Around 20-30% of global clinical trial activities are being conducted in developing

countries. More than 40% of drug development costs are incurred in clinical trials and
India offers immense savings on this aspect. India emerges as a preferred destination for
outsourcing clinical trials because of the availability of a large patient population, 40%
reduced clinical trial cost as compared to West and well-trained medical professionals
along with excellent technological infrastructure. Indian CRO industry is expected to
increase five folds till 2010. There is lot of factors attributing to the CRO industry for the
market to flourish as expected in the next 5 years.

Drug Controller General of India (DCGI) is the nodal agency to evaluate the product
safety, efficacy, clinical trials, market authoritisation and post market surveillance in India.
There are many regulatory agencies under DCGI like ICMR (vaccines), NIB (biologicals),
GEAC-DBT (genetically modified drugs), DGFT (export/import) and CRI/CDTL (drug
testing). Genetic Engineering Approval Committee (GEAC) is responsible to regulate the
proposals involving large scale use of living modified organisms (LMOs) in the
pharmaceutical industry.

Current Situation

As per Indian regulations, it should ideally take 3-6 months for clinical trail drug approval
whereas USFDA provides clinical trial approval within 30 days. Most of the CRO feels that
there is too much of delay in the timelines for drug approvals. If it's a phase III drug,
DCGI will approve in a very short period but if it is a Phase II or first time trial drug in
India, the period could be infinite or unknown. Along with regulations, deficiencies in the
functioning of the ethics committees (EC), investigators' unethical approach to the
recruitment of subjects and the quality of Indian clinical trials makes India a rash and
risky place to outsource. The delay in the process of approval after filing the application
with the regulatory agencies and the absence of clear guidelines from these agencies is
putting enormous pressure on drug development companies.

The timelines for approval are often unpredictable in India as the Drugs Controller's office
depends on external experts and other government agencies such as the Indian Council of
Medical Research (ICMR) and the Department of Biotechnology (DBT) for advice and
there are additional permissions required from Director General of Foreign Trade for the
import of trial samples and export of blood samples to foreign central laboratories. Delay
in approval has resulted into conducting unethical/illegal trials at private clinics without
the fear of regulatory authorities as they fail to take action against such mischief makers in
the society leaving the patients with no avenue for seeking compensation for any mishaps
involving the trial drugs. Hence the government is planning to revise the Biomedical
Research on Human Subjects Bill on Regulation, Control and Safeguards.

As the CRO industry in India is booming, applications for clinical trials are flourishing in
DCGI's office. DCGI do not have adequate experience and manpower to tackle the
increasing application for clinical trial activity in different phases and therapeutic
segments in India
Changing Scenario

The pharma and biotech companies have been demanding restructuring of the regulatory
mechanism in the fast emerging sector. Regulatory association has realized the fact and
trying to improve the situation. Regulatory authorities are recommending effective
mechanisms and have introduced the Schedule Y. DCGI has revised adoption of Good
Clinical Practices (GCP) guidelines, removal of import duty on clinical trial samples,
elimination of restrictions on concurrent trials and anticipated patent law changes.

The Drug and Controller General of India (DCGI) planning to put in place inspection
systems to track the progress of drug trials from beginning to end and a new set of rules
"to emphasize incorporating good clinical-practices protocols". Indian Government is also
planning to introduce draft guidelines on ethical and patient safety issues in different fields
like stem cell research, genetically modified food, genetically modified drugs, biomedical
and behavioral research on HIV/AIDS, assisted reproductive techniques (ARTs), gene
therapy by DBT, policy statement fro genetics and genomics by DBT. Sponsors are now
looking at positive action by the insurance companies to cover the people working in
clinical trial projects and also to protect the interest of the patients.

The Central Government along with the World Health Organisation (WHO) has
undertaken a massive campaign to train regulatory personnel as well as private clinical
investigators of the subtleties of good clinical practices (GCP). Training involves regulatory
personnel to understand the intricacies of inspecting and auditing clinical trials as well as
educating the investigators involved and of complying to the benchmarks set by the
government. The workshops will also focus on standard operating procedures as well as the
role of investigators and ethics committees.

Regulatory bodies are gaining acceptance & visibility after sustained efforts from the
industry leaders. Pharmaceutical sponsors and Contract Research Organizations (CROs)
want the regulatory approval process to be more predictable, accountable and less
cumbersome. If the India has to leverage the clinical trials activity, its regulatory body
needs to be proactive in their set procedures and timelines, be accountable and transparent
for any delays in the approval process and reach the international/US regulatory
standards.

Outsourcing Clinical Trials to India

 ​ atasha Das
chillibreeze writer —N

Global clinical research is exploring India. Yet, it is certainly not the West that is introducing
clinical research to India. Two ancient scripts, Charaka Samhita (a textbook of medicine) and
Sushruta Samhita (a textbook of surgery), compiled as early as 200 B. C. and 200 A. D.
respectively, show India’s age-old proficiency in medical research.

However, a lot has changed in the clinical research scenario since then (​1)​ . Today, clinical trials
are conducted through a regulated approach following certain guidelines laid down by the
International Conference on Harmonization (ICH), which is spearheaded by U.S.A., Europe and
Japan.

The clinical research industry in India has been growing rapidly. During the last 3 years it has
increased from Rs. 20 crores to Rs. 100 crores. According to a recent McKinsey report, by the
year 2010 the industry is expected to grow up to Rs. 5,000 crores.

What makes India so special?

India has become the preferred destination for global clinical trials today. The unique criteria that
make India so attractive (​2-4​) are:

1. India has a huge population base of more than 1 billion (Indians represent about 15% of
the global population)
2. This population is genetically, culturally and socio-economically diverse
3. Asians have been seen to react differently to drugs as compared to their Caucasian
counterparts
4. India has the largest pool of patients (e.g. the highest number of cancer and diabetes
patients are found in India)
5. It is home to a wide variety of diseases ranging from tropical infections to degenerative
diseases
6. The patient population in India is mostly treatment naïve
7. Patient: doctor ratio is high
8. There is no dearth of professionals trained in the field of medicine
9. India has a large pool of highly qualified and dedicated scientists and clinical research
professionals
10. The country is renowned for it’s prowess in information technology
11. English is a primary language of education and communication among Indians

Are Indians being ‘USED’ for the benefit of the Western world?

The use of Indians ‘for the benefit of the Western world’ has extensively been criticized. Before
jumping into any ill-informed conclusions, it would be worthwhile to understand the benefits of
clinical research (​5​).
1 Patients /study subjects who participate in clinical trials

● Have access to the latest medication or treatment modalities

● Get free medical care, which includes costs of investigations and medicine
● Enter into the trial voluntarily after signing an informed consent
● Are not bound to continue to participate in the trial (The consent can be withdrawn at any
time)
● Receive more frequent and focused consultations leading to an improvement in the quality
of healthcare

2 Investigators /physicians who conduct clinical trials

● Get first hand experience with the most recent drugs

● Get global recognition working on the same platform as other international experts on the
project
● Get extensive training in the internationally accepted Good Clinical Practice (GCP) and
Good Laboratory Practice (GLP) guidelines
● Get an opportunity for publication
● Have access to the latest medicines for their patients

3 Sites / Hospitals where the research is conducted

● Get infrastructural development

● Get global recognition

So is India prepared for global clinical trials?

An article in ​Nature Medicine​ suggests that outsourcing clinical trials to India may be ‘rash and
risky’ (​6)​ . This conclusion is drawn on the basis of concerns about timelines for regulatory
approvals, deficiencies in the functioning of the ethics committees, and an unethical approach to
the recruitment of subjects in Indian clinical trials. What then is the actual scenario of clinical
trials in India?

Regulatory affairs in India

The Drugs Controller General of India (DCGI) is responsible for regulatory approvals of clinical
trials in India (​7​). The DCGI’s office depends on external experts and other government agencies
for advice. Additional permissions are required for the export of blood samples to foreign central
laboratories.

All this usually takes about 3 months in India. The US FDA gives an approval in an average of
30 days. However, most US trials are delayed because of the time taken for patient recruitment.
The potential for a fast patient recruitment in India may partly make up for the delay in
regulatory approvals.
Certain recent changes in regulatory affairs encourage clinical trials in India. In 2005, the
Schedule Y of the Drugs and Cosmetics Act was amended. Earlier, foreign drugs trials could be
conducted only at one phase below the highest phase of testing abroad. Now, parallel global
clinical trials are possible in India. Permission is granted for concomitant phase 2 and phase 3
trials.

The Institutional Ethics Committee (IEC) and its role

Though ethics is an important part of medical research, it is very often neglected. The Indian
Council of Medical Research (ICMR) guidelines for clinical trials insist on the setting up of
ethics committees at the institutional levels. The IEC’s responsibility is to scrutinize and approve
the clinical trial before the study begins and also to conduct periodic reviews of the progress of
the trial.

A survey by ICMR shows that there are ethics committees in only about 200 institutions. Most
research institutions in India, however, either do not have an IEC or there is inadequate
representation in it by persons other than those of the medical fraternity. Without a
representation of persons from a non-scientific background, the opinion of the IEC is likely to be
biased in favor of the study. The clinical research guidelines clearly specify the need for such
personnel.

Some IEC’s do not have a regular schedule of meetings, lack standard operatingprocedures
(SOPs) or do not have a proper member representation according to the guidelines.

However, things are changing for the better. The ICMR has a Central Ethics Committee on
Human Research (CECHR). This committee audits the functioning of these IECs. The recently
amended Schedule Y of Drugs and Cosmetic Rules orders the composition of the IEC as per the
ICMR guidelines. The DCGI’s office, in collaboration with WHO, ICMR and many committed
research professionals, has been conducting training programs for members of the Ethics
Committees across the country.

Ethical recruitment of participants

To protect the interests of the study participants, a written informed consent is usually required
before the recruitment. Low literacy levels and poverty in India when added to the pressure from
the sponsors for early completion of patient enrollment do at times lead to unethical recruitment.

An increase in the literacy and socioeconomic levels is expected to increase the awareness of
patients regarding the consent they give for clinical trial studies. The GCP guidelines stress the
need for the implementation and documentation of the informed consent process. A strict
adherence to the study protocol by the investigators and the study team members at the sites, as
emphasized by the GCP guidelines, will help protect the rights of the study participants.

GCP and GLP training

Certain uniform guidelines for GCP and GLP need to be followed while conducting clinical trials
and generating clinical trial data. This increases the credibility of Indian data and makes it
acceptable by global regulatory authorities. Out of the tens of thousands of doctors in India, only
a handful of around 400 to 500 are GCP trained and experienced in conducting clinical trials. A
major investment is required at the beginning of the trial to train medical professionals in the
basics of GCP.

Each year the number of GCP trained personnel is steadily increasing in India. Sponsors,
Contract Research Organizations (CROs) and Site Management Organizations (SMOs) are
making efforts to train more and more numbers of investigators and ethics committee members
on the principles and practice of GCP.

Effective monitoring of clinical trials

The DCGI gives the approval for conducting clinical trials in India. How is the trial being
conducted? Is anybody tampering with the data at any point? At present, there is no central
monitoring mechanism in place to answer these questions.

However, things are going to change from 2006. The DCGI is already training a group of people
to act as clinical trial monitors. Whenever permission for a clinical trial is granted by the DCGI’s
office, these study monitors will oversee them. Proposals for a central clinical trials registry in
India are also being considered.

At present monitoring of clinical trials is done by the representatives of the sponsors or the
CROs.

A bright future for clinical research in India

In spite of all the present pitfalls, the country is certainly gearing up to attract more and more
researchers from around the world to conduct their clinical trial studies in India. The regulatory
system is being polished. Laws are being amended to facilitate the entry of global clinical trials.
Massive and concerted efforts are on to train research professionals and increase the base of
investigators and supporting staff. These initiatives are certain to improve the current situation.
In brief, India is already off the starting blocks and gearing up for an inundation of clinical
research trials. This will ensure the timely conduct and completion of the clinical trials and at the
same time generate high quality data for international submission.

Reference:
1. Nundy S. and Gulhati CM. A New Colonialism? — Conducting Clinical Trials in India.
NEJM​. April 21, 2005. No. 16, Volume 352: 1633-1636.
2. Sinha G. Outsourcing drug work: pharmaceuticals ship R&D and clinical trials to India.
Scientific American Online,​ August 16, 2004.
(http://www.sciam.com/article.cfm?articleID=00033282-DBF5-10F9-975883414B7F0000
) Last Assessed December 21, 2005.
3. Lamberti MJ, Space S, Gammbrill S. Going global. ​Appl Clin Trials​ 2004; 13:84-92.
4. Borfitz D. Lifting India's barriers to clinical trials. ​Center Watch​ 2003; 10(8): 1-9.
5. Anaokar S. Clinical Research in India. www.pharmabiz.com
6. Jayaraman KS. Outsourcing clinical trials to India rash and risky, critics warn. ​Nat Med
2004; 10:440.
7. Bhatt A. Clinical trials in India: Pangs of globalization. ​Indian J Pharmacol ​2004;
36:207-208