system (for paper CRF’s)
• Data entered in the databases
• Electronic checks run for data errors
• Clarification of errors through Data Clarification forms sent to the site.
• Resolution of Data clarification forms and database updated
• The “clean” data is then forwarded to the programmer and statistician
• Data is analyzed and represented in formats as per FDA requirements
• The clinical study report is written
• Data for the clinical trial is submitted to the FDA or relevant regulatory
authorities

THE PROCESS OF CONDUCTING CLINICAL TRIALS

Every clinical trial is designed to answer a set of research questions. The doctors who
conduct a clinical trial follow a study plan called a iaprotocoll.. This spells out what will
be done and why. Studies are carefully designed to safeguard the health of the
participants as well as to answer specific research questions. Some clinical trials test one
new treatment in one group of participants. Other trials compare two or more groups.
Researchers make sure that participants in different groups are similar in certain ways,
such as the nature and stage of their disease. A process called randomization often
decides which treatment each trial participant in a group receives. It’s like tossing a coin;
only a computer does it. The researchers do not know which treatment is better. From
what is known at the time, any one of the treatments chosen could be to benefit to the
participant.

One of the groups may receive standard treatment and the other group the new treatment.
The group receiving the standard treatment is called the control H group. Sometimes, no
standard treatment yet exists. In drug studies of such cases, one group might receive a
new drug and the control group, none. But no one is placed in a control group without
treatment if there is any known treatment that would benefit the participant. The control
group is followed as often and as carefully as the treatment group. If there is firm
evidence that one method is better than the others in a study, the trial is stopped and the
participants in the trial are offered the benefit of the new treatment.

Where do the ideas for trials come from? Ideas for clinical trials usually come from
researchers. After researchers test new therapies or procedures in the laboratory and in
animal studies, the experimental treatments with the most promising laboratory results
are moved into clinical trials. During a trial, more and more information is gained about
an experimental treatment, its risks and how well it may or may not work.

SPONSORING AGENCY OF CLINICAL TRIALS

Clinical trials are sponsored or funded by a variety of organizations or individuals such as
physicians, medical institutions, foundations, voluntary groups, and pharmaceutical
companies, in addition to federal agencies such as the National Institutes of Health
(NIH), the Department of Defense (DOD), and the Department of Veteran’s Affairs
(VA). Trials can take place in a variety of locations, such as hospitals, universities,
doctors’ offices, or community clinics. Clinical trials are conducted in phases. The trials
at each phase have a different purpose and help scientists answer different questions:

HAPPENING DURING STARTS UP A CLINICAL TRIAL

What happens depends on the type of trial and the study protocol. However, some
activities are similar for all clinical trials. The research team will check the participants’
health at the beginning of the trial, give specific instructions for participating, and
monitor their health carefully during the trial. Participants may be required to do some
things between appointments, such as take medication according to a schedule or make a
phone call to report their experiences. Clinical trials take place in a variety of settings,
depending on the type of trial and what is being studied. For example, participants in a
trial of an herb might follow the protocol at home; while a trial that involves specialized
equipment (such as acupuncture) might be carried out in a clinic or other health care
setting. Still other trials may require participants to be in a hospital, clinic, or research
center while the therapy is given.
HAPPENING DURING ENDS UP A CLINICAL TRIAL
The researchers carefully analyze the data from the trial. Then they consider what their
findings mean and whether there should be further testing. If a trial has been completed
and the results have medical importance, they usually report the results first in a peer-
reviewed medical journal (iupeer reviewed means that each report is reviewed before
publication by a group of experts in the same field). A new treatment that has been found
to be safe and effective in a carefully conducted clinical trial may become the new
standard practice.

DIFFERENT PHASES OF A CLINICAL TRIAL

New medicines are continually being developed for the treatment of disease. It is,
however, a complex process with many stages of research and development before a new
medicine can be used to treat patients. A promising new drug must be extensively
investigated before it is thought to be safe to be given to humans. Clinical trials play a
vital role in the development of new medicines and it is thanks to people volunteering for
clinical trials that it is possible for them to be fully investigated and advances in medicine
to be made.

A Phase One Study

Phase I studies are primarily concerned with assessing the drug’s safety. This initial
phase of testing in humans is done in a small number of healthy volunteers (20 to 100),
who are usually paid for participating in the study. The study is designed to determine
what happens to the drug in the human body-how it is absorbed, metabolized, and
excreted. A phase I study will investigate side effects that occur as dosage levels are
increased. This initial phase of testing typically takes several months. About 70 percent
of experimental drugs pass this initial phase of testing.

A Phase Two Study

Once a drug has been shown to be safe, it must be tested for efficacy. This second phase
of testing may last from several months to two years, and involve up to several hundred
patients. Most phase II studies are randomized trials. One group of patients will receive
the experimental drug, while a second control group will receive a standard treatment or
placebo. Often these studies are blinded-neither the patients nor the researchers know
who is getting the experimental drug. In this manner, the study can provide the
pharmaceutical company and the FDA comparative information about the relative safety
of the new drug, and its effectiveness. Only about one-third of experimental drugs
successfully complete both phase I and phase II studies.

A Phase Three Study

In a phase III study, a drug is tested in several hundred to several thousand patients. This
large-scale testing provides the pharmaceutical company and the FDA with a more
thorough understanding of the drug’s effectiveness, benefits, and the range of possible
adverse reactions.

Most phase III studies are randomized and blinded trials.

Phase III studies typically last several years. Seventy to 90 percent of drugs that enter
phase III studies successfully complete this phase of testing. Once a phase III study is
successfully completed, a pharmaceutical company can request FDA approval for
marketing the drug.

Post-Marketing & Late Phase Three/Phase Four Studies

In late phase III/phase IV studies, pharmaceutical companies have several objectives:

* Studies often compare a drug with other drugs already in the market;
* Studies are often designed to monitor a drug’s long-term effectiveness and impact on a
patient’s quality of life; and
* Many studies are designed to determine the cost-effectiveness of a drug therapy relative
to other traditional and new therapies.

Phase 2 and Phase 3 clinical trials generally involve a in control standard. In many
studies, one group of volunteers will be given an experimental or test drug or treatment,
while the control group is given either a standard treatment for the illness or an inactive
pill, liquid or powder that has no treatment value (placebo). This control group provides a
basis for comparison for assessing effects of the test treatment. In some studies, the
control group will receive a placebo instead of an active drug or treatment. In other cases,
it is considered unethical to use placebos, particularly if an effective treatment is
available. Withholding treatment (even for a short time) would subject research
participants to unreasonable risks.

A process called iarandomizationlª› often decides the treatment each trial participant
receives. This process can be compared to a coin toss that is done by computer. During
clinical trials, no one likely knows which therapy is better, and randomization assures
that treatment selection will be free of any preference a physician may have.
Randomization increases the likelihood that the groups of people receiving the test drug
or control are comparable at the start of the trial, enabling comparisons in health status
between groups of patients who participated in the trial. In conjunction with
randomization, a feature known as isblindinglo helps ensure that bias doesn’t distort the
conduct of a trial or the interpretation of its results. Single-blinding means the participant
does not know whether he or she is receiving the experimental drug, an established
treatment for that disease, or a placebo. In a single-blinded trial, the research team does
know what the participant is receiving.
A double-blind trial means that neither the participant nor the research team knows
during the trial which participants receive the experimental drug. The patient will usually
find out what he or she received at a pre-specified time in the trial. Double-blind trials are
thought to produce objective results, since the expectations of the doctor and the
participant about the experimental drug do not affect the outcome; also called double-
masked study.

STUDY PHASE
The Food and Drug Administration in the Code of Federal Regulations define these
phases. Most clinical trials are designated as phase I, II, or III, based on the type of
questions that study is seeking to answer:

* In Phase I clinical trials, researchers test a new 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 clinical trials, the 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 studies, the 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 drug or treatment to be used
safely.

PARTICIPATING IN CLINICAL TRIALS

A clinical trial is a research study with human volunteers to answer specific health
questions. iuInterventionalle trials assess whether experimental treatments or new ways
of using known therapies are safe and effective. If Observational trials address health
issues in large populations.

All clinical trials have guidelines about who can participate in a study, based on such
factors as age, type of disease, medical history and current medical condition. Some trials
seek volunteers with specific illnesses or conditions, while other trials need healthy
volunteers. Factors that allow you to participate in a study are called inclusion criteria
and factors that keep you from participating are called exclusion criteria. The criteria are
used to identify appropriate participants and keep them safe, and to help researchers
ensure they will be able to answer the questions they plan to study.

Clinical trials in the United States must be approved and monitored by an Institutional
Review Board (IRB) to make sure the risks are as low as possible and don’t outweigh any
potential benefits. An IRB is a committee of physicians, statisticians, patient advocates
and other members of the community, which reviews the protocol to ensure that the study
is ethical, and the risks are minimized.
IMPORTANCE OF PARTICIPATION IN CLINICAL TRIALS
People volunteer to participate in clinical trials for different reasons. Some volunteer
because they want to help advance medical knowledge. Others have tried all available
treatments for their condition without success. In a spring 2000 Harris Poll of cancer
clinical trial participants, 76 percent of the respondents said they participated because
they believed that the trial offered the best quality of care for their disease. Helping other
people and receiving more and better attention for their own specific disease were other
reasons cited. People should not, however, be tempted to enroll in a clinical trial simply
because a potential treatment is being offered free during a study, or because of the
promise of money, says David Banks, an FDA pharmacist.

People lured by compensation may overlook the known risks, Banks says. Or (they may
fail) to adequately appreciate the potential for discovery of serious new side effects
during clinical testing of a new treatment Banks also says that clinical trials are generally
not a means for patients to receive long-term treatment for their chronic disease. It’s
important to test medical products in the people they are meant to help. In the past, most
new drug testing had been done on white men. Groups such as women, African-
Americans, and Hispanics often were not adequately represented. It’s important to test
medical products in a wide variety of people because drugs can work differently in
people of various ages, races, ethnicity, and gender. The FDA seeks to ensure that people
from many different groups are included in clinical trials. Trial guidelines, or eligibility
requirements, are developed by the researchers and usually include criteria for age, sex,
type and stage of disease, previous treatment history, and other medical conditions. Some
trials involve people with a particular illness or condition to be studied, while others seek
healthy volunteers. Inclusion or exclusion criteria & medical or social standards used to
determine whether a person may or may not be allowed to enter a clinical trial & help
identify appropriate participants and help to exclude those who may be put at risk by
participating in a trial.

HOW TO JOIN A CLINICAL TRIAL

People are recruited to clinical trials in various ways, including advertising,
announcements in newspapers and other publications, and on the web. Caregivers and
family members who use the web to locate clinical trials are faced with two important
decisions: Is a clinical trial appropriate for the family member with a chronic illness? And
if so, how do you locate a clinical trial in your area?

If you think a clinical trial might be appropriate for your situation-for example, your
loved one seems to meet the inclusion criteria and the trial is taking place at a respected
nearby institution-here are some points to consider:
* Make sure you are clear about your reasons for participating in the trial and aware of
what is involved. Is your family member really well enough to participate? Be aware that
if your loved one has illnesses or conditions in addition to the disease for which a
treatment is being tested, he or she might not be accepted in a drug study.
* Weigh the potential benefits and risks of participation. Clinical trials may offer access
to new treatments before they become available, as well as expert medical care during the
trial. However, there may be unpleasant or serious side effects to the new treatment; the
treatment may not work for the participant (or, in a randomized, placebo-controlled trial,
the participant may not receive the new drug); the time involved may be more than you
originally anticipated and may include travel; hospital stays or complicated dosing
schedules.
- Before signing the informed consent document, know:
- The purpose of the study.
- Who will be participating, and for how long?
- Whether the treatment has been tested before and if so, what were the results?
- The number, types of tests, treatments involved, and whether hospitalization is required.
- Potential risks and side effects, and how they compare with current treatments. This is
critical information, and must be explained to you in clear, direct language.
- Who pays for the treatment, necessary travel and complications from side effects?
- What type of follow-up is involved, and how you will be informed of trial results.

ELEMENTS OF CLINICAL TRIALS

Researchers might include randomization in the trial design. Randomization is used in all
phase III studies and in some phase II studies. It gives the best chance of knowing that the
study results are caused by the treatment and not some other factor, such as people’s
choices or beliefs. Each participant in a randomized trial is assigned by chance (through a
computer or a table of random numbers) to one of two groups:

* The investigational group, made up of people who will receive the therapy, also called
the active treatment; or
* The control group, made up of people who will receive either the standard treatment (if
there is one) for their disease or condition, or a placebo.
Each participant has an equal chance of being assigned to either group. In some complex
trials, there are more than two groups. Researchers design clinical trials to have one or
more endpoints. An endpoint is a measure that determines whether the treatment under
study has an effect. An example of an endpoint is whether a person’s tumor shrinks after
receiving chemotherapy.

Placebo
A placebo is designed to resemble as much as possible the treatment being studied in a
clinical trial, except that the placebo is inactive. An example of a placebo is a pill
containing sugar instead of the drug being studied. By giving one group of participants a
placebo and the other group the active treatment, the researchers can compare how the
two groups respond and get a truer picture of the active treatment.
Another type of placebo is called a iashaml procedure. When the treatment under study is
a procedure (not a drug or other substance), a sham procedure may be designed that
resembles the active treatment but does not have any active treatment qualities. For
example, in a clinical trial of acupuncture, the sham procedure might consist of placing
acupuncture needles in areas of the body that are not expected (from previous
knowledge) to have any therapeutic response.

In recent years, the definition of placebo has been expanded to include other things that
could have an effect on the results of health care. Examples include how a patient and a
health care provider interact, how a patient feels about receiving the care, and what he or
she expects to happen from the care. Therefore, when a treatment is compared to a
placebo in clinical trials, the patients should differ only in whether they receive treatment,
and not in other aspects. Not all clinical trials compare an active treatment to a placebo.
No patient is denied treatment in a clinical trial if there is a standard therapy available
that could improve the comfort and survival of the patient.

A physical or emotional change, occurring after a substance is taken or administered, that

is not the result of any special property of the substance. The change may be beneficial,
reflecting the expectations of the participant and, often, the expectations of the person
giving the substance.

Control or Control Group

A control is the standard by which experimental observations are evaluated. In many
clinical trials, one group of patients will be given an experimental drug or treatment,
while the control group is given either a standard treatment for the illness or a placebo.

Protocol
A protocol is a study plan on which all clinical trials are based. The plan is carefully
designed to safeguard the health of the participants as well as answer specific research
questions. A protocol describes what types of people may participate in the trial; the
schedule of tests, procedures, medications, and dosages; and the length of the study.
While in a clinical trial, participants following a protocol are seen regularly by the
research staff to monitor their health and to determine the safety and effectiveness of their
treatment.

Expanded Access Protocol

Most human use of investigational new drugs takes place in controlled clinical trials
conducted to assess safety and efficacy of new drugs. Data from the trials can serve as the
basis for the drug marketing application. Sometimes, patients do not qualify for these
carefully controlled trials because of other health problems, age, or other factors. For
patients who may benefit from the drug use but don’t qualify for the trials, FDA
regulations enable manufacturers of investigational new drugs to provide for ioexpanded
accessld use of the drug. For example, a treatment IND (Investigational New Drug
application) or treatment protocol is a relatively unrestricted study. The primary intent of
a treatment IND/protocol is to provide for access to the new drug for people with a life-
threatening or serious disease for which there is no good alternative treatment.

A secondary purpose for a treatment IND/protocol is to generate additional information

about the drug, especially its safety. Expanded access protocols can be undertaken only if
clinical investigators are actively studying the experimental treatment in well-controlled
studies, or all studies have been completed. There must be evidence that the drug may be
an effective treatment in patients like those to be treated under the protocol. The drug
cannot expose patients to unreasonable risks given the severity of the disease to be
treated. Some investigational drugs are available from pharmaceutical manufacturers
through expanded access programs listed in ClinicalTrials.gov. The manufacturer
generally manages expanded access protocols, with the investigational treatment
administered by researchers or doctors in office-based practice. If you or a loved one is
interested in treatment with an investigational drug under an expanded access protocol
listed in ClinicalTrials.gov, review the protocol eligibility criteria and location
information and inquire at the Contact Information number.

Informed Consent
Informed consent is a process of learning key facts about a clinical trial before deciding
whether or not to volunteer for the study. First, the doctors and nurses involved in the
trial explain the details of the study. Then you are given an informed consent form to read
and consider carefully. If you agree to take part, you can sign the form. Otherwise, you
may refuse.

The FDA requires that potential participants be given complete information about the
study. This process is known as is informed consent, ld and it must be in writing. The
informed consent process provides an opportunity for the researcher and patient to
exchange information and ask questions. Patients invited to enter a trial are not obligated
to join, but can consent to participate if they find the potential risks and benefits
acceptable. The participant prior to enrollment must sign a consent form before any study
procedures can be performed. Participants also have the right to leave a study at any time.
At the same time, people need to know that circumstances may arise under which their
participation may be terminated by the researcher, without their consent. For example,
sometimes it becomes evident early on that a trial is not working and researchers know
they are not going to get enough meaningful information to make continuation
worthwhile. In addition, if an unexpected change occurs in the health status of
participant, such as toxic effects or sudden kidney problems that may have developed, it
would not be in the best interest of the patient to continue, and certainly not consistent
with what the investigator is trying to study, says. In any case, the circumstances must be
described in the consent document.
Informed Consent Document
A document that describes the rights of the study participants, and includes details about
the study, such as its purpose, duration, required procedures, and key contacts. Risks and
potential benefits are explained in the informed consent document. The participant then
decides whether or not to sign the document. Informed consent is not a contract, and the
participant may withdraw from the trial at any time.

Institutional Review Board (IRB)

A committee of physicians, statisticians, researchers, community advocates, and others
that ensures that a clinical trial is ethical and that the rights of study participants are
protected. All clinical trials in the U.S. must be approved by an IRB before they begin.
Every institution that conducts or supports biomedical or behavioral research involving
human participants must, by federal regulation, have an IRB that initially approves and
periodically reviews the research in order to protect the rights of human participants.

Randomization
Randomization introduces a deliberate element of chance into the assignment of
treatments to subjects in a clinical trial. During subsequent analysis of the trial data, it
provides a sound statistical basis for the quantitative evaluation of the evidence relating
to treatment effects. It also tends to produce treatment groups in which the distributions
of prognostic factors, known and unknown are similar. In combination with blinding,
randomization helps to avoid possible bias in the selection and allocation of subjects
arising from the predictability of treatment assignments.

The randomization schedule of a clinical trial documents the random allocation of

treatments to subjects. In the simplest situation it is a sequential list of treatments (or
treatment sequences in a crossover trial) or corresponding codes by subject Statistical
Principles for Clinical Trials number. The logistics of some trials, such as those with a
screening phase, may make matters more complicated, but the unique pre-planned
assignment of treatment, or treatment sequence, to subject should be clear. Different trial
designs will require different procedures for generating randomization schedules. The
randomization schedule should be reproducible (if the need arises).

Although unrestricted randomization is an acceptable approach, some advantages can

generally be gained by randomizing subjects in blocks. This helps to increase the
comparability of the treatment groups, particularly when subject characteristics may
change over time, as a result, for example, of changes in recruitment policy. It also
provides a better guarantee that the treatment groups will be of nearly equal size. In
crossover trials it provides the means of obtaining balanced designs with their greater
efficiency and easier interpretation. Care should be taken to choose block lengths that are
sufficiently short to limit possible imbalance, but that are long enough to avoid
predictability towards the end of the sequence in a block. Investigators and other relevant
staff should generally be blind to the block length; the use of two or more block lengths,
randomly selected for each block, can achieve the same purpose. (Theoretically, in a
double-blind trial predictability does not matter, but the pharmacological effects of drugs
may provide the opportunity for intelligent guesswork.)

In multi center trials the randomization procedures should be organized centrally. It is

advisable to have a separate random scheme for each center, i.e. to stratify by center or to
allocate several whole blocks to each center. More generally, stratification by important
prognostic factors measured at baseline (e.g. severity of disease, age, sex, etc.) may
sometimes be valuable in order to promote balanced allocation within strata; this has
greater potential benefit in small trials. The use of more than two or three stratification
factors is rarely necessary, is less successful at achieving balance and is logistically
troublesome. The use of a dynamic allocation procedure may help to achieve balance
across a number of stratification factors simultaneously provided the rest of the trial
procedures can be adjusted to accommodate an approach of this type. Factors on which
randomization has been stratified should be accounted for later in the analysis.

The next subject to be randomized into a trial should always receive the treatment
corresponding to the next free number in the appropriate randomization schedule (in the
respective stratum, if randomization is stratified). The appropriate number and associated
treatment for the next subject should only be allocated when entry of that subject to the
randomized part of the trial has been confirmed. Details of the randomization that
facilitate predictability (e.g. block length) should not be contained in the trial protocol.
The sponsor or an independent party in a manner that ensures that blindness is properly
maintained throughout the trial should file the randomization schedule itself securely.
Access to the randomization schedule during the trial should take into account the
possibility that, in an emergency, the blind may have to be broken for any subject. The
procedure to be followed, the necessary documentation, and the subsequent treatment and
assessment of the subject should all be described in the protocol.

Dynamic allocation is an alternative procedure in which the allocation of treatment to a

subject is influenced by the current balance of allocated treatments and, in a stratified
trial, by the stratum to which the subject belongs and the balance within that stratum.
Deterministic dynamic allocation procedures should be avoided and an appropriate
element of randomization should be incorporated for each treatment allocation. Every
effort should be made to retain the double-blind status of the trial.

For example, knowledge of the treatment code may be restricted to a central trial office
from where the dynamic allocation is controlled, generally through telephone Statistical
Principles for Clinical Trials contact. This in turn permits additional checks of eligibility
criteria and establishes entry into the trial, features that can be valuable in certain types of
multicentre trial. The usual system of pre-packing and labeling drug supplies for double-
blind trials can then be followed, but the order of their use is no longer sequential. It is
desirable to use appropriate computer algorithms to keep personnel at the central trial
office blind to the treatment code. The complexity of the logistics and potential impact on
the analysis should be carefully evaluated when considering dynamic allocation.

Blinding
The groups should not only be similar at baseline, but should be treated and observed
similarly during the trial, except for receiving the test and control drug. Clinical trials are
often double-blind (or double-masked), meaning that both subjects and investigators, as
well as sponsor or investigator staff involved in the treatment or clinical evaluation of
subjects, are unaware of each subject’s assigned treatment. Blinding is intended to
minimize the potential biases resulting from differences in management, treatment, or
assessment of patients, or interpretation of results that could arise as a result of subject or
investigator knowledge of the assigned treatment. For example:

* Subjects on active drug might report more favorable outcomes because they expect a
benefit or might be more likely to stay in a study if they knew they were on active drug.
* Observers might be less likely to identify and report treatment responses in a no-
treatment group or might be more sensitive to a favorable outcome or adverse event in
patients receiving active drug.
* Knowledge of treatment assignment could affect vigor of attempts to obtain on-study or
follow-up data.
* Knowledge of treatment assignment could affect decisions about whether a subject
should remain on treatment or receive concomitant medications or other ancillary
therapy.
* Knowledge of treatment assignment could affect decisions as to whether a given
subject’s results should be included in an analysis.
* Knowledge of treatment assignment could affect choice of statistical analysis. Blinding
is intended to ensure that subjective assessments and decisions are not affected by
knowledge of treatment assignment.

PRE-CLINICAL TESTING
The sponsor of the clinical trial needs to gather data regarding safety of a new drug in
small-scale clinical studies before it is studied in humans. Animal studies provide data
regarding the absorption, distribution, metabolism and excretion of a new drug. Data
regarding the short-term toxicity of the drug in animals is also obtained. Short-term
studies in animals can range from 2 weeks to 3 months depending on the proposed action
of the new drug. The sponsor then files the IND (Investigational New Drug) application.
The main purpose of the IND application is to provide documentation that it is indeed
reasonable to conduct human trials with the drug.
CHAPTER – IV
INDIA AS A SIGHT FOR CONDUCTING
CLINICAL TRIALS
Today India's regulatory framework is also compliant to international standards in areas
such as Good Manufacturing Practice and Good Laboratory Practice and the country has
its own Good Clinical Practice guidelines.

The 2005 amendment to the Schedule Y of the Drugs & Cosmetics Act is moving India
towards acceptance of International Conference on Harmonisation guidelines for clinical
research. Also, the implementation of the Product Patient Act confirms the willingness to
accept global confidentiality and data security norms. Even the Medical Devices
Guideline is also in place since March this year,

CLINICAL TRIAL ENVIRONMENT IN INDIA

India has well-defined guidelines for carrying out various phases of clinical trials. These
guidelines are in line with the global guidelines on clinical research (ICH-GCP). The
various guidelines that govern the conduct of clinical trials in India include:
• Schedule Y of drugs and Cosmetics Act, 1940.
• Ethical Guidelines for Biomedical Research on Human Subjects, 2000 also
known as ICMR code
• Good Clinical Practices, 2001.

Speed
For almost all drugs companies, speed is of essence. Typically it takes 10-15
years to develop a new drug and the 20 years clock on a drug patent starts ticking when a
new compound is discovered. So the quicker a product can get to market, the speedier
the return on investment. The faster a drug is developed, the longer its patent protects it.

Patient Enrollment
India certainly has plenty of patients. Every 6th patient in world is from India.
The past experience has shown that in mot of the multi-country trials, patient enrolment
is rapid in India. Many of them have never been treated before and this makes them even
more valuable as participants.
Wide Spectrum of Disease
Apart from the sheer number of patients, there are other compelling reasons why
multinationals drug companies are looking to India to test new drugs. Diseases like
multi-drug resistant Pneumonia, Hepatitis B, Diabetes and some cancers are far more
prevalent in India than in west.

Economy
Clinical trials in India are economic. The overall cost advantage in bringing a
drug to market by leveraging India aggressively could be high as $200 million.
Moreover prevailing norms on the import of all CT material (drugs) make India a
preferred destination for conducting global clinical trials.

Quality of Data
The acceptance of data generated from India at all major conferences and journals
proves its credibility. India has been a part of the many FDA & EMEA registration
studies.

Economic Environment
The present day economic environment is quite favorable for foreign direct
investments. Foreign Direct Investment is over US$2 billion a year.

Proficiency in English Language

The proficiency of India investigators and research professionals in English
language is an added advantage for all medical and scientific communication.

In India selling out to drug companies on clinical trials, the first on the consideration that
as the numbers establish, there is a great deal of money involved in terms of cost savings
to drug companies and revenues for the intermediary enterprises which represent their
interests, in “outsourcing” clinical trials to India. The second on the proposition that
money, in sufficiently large amounts, makes for myopia.

This money-induced myopia has ensured that the authorities have not noticed reports in
the media about two pharmaceutical companies - one based in Bangalore and the other in
Hyderabad - which conducted Phase III trials of genetically engineered drugs apparently
without the appropriate prior approval of either the Drug Controller General of India
(DGCI) or the Genetic Engineering Approval Committee (GEAC). It appears that these
companies applied for and obtained the DCGI permission - but they applied to the GEAC
only after the commencement of the trials.

The authorities have been blind to other reports about a Mumbai-based drug company
that had allegedly gone around the DCGI altogether and prevailed upon private doctors to
prescribe an anti-cancer drug, Letrozole, to over 400 women for “ovulation induction”.
The results were used to promote the drug for unapproved usage through medical
representatives and the core issues involved in all this gets obfuscated by arcane debates
about the legal and ethical right of doctors to prescribe a drug off-label - which is quite
different from off-label drug research. The myopia is such that the government is now
talking about the relaxation of drug testing regulations - which have not been enforced in
the first place - to encourage the “outsourcing” of clinical trials to India from the West.
Actually, regulations even in their present form need not be of much concern to those
interested in conducting contract research and clinical trials in India as nobody has a clue
about the projects underway in the absence of a central registry for medical research in
India. The public knows nothing of the clinical trials carried out in India for the past
several years by multinational pharmaceutical companies, either directly or through what
are known as CROs (clinical/contract research organizations), which do their work for
fees the quantum of which, once again, is not in the public domain. Whatever its other
failures, the Government has apparently succeeded in its initiative to bring drug trials to
India, in that well-known clinical research outfits of the West are uniformly gung-ho
about the diverse advantages that this country has to offer: Staggering diversity of
diseases, drug-native population (which term basically me that people have not been
treated for their diseases so far), high enrolment rates, excellent patient
compliance/retention, competitive costs and an increasingly accommodating regulatory
environment.

How can the people of this country ensure that big business (the Confederation of Indian
Industry has been making a lot of noise about how the trials outsourcing business can go
up by 10 times if regulatory “hurdles” are “streamlined”` and has been lobbying for the
automatic approvals of all applications with the DCGI if they are not cleared within a
timeframe) and government do not collude in selling them?

The introduction in India of Good Clinical Practice (GCP) norms for pharmaceutical
research, based on those formulated by the WHO and the International Conference on
Harmonization of Technical Requirements for Registration of Pharmaceuticals for
Human Use (revised 2000) and now required by the Indian Council of Medical Research
(ICMR), represents a good starting point. The GCP has one problem, though: the
administration of those sections dealing with informed consent, which has been pretty
much left to individual investigators.

The problem here is the size and nature of the population base in India, both of which
work in favour of those conducting the trials. Those who have been involved in the
formulation of ethical guidelines in collaborative research is developing countries
concede that securing a patient’s informed consent can, indeed, be a tricky exercise,
especially if the research involved is a complex one and cannot, therefore, be
communicated easily. And then again, experience has proved that many of those who
agree to participate in trials are often unable to distinguish between treatment and
research.

But, then that is precisely what the Government and its organizations are there for: To set
the rules equitably and to enforce them - and not to drum up business, as it seems to be
intent upon doing in this case. For instance, the drugs being tested should be of
demonstrable value to the host country and a watertight agreement on the post-trial
availability of the drugs at affordable rates must be in place before trials start. The
Government must, in addition, make certain that research is carried out solely on the
basis of informed voluntary consent, and that trial drugs are tested only against the best
available proven treatment.

A re-look at the proposed changes in the Drugs and Cosmetics Act would also be in
order. Drugs are globally put through four phases of trials. Phase I trials use healthy
volunteers to test a drug’s safety. Phase II and III trials test a larger number of volunteers
for the drug’s efficacy and generate data relating to its safety, effective doses and so on.
Phase IV trials are conducted after the drug is marketed in order to monitor its safety
when used on a mass scale.

CONTRACT RESEARCH AND CLINICAL TRIAL ENVIRONMENT

The main question is: Is India selling out to drug companies on clinical trials? The
answer to this question has two parts. The first rests on the consideration that as the
numbers establish, there is a great deal of money involved in terms of cost savings to
drug companies and revenues for the intermediary enterprises which represent their
interests, in ‘outsourcing’ clinical trials to India. The second rests on the proposition that
money, in sufficiently large amounts, makes for myopia.

This money-induced myopia has ensured that the authorities have not noticed reports in
the media about two pharmaceutical companies - one based in Bangalore and the other in
Hyderabad - which conducted Phase III trials of genetically engineered drugs apparently
without the appropriate prior approval of either the Drug Controller General of India
(DGCI) or the Genetic Engineering Approval Committee (GEAC). It appears that these
companies applied for and obtained the DCGI permission - but they applied to the GEAC
only after the commencement of the trials.

The authorities have been blind to other reports about a Mumbai-based drug company
that had allegedly gone around the DCGI altogether and prevailed upon private doctors to
prescribe an anti-cancer drug, Letrozole, to over 400 women for ioovulation induction. ll
The results were used to promote the drug for unapproved usage through medical
representatives and the core issues involved in all this gets obfuscated by arcane debates
about the legal and ethical right of doctors to prescribe a drug off-label - which is quite
different from off-label drug research. The myopia is such that the government is now
talking about the relaxation of drug testing regulations - which have not been enforced in
the first place - to encourage the ihoutsourcingla of clinical trials to India from the West.
Actually, regulations even in their present form need not be of much concern to those
interested in conducting contract research and clinical trials in India as nobody has a clue
about the projects underway in the absence of a central registry for medical research in
India. The public knows nothing of the clinical trials carried out in India for the past
several years by multinational pharmaceutical companies, either directly or through what
are known as CROs (clinical/contract research organizations), which do their work for
fees the quantum of which, once again, is not in the public domain. Whatever its other
failures, the Government has apparently succeeded in its initiative to bring drug trials to
India, in that well-known clinical research outfits of the West are uniformly gung-ho
about the diverse advantages that this country has to offer: Staggering diversity of
diseases, iidrug-naïve populationle (which term basically means that people have not
been treated for their diseases so far), high enrolment rates, excellent patient
compliance/retention, competitive costs and an increasingly accommodating regulatory
environment.

How can the people of this country ensure that big business (the Confederation of Indian
Industry has been making a lot of noise about how the trials outsourcing business can go
up by 10 times if regulatory hurdles are streamlined and has been lobbying for the
automatic approvals of all applications with the DCGI if they are not cleared within a
timeframe) and government do not collude in selling them?

The introduction in India of Good Clinical Practice (GCP) norms for pharmaceutical
research, based on those formulated by the WHO and the International Conference on
Harmonization of Technical Requirements for Registration of Pharmaceuticals for
Human Use (revised 2000) and now required by the Indian Council of Medical Research
(ICMR), represents a good starting point. The GCP has one problem, though: the
administration of those sections dealing with informed consent, which has been pretty
much left to individual investigators.

The problem here is the size and nature of the population base in India, both of which
work in favour of those conducting the trials. Those who have been involved in the
formulation of ethical guidelines in collaborative research is developing countries
concede that securing a patient’s informed consent can, indeed, be a tricky exercise,
especially if the research involved is a complex one and cannot, therefore, be
communicated easily. And then again, experience has proved that many of those who
agree to participate in trials are often unable to distinguish between treatment and
research.

But, then that is precisely what the Government and its organizations are there for: To set
the rules equitably and to enforce them - and not to drum up business, as it seems to be
intent upon doing in this case. For instance, the drugs being tested should be of
demonstrable value to the host country and a watertight agreement on the post-trial
availability of the drugs at affordable rates must be in place before trials start. The
Government must, in addition, make certain that research is carried out solely on the
basis of informed voluntary consent, and that trial drugs are tested only against the best
available proven treatment.

A re-look at the proposed changes in the Drugs and Cosmetics Act would also be in
order. Drugs are globally put through four phases of trials. Phase I trials use healthy
volunteers to test a drug’s safety. Phase II and III trials test a larger number of volunteers
for the drug’s efficacy and generate data relating to its safety, effective doses and so on.
Phase IV trials are conducted after the drug is marketed in order to monitor its safety
when used on a mass scale.

As matters stand, under Schedule Y of the Act, permission to conduct international

clinical trials in India is given one phase behind other countries. By way of illustration, if
a drug is in Phase III trial in some other country, permission will be given only for Phase
II trial in India. However, the DCGI can waive this if the drug that has to be tested is
deemed to be of special relevance to India. The government plans to change this system
on the basis of a recommendation contained in the interim report of an expert committee
which says: Comprehensive revision of Schedule Y, that prescribes requirements of
clinical trials, has been undertaken in order to harness (the) country’s potential to
participate in global multi-centric clinical trials. ln The revision, significantly, does not
make any reference to a system that will ensure that the drugs tested in India will be
made available to the local population at affordable rates. All that the committee has
made certain is that foreign pharmacist will be able to carry out concurrent phase trials on
human guinea pigs in India, putting their lives at risk. It is reliably learnt that the
government is so keen on helping foreign drugs companies and their agents that the
DCGI is allowing concurrent phase trials - though revisions to Schedule Y are yet to be
publicly notified. It is understood that the Government is planning to introduce the
Biomedical Research on Human Subjects (Regulation, Control and Safeguards) Bill,
2004, in Parliament in the winter session. The Bill has apparently been cleared by the
Union Health Ministry and is now under the scrutiny of the Law ministry. To understand
this initiative in its correct perspective, one need only bear in mind the Ronald Reagan’s
characterization of a government’s view of the economy: If it moves, tax it. If it keeps
moving, regulate it. And if it stops moving, subsidize it. India has a tradition of pinching
ideas from the West - and of then mangling them beyond recognition. The Bill under
discussion, if passed into law, will merely allow the government to enhance its regulatory
powers with relation to clinical testing in such a manner that it will be able to tax certain
intermediaries and subsidize the others, depending upon expediency. Given the obvious
nexus of the government, foreign drug companies, high-profile industry lobbies and
opinion-makers, the people have their work cut out for them in ensuring that they are not
sold as lab animals. But, in a country like India, if the people do not protect their own
lives, who else will?

WHAT PROTECTION DO YOU HAVE AS A PARTICIPANT IN A CLINICAL

TRIAL
The ethical and legal codes that govern medical practice apply to clinical trials. In
addition, most clinical research is federally regulated with built-in safeguards to protect
participants. Any well-run clinical trial is received for patient safety, and scientific merit
by the research institutions. Every study should provide for monitoring the data and the
safety of patients on an ongoing basis.

As a clinical trial progresses, researchers report the results at the trial of scientific
meetings, to medical journals, and to various government agencies. Individual
participants’ names will remain secret and will not be mentioned in these reports.

The main question is how are people protected? Most clinical trials are federally
regulated with built-in safeguards to protect participants. Today, the Office for Human
Research Protections (OHRP) in the Department of Health and Human Services (HHS)
leads the department’s programs for the protection of human research participants, and
oversees human protection in HHS-funded research. It’s important that we have the
rapport with the public that allows them to trust us with this program, says Bernard A.
Schwetz, D.V.M., Ph.D., acting director of the OHRP. He adds, Without people willing
to participate, there won’t be any clinical trials. The FDA has authority over clinical trials
for drug, biologic and medical device products regulated by the agency. This authority
includes studies that are HHS-funded (with joint oversight by the FDA and the OHRP),
as well as studies that are solely funded by industry or by private parties. Many clinical
trials are not subject to FDA regulation but are monitored by the institution sponsoring
the trial, such as a hospital. To help protect the rights and welfare of volunteers and verify
the quality and integrity of data submitted for review, the FDA performs inspections of
clinical trial study sites and anyone involved in the research, says David A. Lepay, M.D.,
Ph.D., director of the FDA’s Good Clinical Practice Program. Lepay says that the quality
of clinical trials has improved markedly since the agency started inspecting them back in
1977.

Besides FDA, the help of other government agencies, the review by Institutional Review
Boards, the required monitoring of studies by industry or private sponsors, and the
required oversight and reporting by investigators and their staff, a lot of people are
looking out for the research subject’s safety.

BENEFITS AND 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
Some treatments being studied can have unpleasant, or even serious, side effects. Often
these are temporary and end when the treatment is stopped. Others, however, can be
permanent. Some side effects appear during treatment, and others may not show up until
after the study is over. The risks depend on the treatment being studied and the health of
the people participating in the trial. All known risks must be fully explained by the
researchers before the trial begins. If new risk information becomes available during the
trial, participants must be informed. Some other risks are:

* 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.

THE CRO MARKET

A "CRO" is a clinical research organization. There are literally hundreds of CROs

worldwide employing a workforce of nearly 100,000 professionals. In 1992, estimated
CRO market size was $1 billion while today that number is over $6 billion and growing.

CROs provide independent product development services primarily for the

pharmaceutical, biotechnology and medical device industries. Companies in these
industries outsource product development services to CROs in order to manage the
product development process more efficiently and cost-effectively, and to maximize the
benefits in time and profit of patient-protected products.

The CRO industry has evolved from providing primarily preclinical services or single-
service support in clinical monitoring and data management to a full-service industry
offering services from the earliest stages of development through clinical trials and
commercialization of products.
CROs contribute to a large percentage of all products developed worldwide. Their
continued success is reliant on high ethical and professional standards, and compliance
with Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) guidelines as
prescribed by the regulatory authorities.

Selection of Optimal CRO

Because the world of product development is getting more complex. Because time to
market is critical. Because regulatory issues grow more intricate by the day. Because
R&D requires more of your budget at a time when every dollar and every Euro counts.

CROs offer pharmaceutical, biotechnology, and medical-device companies the resources

and expertise to conduct clinical trials in a manner that's streamlined, professional, and
cost-effective. As a matter of course CROs act as partners, helping clients address
everything from subject recruiting to data-collection and analysis, from clinical trial
planning to regulatory filing.

For a relationship so close, it's important to choose the right partner. Product sponsors
need a CRO with whom they can communicate closely and honestly, with whom they can
work through bad news as well as good. The CRO-sponsor relationship is one of shared
vision, complementary expertise, and trust. The CRO's team should operate as a part of
your team, looking out for your interests, understanding the demands of your market,
seeking ways to make each clinical effort more cost-effective, more thorough and more
timely.

Clients, regulators, even competitors, recognize the right CRO for its professional
approach. It subscribes to A CRO's Code of Ethics and its employees comply with
regulatory Good Clinical Practice (GCP) and Good Laboratory Practice (GLP)
guidelines. Its commitment to patient safety and research quality should be
uncompromising.

Your CRO should provide regulatory expertise appropriate to a product's unique clinical
approach and market targets. Trials should be paired with stringent quality assurance
procedures and detailed product management, to make sure deadlines are met and
budgets followed. Reporting should be clear, thorough, and accurate.

Simply put, the optimal CRO streamlines the complex process of taking products from
laboratory to market – safely, efficiently, and cost-effectively.

Outsourcing in Clinical Research - The Indian Perspective

Introduction
New pharmaceutical strategies pursue increased Research and Development (R&D)
investments ranging 15-20% in contrast to late 80’s period where classical model across
was 10%. The annual budget allocation spent with clinical research organizations (CRO)
is approximately $12 billion in an attempt to increase throughput, which has
predominantly benefited CRO’s who have seen their turnover boost growth of 20-30%
year on year. The $9.57bn world market for contract clinical research services growing at
13.4% comprising of pre-clinical and Phase I, II, and III clinical services provided by
CRO to pharmaceutical and biotechnology drug developers. U.S. still holds majority
stake in the slice with more than half of 1000 companies engaged in the business having
their base in US. This is primarily due to the status of U.S. as the world’s largest drug
market and the favorable conditions it offers for contract research services. Recent trends
have seen clinical research segment gaining weight outside US boundaries, getting
established in Europe and Asia. India and China share the major chunk of benefits from a
rise in clinical research activities in Asia. The revenues still remain relatively low in
comparison to overall CRO sales because of the extremely low currency valuations in
these regions.

Reasons for outsourcing in Clinical Research in India

Indian Clinical Research focus is shifting from cost advantages to quality and rapid
response. India, with second largest population in the world, and with every sixth patient
in the world being an Indian, is going through an upheaval economically, socially and
scientifically. Increased awareness of Good Clinical Practices (GCP) requirements,
stronger desire of international acceptability of research done in India has brought
favorable changes in the attitude of clinicians in India towards participation in clinical
trials. Investigators are eager to take part in GCP clinical trials and are also willing to
adhere to constraints of the protocol. Current outsourced clinical trial activity in India is
at around Rs. 3.5 billion (about US $ 75 million) and is estimated to go up to Rs13.2
billion (about US $ 281 million) by 2010. According to statistics compiled by the Indian
Council of Medical Research (ICMR), the total turnover from clinical trials in India in
’03 was Rs 2.25 billion. Just 800 people are full time employees, while an additional
1,500 people work as site staff. The total number of patients undergoing clinical trials is
10,000. The clinical trials legislative requirements are guided by specifications of
schedule Y of Drugs and Cosmetics Act in India. Recently the Ministry of Health, along
with DCGI and ICMR has come out with draft guidelines for research in human subjects.
These are essentially based on Declaration of Helsinki, WHO guidelines and ICH
requirements for GCP. The Department of Science and Technology has taken initiative
for establishing quality requirements by setting up National Board for Accreditation of
Testing and Calibration Laboratories for clinical and diagnostic laboratories (NABL).

The following figure outlines the advantages offered for conducting clinical trails in
India.
 Company Revenues (Rs. million)
Quintiles Spectral 625.5
Syngene 384.8
Vimta Labs 351.1
Pfizer 180
Lambda Therapeutics 160
TOP 5 1701.4
Others 1050.0
Total BioServices Revenue 2751.4

(*Note: SiroClinpharm has not confirmed it revenues. In 2003-04, its service revenues
were Rs 312.0 million and in 2003-04 it might have crossed over Rs 500 million. Its
number of projects has doubled in 2003-04.)

Industry Insight - Clinical Trials in India :

The costs of conducting clinical trails in the developed countries have increased over the
years, leaving research-based multinationals with little choice, but to outsource stages of
clinical trails to developing countries such as India and China. Nearly 30 per cent of the
clinical trials will be outsourced to developing countries in the near future. India will play
an increasingly important role in the clinical trails segment due to genetically-diverse
population, abundant technical talent, low costs and sound infrastructure among other
reasons. The industry insight on Clinical Trials in India had been launched in Aug 2005
to give in insight into the emerging sector of Indian healthcare industry. The report,
organized in nine chapters presents the global scenario and Indian scenario in terms of
infrastructure, regulatory developments, major diseases, competition and trends in drug
development. The report analyses the potential of Indian CRO industry and studies India
as a destination for CROs. The report also discusses GCP compliance, CT in herbal
medicines; new drug launches world over; education and training requirements; quality
control and market and R&D productivity. The report gives a brief profile of 30 CROs
with the brief description of their facilities and quality policies available and other vital
information. The report also throws light on bioavailability and bio-equivalence studies in
India. The report discusses technology, issues and challenges, critical success factors,
regulatory issues as separate chapters in detail. In the end, the report presents outlook for
the CRO Industry.

Bayesian Approaches to Clinical Trials and The Bayesian approach involves collecting
data from past experience in order to reach conclusions about future events. Bayesian
methods have become increasingly popular in recent years, notably in medical research.
There are a large number of books on Bayesian analysis, but very few that cover clinical
trials and biostatistical applications in any capacity. There is no book available that is
introductory in nature and covers such a broad array of essential topics. This book
provides a valuable overview of this rapidly evolving field, not only for statisticians in
the pharmaceutical industry, but also to anyone involved in conducting clinical trials and
HTA work. Comprehensive coverage of Bayesian methods in medical research Illustrated
throughout by case studies and worked at the forefront of research into Bayesian methods
in medical research Suitable for those with a limited statistical background.

Products and Services : Product Development and Support of Clinical Trials

including Contract Research Organizations (CROs)

Clinical trials are the basis for determining the safety and efficacy of pharmaceuticals,
biologics and medical devices. Generally speaking, Contract Research Organizations
(CROs) design, manage, monitor and analyze pre-clinical and clinical trials. Other
companies on this page provide various types of support services for pharmaceutical
development.
CHAPTER – V
LINKS TO GENERAL INFORMATION ON
CLINICAL TRIALS
The following U.S. government web sites guide consumers to answers to questions and
provide contacts to clinical trials, and to information on drugs and important health care
issues. The clinical trials discussed in these sites are all available in ClinicalTrials.gov.

Clinical Trials at the National Institutes of Health.

The NIH Clinical Center in Bethesda, Maryland is the research hospital of the National
Institutes of Health (NIH). There, through clinical research, scientific discoveries in the
laboratory are translated into new and better medical treatments and therapies for people.
Their web site guides potential participants, their families and physicians about
participating in clinical trials in Bethesda, Maryland:
http://www.cc.nih.gov/
Recruitment information for sick or healthy participants:
http://www.cc.nih.gov/ccc/prrc/info.html#patients

Cancer Trials
The National Cancer Institute (NCI) is the U.S. government’s focal point for clinical
trials on cancer. Most U.S. government agencies that conduct cancer research, such as
DOD or VA, do so in partnership with NCI.
http://www.nci.nih.gov/

NCI provides information on understanding cancer trials, types of cancer, finding trials,
resources for researchers, most requested pages, and more:
http://www.cancer.gov/clinical_trials/

NCI Clinical Trials Education Series provides publications for individuals and health care
professionals to understand clinical trials, such as self-paced workbooks, slide programs
on CD-ROM, booklets and videos:
http://www.nci.nih.gov/clinicaltrials/resources/clinical-trials-education-series
The Veterans Administration (VA) and NCI provide information on their interagency
partnership agreement in clinical trials for cancer:
http://www.va.gov/cancer/

The FDA Cancer Liaison Program, Office of Special Health Issues with NCI answers
questions directed to FDA by participants, their families, and participant advocates about
therapies for life-threatening diseases: http://www.fda.gov/oashi/cancer/cancer.html
Vision Trials
The National Eye Institute (NEI) provides a clinical studies database, vision research
information, and free education resources:
http://www.nei.nih.gov/resources/

Mental Health Trials

National Institute of Mental Health (NIMH) supports FAQs for potential participants in
mental health research; read ieA Participant’s Guide to Mental Health Clinical Research
in: http://www.nimh.nih.gov/Publicat/clinres.cfm

Information on Bioethics
NIH Office of Extramural Research (OER), and the NIH Inter-Institute Bioethics Interest
Group OER provides information on policies and regulations, Institutional Review Board
resources, guidance for clinical investigators, research resources, courses and tutorials on
bioethical issues in human studies:
http://www.nih.gov/sigs/bioethics/

The National Library of Medicine (NLM) compiled a comprehensive bibliography from

1989 through November 1998, i9Ethical Issues in Research Involving Human
Participants, lg compiled by the National Library of Medicine:
http://www.nlm.nih.gov/pubs/cbm/hum_exp.html

HHS Office of Human Research Protection (OHRP)

OHRP provides a guide and training materials on regulations and procedures governing
research with human subjects; includes a guidance document on financial relationships in
clinical research:
http://www.hhs.gov/ohrp/

INFORMATION ON MEDICARE COVERAGE

Centers for Medicare and Medicaid Services (CMS)
CMS provides information on the September 19, 2000 final national coverage decision
regarding Medicare payments for routine costs, and reasonable and necessary items in
clinical trials; read ieMedicare Coverage Policy ~ Clinical Trials.lr This decision is based
upon the authority found in 1862(a)(1)(E) of the Social Security Act:
http://www.medicaid.com/coverage/8d2.asp
Clinical Trials and Medicare Quick Reference Guide:
http://www.medicaid.com/medlearn/refctmed.asp

MedlinePlus Clinical Trials irHealth Topicslh Information

Medline Plus is a web-based information service from the National Library of Medicine.
Its itHealth Topicslh section has extensive information from NIH and other trusted
sources on over 550 diseases and conditions, including a link to clinical trials. It also
includes an informative in Clinical Trialslc health topic page, with some material in
Spanish, and an interactive tutorial on clinical trials.
http://www.nlm.nih.gov/medlineplus/clinicaltrials.html

Information on Drugs
The Food and Drug Administration is the U.S. government agency responsible for
ensuring the safety and effectiveness of all drugs. After a clinical trial, it looks at the
evidence to determine if a new drug or treatment is safe to approve as a marketable new
product and is an improvement over the standard therapy (See Approved Drugs). FDA
web sites provide valuable information to consumers on its activities in regulation and
approval of drugs.
http://www.fda.gov/

FDA provides the following general information about newly approved prescription
drugs:
* Information on how drugs are developed in the U.S., read ieFrom Test Tube to
Participant: New Drug Development in the U.S.,lp third Edition, September, 1999:
http://www.fda.gov/cder/about/whatwedo/testtube.pdf
* Consumer information about drugs approved since 1998:
http://www.fda.gov/cder/consumerinfo/
* Information on products regulated by FDA:
http://www.fda.gov/cder/drug/
* New and generic drug approvals since 1988:
http://www.fda.gov/cder/approval/
* FAQs to CDER:
http://www.fda.gov/cder/about/faq/
* The FDA Electronic Orange Book, which gives current approved drug products:
http://www.fda.gov/cder/ob/
* Medline Plus Drug Information.
* Medline Plus Guide to over 9,000 prescription and over-the-counter medications:
http://www.nlm.nih.gov/medlineplus/druginformation.html

D.A.E. Clinical Trial Centre

A national centre for clinical trials has been established At Tata Memorial Hospital not
only to initiate clinicians in the concept of scientific and evidence-based medicine but
also to address burning medical and epidemiological questions in which the west is
unlikely to have any interest. Scientific leads from laboratory ultimately need to be
answered in human subjects in the form of a randomized clinical trial. But, due to a lack
of understanding as to how such a question should be addressed in a clinical setting and a
lack of interaction between the clinician and the laboratory scientist, many important
scientific leads are lost by default. The scientific community, other funding agencies and
ultimately patients may benefit from testing the efficacy of newly synthesized biological
products such as engineered enzymes, genetic materials and other substances emanating
from laboratories. In the sphere of public health, where very large trials are a norm, the
ICMR as well as NPC would benefit from having a centralized facility to conduct trials
involving thousands of subjects. The testing of a new vaccine for common diseases such
as cervical cancer (caused by the human papilloma virus) is one such example. Other
examples could include whether many of the commonly used indigenous herbal products
are truly beneficial or even superior to conventional allopathic remedies. Recent research
in India in animal systems suggests that 'haldi' or its active ingredient curcumin helps to
prevent oral cancer. This, however, has not been confirmed in humans in the absence of a
large well-conducted randomized clinical trial. For the Ministry of Health, the assessment
of efficacy and cost-effectiveness of new and expensive drugs or technologies imported
from the west for general use in our country with limited health care resources is
essential. The randomized clinical trial offers a unique opportunity to test these issues
scientifically before they are sanctioned for routine health care

Objectives :

Educating and Training

Education and Training will form an important activity of the DAECTC. The current
medical curriculum does not offer any training in clinical research either at the
undergraduate or at the postgraduate level. In order to fill this void and DAECTC could
play a major role in education and training in the area of cancer.

Regular workshops on clinical research methodology will be held to give intensive

training in good clinical practice, principals of randomized clinical trails, case-control
and cohort studies, data accrual and management, quality of control of data, statistical
methodology etc. The participants will also be given hands-on training in the use of
software packages for data collection, data management and statistical analysis.

Research fellowships would be offered which would enable young oncologists from other
centres to come and train at this centre. This will help to create a pool of trained clinical
scientists in the country capable of conducting independent clinical research and
undertake clinical trials, which could be utilized for the conduct of national multicentre
trials.

Co-ordinating Clinical Research and Networking with Centres of Excellence :

The DAECTC will form the nodal point for the co-ordination of randomized clinical
trials and other clinical research activities in cancer in the country. A Core Group
consisting of well known academic oncologists representing 8-10 centres of excellence
will institute identify important research projects, direct and co-ordinate the research
activities of DAECTC.
Centralized Laboratory

A centralized laboratory is essential for undertaking standardized assays in any multi-

centre research programme. With the laboratory facilities that would be available at
ACTREC it will be possible to carry out sophisticated laboratory tests, which form part
of clinical research projects. These include hormone assays, receptors assays, enzyme
assays, specific genetic markers etc.

Advisory Function

DAECTC would play an important role by offering advice on design, protocol writing,
sample size, designing case record forms etc. for other centres, which lack the necessary
expertise.

Holding National /International Conferences

The DAECTC would from time to time hold national and international conferences to
promote clinical research activities in the country. The first meeting on practice of
evidence based medicine and formulating guidelines for uniformity of standards of care
across the country was held on 28 February and 1-2 March at the Tata Memorial
Hospital.

Spectra Clinical Research Centre (SCRC), the clinical research unit of the Apollo
Hospitals Group --the single largest health care corporate hospital network in the
country--will accelerate the implementation of its clinical research courses. SCRC
focuses its education resources at the study site to increase GCP awareness, compliance,
and career development. Its leverage is its association with health care facilities of the
Apollo Hospitals Group, which is poised to have the widest catchments (urban and rural)
for clinical trial recruitments.

Biocon's new biologics

Finance minister, P Chidambaram recently inaugurated Biocon Biopharmaceuticals,

claimed to be India's largest multi-product biologics facility at Biocon Park,
Bommasandra Industrial Area - Phase IV.

Biocon established Biocon Biopharmaceuticals Private Limited (BBPL) in collaboration

with CIMAB, representing the Centre of Molecular Immunology, Cuba. The state-of-the-
art cGMP compliant facility is designed to manufacture a broad range of novel and bio-
similar therapeutic products through large scale cell-culture fermentation for the
treatment of cancer, auto-immune and metabolic diseases.
The facility is also designed to cater to contract manufacturing needs of international
biopharmaceutical companies. Biocon's multi-disciplinary technological capabilities and
growing expertise in clinical development has enabled rapid advances in the field of
protein therapeutics. Biocon believes that such novel products of biotechnology will
provide quantum growth drivers for the future.

The l,20,000 sft building spread over three floors comprises process, laboratory and
technical support areas. The new facility represents a significant advancement in terms of
technical sophistication over Biocon's existing facilities and comprises three distinct
modules - cell culture module for monoclonal antibodies and other cell culture products;
aseptic formulation and filling module for sterile products in vials, cartridges, lyophils
and syringes; and quality control module.

Biocon and Biocon BioPharmaceuticals as a key global player in the field of cell culture
fermentation technology. The plant is designed with an in-built 4-fold expansion capacity
keeping in mind Biocon Biopharmaceuticals' research pipeline and global market trends.
This new facility will provide immediate job opportunities to over a hundred scientific
and technical personnel."

IMRB survey reconfirms benefits of Bt cotton

As against the general notion about the failure of the cotton crop, IMRB International (a
part of the WPP's Kantar Group of Companies) with over three decades of market
research experience in India has found that farmers who planted Bollgard cotton earned
an additional Rs 2,100 crore in income based on 3.125 million acreage penetration for the
2005 crop.

IMRB survey of Bollgard has reconfirmed for us the earlier findings that farmers stand to
benefit from the usage of this technology. A total of 31 districts were covered as part of
the research out of the 80 cotton districts across cotton growing states in India. Better
yields and less pesticide usage have been the key triggers for farmers choosing Bollgard
over conventional cotton."

The IMRB International survey estimated that there has been a 64 percent or 4.16
quintals per acre increase in Bollgard yields when compared with conventional cotton.
The net profit increase for farmers using Bollgard is Rs 6,727 per acre or over 118
percent. It also observed that there is a reduction of an average 2.4 pesticide sprays
against bollworm that translates to a 25 percent reduction in total pesticides spend.

ICRI partners with Cranfield University

To drive an international perspective to clinical research education in India and to deliver
on India's growing demand for skilled clinical research professionals, Mumbai-based
Institute of Clinical Research (India) has entered into an academic alliance with Europe's
research led institution, Cranfield University, the UK. This alliance would further the
cause of ICRI in India in grooming professionals in clinical research to face exciting
challenges posed by the pharmaceutical sector and also pave the way for new career
opportunities in this field.

This alliance gives us an opportunity to address the growing demand for clinical research
professionals in India. The perfect combination of ICRI's networking with the Indian
pharmaceutical sector and their current course orientation and Cranfield University's
distinctive competences in biomedical sciences and clinical research data studies bring
immense potential to furthering the cause of clinical research in India.

Cranfield University would undertake responsibility for the quality academic orientation
in clinical research and training methodologies, evaluative studies, project assessment,
knowledge exchange and final certification of Cranfield-ICRI's two-year full time
Masters program in clinical research.

Shasun to launch its first rDNA product in 2007

Recognising the role of biopharmaceuticals in the future of global pharmaceutical

industry in enhancing therapeutic effectiveness, improving lifestyle quality and
strengthening corporate profitability, Chennai-based Shasun Chemicals and Drugs Ltd, a
premier service provider to the pharmaceutical industry has been engaged in developing
technologies for recombinant biogenerics using the microbial expression platform. And it
will launch its first biotech product r-Streptokinase in 2007.

One of our product under development has successfully cleared animal toxicity studies
and is under clinical testing. Meanwhile, we have developed capabilities in the area of
biotechnology services like upstream and downstream processing, analytical and quality
assurance. And the cGMP production facility for biopharmaceutical proteins is nearing
completion. We are looking for tie-ups with suitable co-marketing partners to launch
these products in the Indian market.

Shasun offers services in research, development and manufacturing (including Contract

Research and Manufacturing Services- CRAMS) and set up its biotech R&D facility in
2002. Currently it has a team of 22 scientists. It is also looking for tech transfer and
discussions are on with a couple of companies for the same, Govindarajan said.

Shasun reported a significant growth in the business of CRAMS as its revenue grew to Rs
38 crore in 2005-06 from Rs 24.5 crore (2004-05). The company recently acquired the
pharmaceutical custom synthesis business of the Rhodia Group, the UK and is targeting
to close FY07 with a Rs 750–800 crore and FY08 with Rs 1000 crore.

Indian groups oppose patenting of AIDS drug

The Indian Network of People Living with HIV/AIDS (INP+), the Manipur Network of
Positive People (MNP+), represented by the Lawyers' Collective HIV/AIDS Unit
officially submitted their opposition to a patent application filed in the Kolkata patent
office by GlaxoSmithKline (GSK) for Combivir, a fixed-dose combination of two
essential AIDS drugs zidovudine/lamivudine. The opposition is based on technical and
health grounds.

"We are objecting to the patenting of Combivir because it is not a new invention but
simply the combination of two existing drugs. More importantly, the granting of such a
patent risks increasing the cost of anti-retroviral treatment for many people living with
HIV/AIDS, thereby further increasing the burden on developing countries already
struggling to treat patients," said KK Abraham, president of INP+. Combivir is a widely
used fixed dose combination and is used extensively in projects run by international aid
organization Medecins Sans Frontieres (MSF). Almost all the Combivir used by MSF is
generic. India, Burkina Faso, Mongolia, Central African Republic, Malawi, Peru, the
Republic of Kyrgizstan, Cambodia, Ukraine and Swaziland are other countries also
identified by the Global Fund as using generic Combivir, the release said.

Mascon files its first patent in bioinformatics

Mascon Life Sciences has filed its first patent, which is also probably India's first patent
as well, in the bioinformatics arena. This invention is in the field of theoretical biology.
Here the DNA is converted into a unique signal, which is further processed in order to
extract the needed biological features.

This patent is in the basic sciences area and is going to revolutionize the entire
bioinformatics research.

We have developed different mathematical models and functions for different biological
features. The theory of decoding the DNA sequence into a unique signal is of very basic
in nature and has produced remarkable results when applied to extract the features from a
genome.

The patent has been filed as Indian Patent vide Patent Application No. 953/DEL/2005,
and the US patent has been applied for. The patent is titled "Method for conversion of
DNA sequence to a number string and application therefore in accelerated drug design".

Panacea Biotec opens pharmaceutical formulation plant at Baddi

Panacea Biotec has commenced production in its new pharmaceutical formulation plant
at Baddi, Himachal Pradesh with an investment of around Rs 45 crore. This plant is in
compliance with global standards including US FDA and UK MHRA, SA MCC and
WHO cGMP.

Situated amidst picturesque surroundings in the state of Himachal Pradesh, Panacea

Biotec's facility in Baddi is spread over 70,000 sm and will cater to the manufacturing of
oral and topical pharmaceutical finished dosage forms. The facility is equipped with
modern equipment and machinery to meet the regulatory standards of the US, European
and South African markets.

The Baddi facility with high capacities and scope for future expansion is designed to
produce various formulations viz. tablets, capsules, ointments and liquids. The facility
has an installed capacity of 900 million tablets, 120 million capsules, 12 million
ointment/gel tubes and 1.2 million litres liquid orals per annum

Pfizer

Pfizer has contributed to the development of clinical research and Biometrics in India,
being the first multinational to establish clinical research operations in India. One of its
initiatives has been the Academy for Clinical Excellence (ACE), first organization in
India that is dedicated to training and education in clinical research.

Clinical Trials : Corner Stones of Research and Innovation

All new treatments are carefully studied in laboratories, before they are tested in patients.
Initially, a drug is considered because it changes cells or parts of cells in a way that
suggests it will destroy the disease or help the body deal with the side effects of the
treatment. Then, the new treatment is tested in animals to learn what it does in the body.
But this early research cannot predict exactly how a new treatment will work in people or
define all the side effects that might occur.

Clinical trials are designed to help us find out how to give a new treatment safely and
effectively to people. All patient who participate in a clinical trial provide information on
the effectiveness and risks of the new treatment.

Reliance Clinical Research Services

Reliance Clinical Research Services (RCRS) is now addressing the clinical research
services market in USA and Europe. RCRS is mandated to emerge as an India-based,
world-class contract clinical research services organization. RCRS is part of the Reliance
Group of Companies, India's largest private sector company, and a component of the life
sciences initiative of Reliance.
RCRS bridges science to the market place by performing, assisting and managing
pharmaceutical, biotechnology product and medical device development through
preclinical and clinical (Phase I to Phase IV) studies. The vision of RCRS is to become a
world-class full-service contract clinical research service provider with an accent on
quality delivery to ICH-GCP (International Conference on Harmonisation - Good
Clinical Practice) standards and conduct of speedy clinical trials. RCRS provides services
in project management, clinical operations, site management, biometrics (data
management and biostatistics), medical affairs (pharmacovigilance and medical writing),
regulatory affairs, animal studies, quality assurance, molecular diagnostics, ICH-GCP
training, archival facility and drug storage and supplies.

The value proposition of RCRS is built around a strong knowledge base and network in
the medical domain, full service project planning, conduct and management of trials
throughout India, in-house molecular diagnostic support and in-house Phase - I and pre-
clinical toxicity ability.

RCRS is currently conducting several studies for clients based in the USA, UK and
Middle East. RCRS is working for indications in Oncology, Burn wounds,
Cardiovascular, Endocrinology, Nephrology, Gastroenterology, Infectious diseases and
Vaccines.

Costs of clinical trials in USA and Europe have skyrocketed, and recruiting qualified,
therapy-naïve patients, i.e. patients who have not received any prior treatment, can be
extremely time consuming and delay completion of these trials for months or even years.
Many health care companies, both large and small, find doing clinical trials in India an
attractive option.

Completing clinical drug trials and product development in India could be up to 75%
faster. As per Rabo India Finance, although the average costs of doing Phase I/II/III drug
trials in US are $20/50/100 million respectively, in India they are 50-60% of the same.

In recent years, India has created a favourable environment for clinical trials. India signed
the WTO agreement (fully effective in 2005) to alleviate issues related to protection of
Intellectual Property. Regulatory laws have been updated to conform to the global GCP
guidelines. All medical facilities have been mandated to meet the GCP procedures and
training support of medical personnel necessary to achieve this goal provided. India has
provided exemptions for import duties on clinical trials products and eliminated the
procedural hurdles that were prevalent in the past.
India has a very large pool of highly trained physicians, nurses, and technical personnel
and numerous world-class medical facilities that meet the global requirements for clinical
testing. Many major pharmaceutical companies have already successfully used clinical
trials' data from India for US FDA NDA submissions.The broadly developed information
technology infrastructure in India provides added advantage to ensure speedy conduct of
studies and flow of information / data from the sites to the sponsors' databases.

As a result, India is seeing a rapid growth of clinical trials. The setting of a large, diverse,
and therapy-naïve population, low cost for technical services, and use of English as the
primary business and medical language is ideal for completing trials rapidly and cost
efficiently.

Clinical Research in India : Cost of research - US vis-a-vis India

Average US cost
Study India Cost
(In millions)
Phase 1 (normally tests on small groups of healthy 50% less than the
$20
humans) average cost in US
Phase II (tests on individuals afflicted with the 60% less than the
$50
condition for which the drug was developed) average cost in US
Phase III (tests on large groups of afflicted 60% less than the
$100
patients) average cost in US
Other Companies and their Research Products
Drug Company Molecules Researched
Alcon Vegamox
AstraZeneca Merenem
Cangene Hepatitis B Vaccine
Eli Lilly Alimta
Gemcitabine (breast cancer)
Cialis (erectile dysfunction)
Xygris (Septicemia)
Glaxo Lamictal
Jannsen Resperidal
Novartis Tegaserod
Pfizer Voriconazole
Roche Peg-Interferon
Santen Quixin
Wyeth Influenza A Vaccine
CHAPTER – VI

CLINICAL TRIALS LABORATORIES IN INDIA

Central Drug Research Institute (CDRI)
Chattar Manzil Palace
P.B. No 173
Lucknow - 226001
Tel: (+91) 522 232411
Fax: (+91) 522 243405
Website: http://www.cdriindia.org

Centre for Cellular & Molecular Biology (CCMB)

RRL Campus
Uppal Road
Hyderabad - 500007
Andhra Pradesh, India.
Tel: (+91 40) 2716 0222 - 41
Fax: (+91 40) 2716 0591, 2716 0311
E-mail: lalji@ccmb.res.in
Website: http://www.ccmb.res.in

Indian Institute of Chemical Biology (IICB)

4, Raja S. C. Mullick Road
Calcutta - 700032
Tel: (+91 33) 2473 3492, 2473 0492
Fax: (+91 33) 2473 0286
E-mail: director@iicb.res.in
Website: http://www.iicb.res.in

Institute of Microbial Technology (IMT)

Post Box No 1304
Sector 39-A
Chandigarh - 160036, India.
Tel: (+91 172) 695225, 695226, 694710, 695219, 690713, 690173, 690908, 690025
Fax: (+91 172) 690632
Website: http://imtech.res.in
OM-First Limited
Ahmedabad, India.
Tel: (91 79) 404 849
Fax: (91 79) 656 6103
E-mail: omfirst@ad1.vsnl.net.in
Has office in London as well.
E-mail in London: INFO@OMFIRST.CO.UK
Contact person in London: Paresh Patel.

Quintiles Spectral Limited

3 Ashoknagar Bungalows
Behind Sundarvan
Satellite Road
Ahmedabad 380 015
Tel: (+91 79) 692 3303
Fax: (+91 79) 692 4311
Email: rajiv.ramanathan@quintiles.com
Website: http://www.quintiles.com

Specialty Ranbaxy Limited

Plot 113, MIDC 15th Street
Andheri (East)
Mumbai - 400 093
Tel: (91 22) 5690 3851
Fax: (91 22) 5690 3865
e-mail: cservice@srlranbaxy.com
Website: http://www.srlranbaxy.com

Metropolis Health Services (India) Pvt. Ltd.

250 D, Udyog Bhavan,
Hind Cycle Marg
Behind Glaxo
Worli, Mumbai - 400 030
Tel: 91-22-56622040, 91-22-56611067
Fax: 91-22-56622080
Email: support@metropolisindia.com
Website: http://www.metropolisindia.com
Status of Clinical Trials in India

Clinical trials of bio-tech and medicinal products for approval purposes are done usually
in hospitals in India. Most of the hospitals conduct clinical trials, if they have doctors
interested in this activity. Information on the terms and conditions and the cost is not
readily available.

All types of hospitals carry out clinical trials, large and small as also municipal and
government hospitals. Large private hospitals and clinics too perform this work. The
basic requirement is the presence of doctors who have an interest in this work.

On the basis of preliminary enquiries, there are already companies or agencies engaged
exclusively for clinical trials in India. Examples are Quintiles in Ahmedabad, Clinfarm
Consultants and Specialty Ranbaxy in Mumbai and Kumar in New Delhi. Quintiles and
Specialty Ranbaxy have foreign tie-ups giving them the technological advantage over the
purely local ones.

Outlook for Bio-tech/Pharma Sectors:

India at present recognises only process patents. However, by 2005 by virtue of WTO
rules, India will have to implement product patents. This will lead to widening of the
market for indigenous (say, Ayurvedic products) as they will have the authenticity of
internationally recognised product patents. Product patent protection will encourage
multinational companies to import technology into India to develop new products.

These developments will open up increased opportunities for the clinical trials of bio-tech
and medicinal products.

Assessing marketing viability involves the following steps:

A) estimating and forecasting the market (i.e., demand) for clinical trials for the next 10
years (in terms of number of products and total cost);
B) estimating and forecasting the supply of clinical trial service and segmenting it
among: (i) large hospitals, (ii) small hospitals and (iii) contract clinical companies;
C) quantifying the demand-supply gap for clinical trial service available to contract
research organizations during the next 10 years; and
D) estimating and projecting the revenues of the proposed contract research organisation
for the next 10 years and thus establishing its marketing viability.

CHAPTER – VII
FUTURE OF CLINICAL TRIALS IN INDIA
 Future of clinical trials in India
Many factors have fuelled the growth of Clinical Research in India.
• There is a positive change in the business environment in India. There
has been a move to bring in regulations regarding data protection and data
exclusivity.
• Infrastructure required for conducting clinical research is available. This
includes connectivity with remote locations. It is possible to conduct meetings/
training through audio-visual media.
• Since cost of drug research and development is high, pharmaceutical
companies worldwide are attempting to lessen the time and cost required to
bring a new drug to the patient. A large number of Contract Research
Organizations have established operations in India, further influencing the
clinical research culture.
• There is increased awareness regarding ICH–GCP (The International
Conference on Harmonisation-Good Clinical Practice) guidelines for conduct
of clinical research.
• The availability of a large pool of scientifically trained, English
speaking personnel.

CHAPTER – VIII
CONCLUSION

Unlike their global counterparts, the Indian pharmaceutical market--estimated at 400

billion Indian rupees (US $8 billion) in 2001-is in a business climate of token R&D
investment. India was, until recently, protected from global product patent laws. The
upside in Indian pharmaceutical history is its self-reliant, independent, international-
standard manufacturing base.

A CII study predicts that the clinical trials market will grow to $200 million by 2007 and
anywhere between $500 million and $1 billion by 2010, .

The fact that entire education in modern medicine in India is in English, is an added
attraction? All source documents, hospital papers, lab reports, clinical notes are generally
written and printed in English, avoiding need of translation as in China or Japan for
auditors from the west, those in the field. The trials are going on in diverse areas. The
highest number of studies have been done in infection and oncology areas in the last few
areas.

The fact that entire education in modern medicine in India is in English, is an added
attraction? All source documents, hospital papers, lab reports, clinical notes are generally
written and printed in English, avoiding need of translation as in China or Japan for
auditors from the west, those in the field. The trials are going on in diverse areas. The
highest number of studies have been done in infection and oncology areas in the last few
areas.

BIBLIOGRAPHY
• Laurence D.R., Bennett P.N., Clinical Pharmacology, 8th edition, 1997,
published by Churchill Living Stone Publication, P. 217,637.
• Walker Roger, Edwards Cline Clinical Pharmacy and Therapeutics, 3rd
edition, 2003, published by Churchill Living Stone Publication, P. 112, 640.
• Bennett P.N., Brown M.J., Clinical Pharmacology, 9th edition, published
by Churchill Living Stone Publication, P. 57, 260.
• A. Catto Allen, Sutton Lynda Clinical Drug Trials and Tribulation, 2nd
edition, published by Marcel Dekker, P. 21-413.
• Schoenwald D. Ronald Pharmacoknetics in Drug Discovery and
Development, published by CRC Press, P. 115, 267.
• www.AdvancedWebSearch.info (May 02, 2006)
• www. bioinformatics-india.com/new/?q=node/ (May 11, 2006)
• www.cseindia.org/programme/health/activist.htm (May 04, 2006)
• www.cato.com/biotech/bio-edu.html (May 08, 2006)
• www.cato.com/biotech/bio-prod-cro.html (May 07, 2006)
• www.diahome.org, (May 08, 2006)
• www.entlink.net/research/research/Clinical-Trials.cfm (May 09, 2006)
• www.Expert-Expert.com (May 03, 2006)
• www.firstclinical.com/resources/training.html (May 15, 2006)
• http://www.fda.gov/cder/about/default.htm (May 01, 2006)
• www.findtbresources.org/ scripts/index.cfm?FuseAction=Links (May
14, 2006)
• www.findtbresources.org/scripts/ index.cfm=Organizations (May 11,
2006)
• www.fic.nih.gov/programs/bioethics/bioethicsaward.html (May 07,
2006)
• www.fic.nih.gov.portia.nesl.edu/ programs/aitrp/aitrp.html (May 04,
2006)
• www.info.com/ClinicalResearc (May 16, 2006)
• www.iis1.india.pfizer.com/Functional_Areas/ Medical_Research/
clinical_trial/ mrd_clinical_trials.asp (May 02, 2006)
• www. instituteofclinicalresearch.org:81/ blog/?sectionid=5
• www.inctr.org/publications/report/2005_04_04.shtml (May 20, 2006)
• www.medicalnewstoday.com/medicalnews.php?newsid (May 09, 2006)
• www.manipal.edu/media/quintiles+manipal4clinical_research.htm(May
15, 2006)
• www.med.nyu.edu/cih/about/people.html (May 12, 2006)
• www.ophth.wisc.edu/training/Res_Training.html (May 03, 2006)
• www.researchandmarkets.com/ reportinfo.asp?report_id (May 06,
2006)
• www.surfindia.com/education/medical-institute (May 14, 2006)
• www.tatamemorialcentre.com/research/dae.htm (May 16, 2006)
• www.usfcenter.org/Faculty/index.asp (May 10, 2006)
• www.visioncrc.org/our_activities/ professional_education.asp (May 10,
2006)