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Clinical research in India: Great expectations?

Thatte UM, Bavdekar SB1

Departments of Clinical ABSTRACT

Pharmacology and
India is considered as a preferred site for conducting global clinical trials. Existence of a large treatment-naïve
1
Pediatrics, Seth GS Medical
College and KEM Hospital, population, availability of English-speaking, skilled doctors, plenty of clinical material, and cost-savings are
Mumbai - 400 012, India obvious advantages for carrying out clinical research in India. However, challenges exist at various levels.
Lack of formal training in bioethics and research methodology, heavy burden of clinical duties and sub-optimal
Correspondence: administrative support restrict investigators. Absence of oversight of functioning of ethics committees (ECs) and
Dr. Urmila M Thatte lack of mechanisms for ensuring quality of ethics review heighten societal concerns about safety of participants.
E-mail:
urmilathatte@rediffmail.com
Conducting research on issues not relevant to local needs and failure to ensure post-trial access further enhance
society’s cynicism. These issues need to be tackled through capacity building, training of investigators and EC
members, strengthening of EC functioning and encouraging greater community participation.

Received : 16-05-08
Review completed : 27-07-08
Accepted : 04-09-08
PubMed ID : 18953154
J Postgrad Med 2008;54:318-23 KEY WORDS: Clinical trial, research ethics, bioethics

T he search for new medicines is as old as mankind.

As newer disorders are described and novel targets for
old diseases get discovered, this pursuit only becomes more
intense. Clinical trials involving human participants constitute
an essential step in the drug development process and India
has attracted its fair share of attention; with both good[1,2] and
bad[3-5] reports in this regard. All the stakeholders [including
sponsors, regulatory agencies, investigators, ethics committees
(ECs), research participants and society at large] can potentially
benefit from the ethical and scientific conduct of clinical trials
in India. Participants could benefit from getting an effective
therapy; investigators can upgrade their skills and infrastructure,
while the sponsor or Clinical Research Organizations (CROs)
would save costs. More importantly, as the safety and efficacy
data from the Indian pool becomes a part of the global database
on a new drug, future generations of Indian patients can profit
from this knowledge. Conducting clinical trials is also a business
opportunity for India. It has been projected that over the next
few years, up to 65% of FDA-regulated clinical trials will be
conducted outside the US[6] and, that India and China would
be the most attractive locations for this.[2] It is estimated that
the clinical trial market would generate business worth over US
$1.5-2 billion.[7]
India is an attractive site for clinical trials for various reasons
summarized in Table 1.[1,4,7-12] However, a review of available
information suggests that India accounts for just 0.1% of the
R and D budget of the US pharmaceutical industry.[7] Also, the
Indian sites account for only a miniscule proportion of global
clinical trials: of the 57811 trials registered at clinicaltrials.gov,
only 749 (1.2%) are being conducted in India, compared to
33604 (59%) in the US, 987(1.7%) in Japan and 879 (1.5%) in
China.[13] To realize the full potential for clinical trials in India,
sites would need to enroll as many as 0.2 million subjects in
4000 trials conducted over 10000 centers! Are we really ready
and capable to face this deluge? This communication seeks to
identify societal concerns and the challenges that investigators
and ECs face and suggest steps that could help address some
of these concerns.
Investigators
The investigator is responsible for ensuring proper and ethical
conduct of the clinical trial at the study site.[14] The various
challenges that investigators may face include [Table 2]:
Infrastructure and staff: Adequate infrastructure including space,
communication and data management equipment, archiving
facilities, biological sample or investigator product storage
facilities, uninterrupted electricity supply etc. are necessary
for appropriate conduct of clinical trials. This is probably the
easiest challenge to address as sponsors can set up facilities at
newer sites– and identification of new investigators outside of
the usual metropolitan sites is an attractive proposition. Another
problem that investigators face is the high turnover of junior
staff necessitating conduct of repeated training programs for the

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Table 1: Reasons for India being an attractive site for
conducting clinical trials[1,4,7-12]
• Sizeable population of treatment-naïve patients
• Significant number of English-speaking highly skilled and trained
physicians
• Presence of well-equipped and state-of-the-art healthcare institutions
across the country
• Large hospitals with considerable patient load with facilities for
undertaking trials
• Good communication networks and information technology capabilities
• Availability of certified/ accredited central laboratories
• High enrollment rates
• Good patient compliance/ retention
• Cost-savings
• Availability of infrastructure to manage other tasks involved in clinical
trials: data entry, data management, analysis and report writing.
• Improved regulatory environment [Notification of amended Schedule
Y, publication of revised national guidelines for biomedical research,
changes in rules doing away with “phase lag” in clinical trials and
introduction of a new patent regime in pharmaceuticals respecting
product patents (instead of just process patents)]
• Negative perceptions associated in the minds of potential participants
and stringent regulatory requirements in developed countries pushing
clinical research to developing countries
new recruits. This also has an adverse impact on efficiency.
The myth of numbers: Although India is said to have a large
number of doctors, it is in fact, facing a shortage of doctors in
terms of its huge population.[15,16] Due to a poor doctor-patient
ratio (especially in the public health sector), clinicians need to
spend a large proportion of their time in performing clinical
duties and providing patient care. In addition, the burden of
educational and administrative tasks leaves very little time
for clinical research. Hard-pressed clinicians shy away from
research, and if they do take it up, paucity of time tends to
compromise the quality. The latter manifests itself in terms of
frequent protocol violations, non-adherence to ethical standards
or less than optimal documentation. On the other hand, there
are times when fears are expressed that participating as an
investigator could compromise patient care duties, teaching
assignments or administrative responsibilities. As the number
of trained and experienced investigators with the right attitudes
and requisite skills is very limited, the same physician is often
flooded with clinical trials. This can bring in conflicts of interest
and relegation of responsibilities to junior untrained staff again
compromising quality.
Knowledge, skills and attitude: India can boast of highly trained
and experienced physicians in the fields of oncology, cardiology,
neurology and gastroenterology where a large part of new drug
development activity is focused. Unfortunately, these numbers
do not necessarily translate into having a large pool of trained
investigators. Apart from being experts in the chosen field,
investigators need to have special knowledge about basic
principles of clinical research, protocol designing, ethical and
regulatory requirements, Good Clinical Practices (GCP) and
drug development before they can be considered eligible to
conduct clinical trials.
Lack of formal training in research methodology and bioethics
J Postgrad Med October 2008 Vol 54 Issue 4
Thatte and Bavdekar: Clinical research in India !
during graduate and postgraduate courses is a definite handicap
for the investigators. In a survey carried out in two Swiss
teaching hospitals, a majority of investigators conceded their
inability to carry out research-related activities.[17] The situation
is unlikely to be better in India. From the point of patient safety,
lack of training in pharmacovigilance could compromise the
investigators abilities to detect, assess, understand and report
adverse events during a clinical trial. Physicians also need
to develop skills related to counseling prospective research
participants. All this has become even more pertinent since
India is being increasingly considered for early drug development
studies e.g. Phase-1 (35 trials at clinicaltrials.gov) and Phase-2
(179 at clinicaltrials.gov) trials.[13]
Investigators also need to have the right attitude to clinical
research that inherently embraces ethical principles underlying
clinical research. The characteristics of a “good investigator” are
integrity, enthusiasm and experience!
Practices: Managing variability in standard of care amongst
various Indian sites is a great challenge in itself. The difference
between the public and private healthcare facilities in terms
of scale of operations, patient characteristics, facilities and
infrastructure available, access to medicines and practices
followed is vast and this could have a telling effect on the
generalizability of results. Poor documentation practices are
a bane of many health facilities. Source notes are often not
maintained up to the required standard and sometimes there are
no source documents at all. Lack of systematically maintained
patient databases also tends to slow recruitment rates.
Administrative support: Beleaguered as they are by the paucity of
human and financial resources, patient care and not research, is a
priority for many healthcare institutions. In hospitals attached to
medical colleges, medical and para-medical teaching activities
take precedence over research and therefore administrative
support is not very forthcoming. Thus, institutions hardly
ever develop written policies on administrative, medico-legal
and financial issues related to clinical trials leading to ad
hocism and inconsistency in decision-making. Fewer training
opportunities for researchers and lack of establishment of
functional institutional ECs further illustrate the inadequacy
of administrative support. Many existing ECs have been
reported to function below par not adhering to national
guidelines.[18] Investigators, meets are organized with a view to
train investigators and team members, to discuss center-specific
issues and ensure uniformity in the conduct of the trial across
centers. However, due to suspicions of an unethical nexus
amongst the pharmaceutical industry, CROs and investigators,
investigators are often discouraged from attending these
meetings, which in fact, could compromise research quality.
Private sector: The private sector plays an important role in
providing healthcare, especially in the urban setting and private
practitioners are showing greater interest in conducting clinical
research. Although many large corporate hospitals have adequate
administrative backup, including institutional ECs, the smaller
players in nursing homes and private clinics typically lack this
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! Thatte and Bavdekar: Clinical research in India
type of support. The questions related to existence of medico-
legal support, awareness of the staff regarding responsibilities
of clinical research, availability of facilities and skills to manage
serious adverse events and infrastructure for archiving are yet to
be answered. Access to appropriate ethical oversight is a major
challenge in this scenario.
Other issues: Indian investigators are rarely a part of the team
consulted for writing a protocol. This further alienates them
from the excitement of research and there is no sense of
“ownership” of the research conducted.
While conducting a clinical trial, an investigator has to assume
the dual roles of “investigator” and “healthcare provider”.
This leads to confusion in the minds of several investigators,
which in turn can lead to “therapeutic misconception”. Many
investigators undertake trials with the aim of providing their
patients with free treatment. This runs contrary to the basic
tenets of clinical research, as some of the patients are likely
to receive a new drug whose efficacy and safety are yet to be
proved.
Ideally, clinicians should agree to become investigators to
“discover something new or validate something that is known”,
thereby contributing to generalizable knowledge. Financial
benefits and peer recognition are also factors that motivate
them. As sponsors scramble to meet recruitment targets, they
tend to implement the “payment for performance” strategy.
This could lead to compromising ethical requirements while
undertaking hasty recruitment of subjects and could result in
poor quality research.
Ethical Oversight
Oversight of a clinical trial by an appropriate Independent
Review Board or EC is mandatory for clinical research.[9,10]
These committees are responsible for safeguarding the rights
and wellbeing of research participants by reviewing and
approving the study protocol, performing periodic review of
safety data and progress of the study and also monitoring the
conduct of the study. However, ECs face daunting challenges
such as, reluctance of individuals to serve on these committees,
infrequent meetings, heavy workload, inadequate space and
lack of administrative support. These constraints not only lead
to delays in approvals but also force most of the ECs to restrict
their activities to initial appraisal and approval of study protocol
and documents, review of reported serious adverse events and
examination of the periodic and final report submitted by the
investigators. Hardly ever does any EC undertake in-depth
monitoring of studies or scrutinizes the process of obtaining
consent.
In the absence of any formal training in bioethics, most members
undertake mere scientific review of research proposals. They are
not well informed about issues related to reduced autonomy,
increased vulnerability, distributive justice, use of placebo,
obtaining and documenting consent, management of and
compensation for study-related injury.[19,20] This compromises
the quality of ethical review of proposal.
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Lack of active participation by the non-medical members in the
discussions at the meetings, common practice of appointment
of institutional head as the Chairman compromising its
independence, absence of written standard operating procedures
(SOPs) and poor archiving and record keeping are some of the
other areas of concern related to the functioning of the ECs.
Schedule Y has understandably specified that the legal expert
and lay person have to be present to fulfill the quorum. This
makes arrangements of meetings a daunting task with these
members achieving “prima donna” status [Table 3]!
Societal Concerns
Relevance: When individuals participate in clinical trials, they do
so in the hope that they would benefit from the treatment but
also expect that their participation would result in improving
healthcare in general. Implicit in this hope is the expectation
that the community or the society that they come from
would also derive some benefit. Analysis of trials registered
at clinicaltrials.gov that are being conducted at Indian sites
indicate that studies related to diabetes (113), psychiatric
disorders (77), cardiology (91) and oncology (48) far outnumber
those in other fields.[13] This list is obviously not in tune with
the country’s list of major health problems such as tuberculosis,
malaria, kala azar, diarrheal and acute respiratory diseases. Use
of Indian participants for finding solutions to problems of
the western world could be labeled as “neo-colonization” and
Table 2: Challenges for investigators
Infrastructure and staff:
Inadequate infrastructure
High turnover of junior staff
The myth of numbers:
Poor doctor-patient ratio: less time for research, compromise in
quality or patient care duties, teaching assignments or administrative
responsibilities.
Multiple trials with experienced investigators: conflicts of interest and
relegation of responsibilities.
Knowledge, skills and attitude:
Poor knowledge in GCP and drug development process
Lack of formal training in research methodology and bioethics
Lack of training in pharmacovigilance
Reduced opportunities for development of skills required in the conduct
of clinical trials: counseling research participants, documentation,
reporting SAE
Need to have integrity, enthusiasm and experience
Practices:
Variability in standard of care
Poor documentation practices
Lack of systematically maintained patient databases
Administrative Support:
Research not a priority: Lack of encouragement for conducting research
Absence of written policies: ad hocism and inconsistency in decision-
making
Poor support for establishment of functional Ethics Committees
Private Sector:
Poor administrative backup
Inadequate infrastructure and skills to manage serious adverse events
Poor access to appropriate ethical oversight
Other Issues:
Non-participation in protocol writing
Dual roles of “investigator” and “healthcare provider”: Therapeutic
misconception”
Conflicts of interest due to “payment for performance” strategy
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exploitation.[3]
Post-trial access: Many drugs are developed using research
participants from developing countries including India.
However, if the drug is marketed (and it may never be), it is
often not within the reach of most Indians. This approach,
where the risks are borne by individuals without benefits for
the society, amounts to exploitation. This issue of post-trial
access is not only the responsibility of the sponsor but also of
the government. Medicines that are being evaluated in the
Indian population must be made available to the population
at an affordable price.[21]
Loss of voluntariness and autonomy: When patients from the
economically challenged sections of society are invited to
participate in trials, the question of whether they have any real
choice in consenting often arises. It is known that 75% of the
total out-of-pocket health expenditure is spent on drugs in India,
and therefore it is not surprising an individual may be forced to
participate in a trial overlooking the risks involved and ignoring
the fact that he/she may be receiving an ineffective treatment
which is under trial (or even a placebo).[22] Such examples are
the “rule rather than exception” and are examples of “reduced
voluntariness” or “loss of autonomy”.
Other issues: Another issue that impacts society is the lack
of translation of research activity to tangible human benefit.
High costs, slow results, lack of funding, regulatory burdens,
fragmented infrastructure, incompatible databases, and a
shortage of qualified investigators and willing participants are
the major road-blocks identified that impair translation of
research into useful medicines for society.[23]
It is pertinent to ask whether the Indian community is prepared
for clinical trials.[19] This is particularly highlighted in vulnerable
populations like women with human immunodeficiency
virus (HIV) infection. Creating awareness among potential
Table 3: Major ethical and societal concerns
A) Issues related to ethical oversight
Reluctance of individuals to serve on Ethics Committees
Inadequate initial and continuing formal training in bioethics
Infrequent meetings
Lack of participation by non-medical personnel in discussions at the
meetings
Heavy workload
Infrastructural shortcomings
Inadequate administrative support
No standard operating procedures (SOPs)
Poor record keeping and archiving
Lack of accreditation procedure and quality control measures
Potential compromise of independence
B) Societal Concerns
Relevance: Trials in areas not focused on health priorities of the
community
Lack of post-trial access; Important for participants with chronic
diseases, more relevant in poor patients
Loss of voluntariness and autonomy
Other Issues
Lack of translation of research activity into tangible human benefit
Lack of participation of the community in clinical trials
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Thatte and Bavdekar: Clinical research in India !
participants about the disease and the possible therapies being
offered is a challenge that needs to be addressed to improve
recruitment. Further, individual participation can be maximized
when the community understands the need of specific research
studies.[19]
Possible Answers and Solutions
What is the way forward if India has to remain the preferred
location for conducting clinical trials and at the same time
ensure that the research done conforms to the highest
standards of quality and ethics? These are summarized in
Table 4.
Capacity building: This is one of the most important strategies
for overcoming many of the challenges enumerated above.
EC members, investigators and regulators need to undergo
training in bioethics, research methodology and regulatory
requirements.[24] It is heartening to note that Central Drug
Standard Control Organization (CDSCO) has recognized
this need and has organized workshops for training in
GCP.[25]The Indian Council of Medical Research (ICMR)
has also held workshops for training EC members as well
as undergraduate and postgraduate medical and science
students.[26] These efforts should be continued to improve the
skill sets amongst researchers and EC members till a critical
mass of trained personnel is created in various institutions
across the country.
The Forum for Ethics Review Committees of India (FERCI)
has been established with promotion of capacity building of
EC members as one of its primary mandates. It can make its
valuable contribution by complementing the efforts of CDSCO
and ICMR in this regard.
Expanding investigator site base is the key to be able to meet the
real demand. A search of the clinicaltrials.gov website revealed
that metropolitan cities like Mumbai, Delhi, Bangalore, Chennai
and Hyderabad account for the majority of sites conducting
trials in India.[13] Other cities like Ahmedabad, Lucknow, Jaipur
and Ludhiana appear to be used but their full potential is yet to
be tapped. Mysore, Cochin, Manipal, Nagpur and Kolkata are
examples of cities with good medical infrastructure and patient
population. These sites must be strengthened to be able to
take advantage of the demand that has been created for more
clinical trial centers.
Table 4: Recommendations
• Capacity building of all stakeholders
• Expansion of research site base
• Accreditation of investigator sites
• Mandatory GCP training for prospective investigators and EC
members
• Improvements in functioning of the ECs
• Regulatory inspections
• Dynamic modifications of National Guidelines
• Awareness creation programs for building confidence of the community
and enhancing meaningful participation
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! Thatte and Bavdekar: Clinical research in India
Accreditation of investigator sites: Another possible step to
improve the quality of investigator sites would be to have a
system for accreditation of investigator sites– where training,
infrastructure, human resources and ethical conduct could
form part of the accreditation process. This would also be an
incentive for the investigator sites in the more remote areas of
the country to participate in the clinical trial process.
Mandatory training: Investigators wishing to participate in a
clinical trial could be mandated to undergo GCP training by
regulatory authorities and institutional ECs. The GCP training
could be imparted through an online course, which would be
easy to administer and would be less expensive.
Private sector: Private healthcare sector plays an important role in
the delivery of healthcare to Indian masses. If properly informed
and trained, there is no reason why private practitioners cannot
make their contribution to research.
Improvement in functioning of ECs: Mandatory training of EC
members, formulation and functioning according to SOPs,
improved documentation and archival practices are some of the
recommended changes to the working of ECs. A mechanism
needs to be developed that would enable ECs to share their
views on controversial issues related to clinical trials. This
would aid in capacity building, learning through dialogue
and communication, and would discourage “EC shopping”.
The FERCI could play an important role in developing this
mechanism. For many smaller institutions that take up clinical
trials infrequently, it is neither feasible nor cost-effective to
set up institutional ECs. They get their protocols approved by
independent ECs. These independent ECs are autonomous
and there is no organization that supervises or oversees their
functioning. There is a need to have a mechanism which would
assure sponsors and society at large regarding adherence to
guidelines, quality of ethical review and monitoring of clinical
trials. ICMR and FERCI could provide such an assurance
through a process of registration, accreditation and periodic
inspections of ECs.
Other measures: Adherence to national and international
guidelines is of utmost importance and this needs to be enforced
through regulatory inspection of sites, CROs and sponsors as
well as ECs. Implementation of the law with greater clarity about
liability and punishments would also protect participants in a
better way. National Guidelines should be amended to provide
greater clarity on issues such as compensation for study-related
injury, risk-benefit analysis while reviewing research protocols,
role of ECs in serious adverse events review process and role of
the Data Safety Monitoring Board.
Building confidence in the community is an important aspect
to be addressed and for this media have to be also educated.
The involvement of non-governmental organizations (NGOs)
in research from the outset can help the researchers gain
confidence of the community. A useful and effective approach
to increasing community participation is to set up a Community
Advisory Board (CAB) which is an independent panel of
representatives of stakeholders in community-based research.
! 322
For example, if the research involves intervention in HIV, it has
been suggested that members of the CAB could be drawn from
women’s organizations, sex workers, truckers, people living with
HIV, NGO representatives, grass-root level workers, lawyers, etc.,
all of whom are likely to be interested in the development of
the intervention.[19]
Conclusions
For obvious advantages, global players view India as a favored
destination for conducting clinical trials. The activity, in the
long run, has the potential to help our citizens, professionals and
society. However, our infrastructure and systems are not yet in
the optimal state to meet this challenge. Indian policy makers,
administrators and professionals should initiate positive steps
to ensure that this opportunity is exploited to its maximum
potential.
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