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How ethical are clinical trials in India?
Globalization of international clinical trials creates new
questions regarding ethics in conduct of clinical trials
in human subjects and conducting research on
marginalized or oppressed populations writes P. Sree
Sudha.

Bishwajit Bhattacharyya
C.R.Dua
Diljeet Titus
Hemant Batra
John Callagy
K.K.Lahiri
K.S.Bagga
Lalit Bhasin
Dr. Linda S. Spedding
Martin Rogers
M.L.Sarin
Prof. V.S.Mani
Rajiv Atmaram
Rajiv K.Luthra
Rajiv Nayar

Editors
Gitanjali Saraf
Vikramaditya Rai
Sagar S.P. Singamsetty

Clinical trials form an integral part of the drug discovery process worldwide.
Clinical trials are the set of practices required to certify a new drug
molecule as safe and efficacious for the market. Medical research, in
general, is a good thing and absolutely necessary to cure number of chronic
diseases. At present in India we have 40 million asthmatic patients, about
34 million diabetic patients, 8-10 million people with HIV, 8 million epileptic
patients, 3 million cancer patients, more than 2 million cardiac-related
deaths, 1.5 million people with Alzheimer's disease; 15% of the population
is hypertensive, and 1% suffers from schizophrenia In order to give best
treatment to above diseases research on humans is both necessary and
desirable.
A clinical trial is defined as "any research study that prospectively assigns
human participants or groups of humans to one or more health-related
interventions to evaluate the effects on health outcomes." Interventions
include not only drugs but also cells and other biological products, surgical
procedures, radiological procedures, devices, behavioral treatments,
process-of-care changes, preventive care, etc. A set of guidelines are
already in place in India for the ethical conduct of studies to safeguard the
interests of patients or volunteers participating in the study.
Research subjects' have long been controversial, even after decades of
debate, experience, and Regulation. In this review, this paper aims at
discuss the International and National Laws on Clinical Trials, ethics in
clinical research, next it reviewed some current controversies on clinical
trials and concludes with a discussion we need more standards and
Legislations for future medical research on human subjects.
Clinical Trials Practice in India
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

Founder & Managing Editor

Vikrant Pachnanda

Associate Editors
Naina Pachnanda
Shashank Manish
Vishwam Jindal

Editorial Team

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. 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. There are number of laws
governing clinical research in India.

Indian Acts/Orders related to Clinical Trials is:

Drugs and Cosmetics Act - 1940

Medical Council of India Act - 1956, (amended in the year2002)

Central Council for Indian Medicine Act - 1970

Guidelines for Exchange of Biological Material (MOH order, 1997)

Right to Information Act - 2005,

The Biomedical Research on Human Subjects (regulation, control

and safeguards) Bill - 2005

Conference Corner
Internship Corner
Scholarship Corner

Even though we have number of legislations the important one for clinical
trials is The Indian Council of Medical Research (ICMR) - 1947(amended in
the year2002) , which was set up in order to foster a research culture in
India, improve and develop infrastructure and foster community support.
The Drugs and Cosmetics Act, The Medical Council of India (MCI) Act states
that all clinical trials in India should follow the ICMR guidelines of 2000. The
ICMR has a mechanism of review for its own institutions, and so do other
government agencies. Every doctor is governed by the MCI Act. Any doctor
doing wrong in a trial or in practice can be prosecuted and the hospital can
be closed. The MCI Act is very strong; the MCI has the power to take
punitive measures.
The Drugs Controller General of India (DCGI) is responsible for regulatory
approvals of clinical trials in India. 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.
The ICMR has a Central Ethics Committee on Human Research (CECHR).
This committee audits the functioning of this Institutional Ethics Committee
(IEC). The recently amended Schedule Y of Drugs and Cosmetic Rules order
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.
Regulatory changes in India regarding clinical trials:
Schedule Y of the Drugs and Cosmetics Act -1940 was amended in the year
2005. Earlier, we required that all foreign drugs be retested at one phase
below the highest phase of testing abroad. Now parallel global clinical trials
have come. Schedule Y now permits concomitant phase 2 and phase 3
trials. India can become part of global trials. But even then phase 1 has to
be repeated for safety. The advantage is that, if we become part of a global
trial, a part of a global movement to develop drugs, we can demand an
affordable price. For example if a new anti-malarial drug is developed by a

multinational company, India is part of the global trial; India can have a
claim on it. ICMR should not approve drugs which are not relevant to India.
India Advantage for clinical trials includes;

large numbers of people with a range of illnesses,

relatively low costs, availability of trained human power and

infrastructure,

high enrolment rates (higher than in the West),

good patient compliance/ retention, and

an "increasingly accommodating regulatory environment"

As stated earlier India have people with the right diseases. They're also
'treatment nave' - they will not have been able to afford treatment - so they
are ideal for testing new drugs. This situation made India as an international
hub for clinical trials. Using the loopholes in the law the multinational
companies are outsourcing clinical trials to India. A recent study reveals
that outsourcing clinical trials to India may be 'rash and risky'. This opinion
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 illiterate and vulnerable Indian people to
clinical trials. In order to control the above situation and make the clinical
trials transparent the ICMR is maintaining a clinical trial registry in India. It
is described in detail below:
Clinical Trial Registration in India
In order to make clinical data and reports available to all, an online clinical
registry has been initiated by the Indian Council of Medical Research (ICMR)
for the registration of any interventional trial to ensure the following goals:

Transparency and accountability of clinical research

Internal validity of clinical trials

To oversee the ethical conduct of clinical trials

Reporting of results of clinical trials

The clinical trial registry of India (CTRI) is the online registry of prospective
clinical trials in India. This is the initiative started by the National Institute of
Medical Statistics (NIMS) of the Indian Council of Medical Research and is
supported by the Department of Science and Technology (DST) and the
World Health Organization (WHO).
CTRI will create a database of prospective clinical trials in India after their
registration. The data and reports of these clinical trials and their status will
be available to the public and professionals free of cost after formal
registration on their website.

Currently, the registration of clinical trials is only voluntary and not

mandatory. With increased awareness about this initiative and wide
acceptance of the purpose of CT registration, it is likely that it may become
mandatory in the future for initiation of clinical trials in India. It has been
affirmed that CT registration should be done before the actual enrollment of
study subjects in the trial. The principal investigator or sponsor should
share the responsibility of CT registration. In the case of multi-centric
studies, the lead investigator or sponsor should ensure that the CT is
registered. For the registration of a CT, it is essential to declare 20 items
relevant to the CT as determined by the International Clinical Trial
Registration Platform (ICTRP) of the World Health Organization (ICRTP-WHO).
For registration with the CTRI, additional items related to the EC or IRB's
permission and that of Director Controller General of India (DCGI) are
included. At the end of a successful registration, each CT is assigned a
unique WHO identification number called the Unique Trial Reference
Number (UTRN).
Clinical Trials Practice in USA
In the United States, the clinical-trials procedure is an elaborate one,
conducted in a number of stages and contributing to the immense time, risk
and expense of the drug development process. First, there is pre-clinical
toxicological testing of a potential new drug molecule. This is usually
performed on animals, in order to determine whether the molecule being
tested is safe enough to put into a living system. The second stage is that of
dosage studies, designed to come up with a metric for the dose of the drug
to be administered.
Predictably, the efficacy of a drug increases with its dose, but so too does
its toxicity; the aim is therefore to find an optimum range within which
efficacy is maximized without too greatly compromising safety. If the drug is
too toxic when tried on animals, the trial will not proceed any further, but if
acceptable dose ranges can be determined, the third stage is a three-phase
trial in humans.
Phase 1 trials are conducted on a small number of healthy volunteers to
test the drug's basic safety, since drugs that seem safe in animals may still
show adverse effects in humans. Phase 2, which serve as a bridge, involve
larger, scaled-up efficacy and safety trials on as many as a few hundred
subjects, who may be either patients or healthy individuals. Phase 3
involves large-scale randomized trials on several thousand people, usually
patients suffering from the ailment for which the therapy has been
developed. These trials are frequently coordinated across multiple centres,
increasingly on a global scale. The sponsors for trials are generally
biotechnology or pharmaceutical companies, since drug development in the
US and most other parts of the world is undertaken largely by the private
sector. Universities and publicly funded laboratories play a major role in the
early stages of discovery-the identification of potential lead molecules and
the conduct of pre-clinical tests-but the institutional structure of drug
development is such that they increasingly license promising molecules to
corporations that take them through clinical trials.
This means that the biomedical and experimental rationales for clinical
trials are completely entwined with the market value these companies see
in the drugs that eventually get developed, and the market risk that attends
the drug development process. Because of complexity of Regulations in
USA, number of multinational companies is coming India to conduct clinical
trials on human subjects.

International Laws on Clinical Trials:

There are many international instruments that confer and safeguard the
rights of participants in clinical trials. Modern ethics in human research
mainly emerged after World War II, when Nazi physicians used prisoners for
inhumane 'experiments'. This resulted in the creation of the Nuremberg
Code in 1947, which clearly stated voluntary consent as an absolute
requirement for human subjects' research. As a result, it became almost
impossible to conduct any clinical research in mentally impaired and other
vulnerable groups.
In 1964, the Declaration of Helsinki - proposed by the World Medical
Association - changed some of the absolute rules of the Nuremberg code;
for example, it allowed the use of surrogate consent in the case of
individuals with impaired decision making. International Covenant on Civil
and Political Rights (ICCPR) - 1966 (particularly Article 7 as it relates to
consent for medical and scientific experiments) ; the Council for
International Organizations of Medical Sciences (CIOMS) international
ethical guidelines -1993 (since revised) ; and, the International Conference
on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use - Good Clinical Practice: Consolidated
Guidelines -1996. On a European level [EU], the EU has issued its directive
on good practice in clinical trials and the Council of Europe has issued a
Convention on Human Rights and Biomedicine on biomedical research. Most
recently, UNESCO has developed a Universal Declaration on Bioethics and
Human Rights.
The Nuremberg Code and the ICCPR do not seriously focusing on human
rights in clinical trials. Neither document recognizes the distinction between
therapeutic and non-therapeutic research. This fundamental deficiency is
that they have largely been ignored by the medical profession. According to
Article 1 of the Nuremberg Code and Article 7 of ICCPR (both addressing
consent) means consent would be necessary in all circumstances i.e. those
who become unconscious due to an accident or disease or those who are
mentally handicapped could not, if no standard treatment exists, be offered
new therapeutic measures that might restore their health or save their
lives.
Such a rigid interpretation would mean that the respective provisions
exclude many of those they were designed to protect. Furthermore, Article 7
of ICCPR is to be reads "No one shall be subjected to torture or to cruel,
inhuman or degrading treatment or punishment. In particular, no one shall
be subjected without his free consent to medical or scientific
experimentation."
The Article prohibits experiments that violate the integrity of the person by
cruel, undignified or inhuman treatment. Clinical research carried out in
accordance with general principles would not violate this provision. Yet the
right to health argument confounds this. Recently XVI International AIDS
Conference in Toronto, UNAIDS presented an ethical argument as to why
trial participants that seroconvert during a trial do not require access to
effective treatment. UNAIDS representatives considered these issues as
ethical and not obligatory legal issues.
However, CIOMS guidelines make some reference to the Declaration of
Helsinki and it is "the fundamental document in the field of ethics in
biomedical research." The recent version also enunciates the laudable goal
that "the research is responsive to the health needs and the priorities of the
population or community in which it is to be carried out; and any

intervention or product developed, or knowledge generated, will be made

reasonably available for the benefit of that population or
community." Nevertheless, as stated in the Declaration of Helsinki, human
rights issues are coming to be seen as within the proper domain of public
law and private law remedies such as negligence and the tort of trespass do
not constitute a potent deterrent for unscrupulous researchers operating in
under-developed countries where access to legal advice is scarce and/or
prohibitively expensive. But in reality a strong civil law is helping effected
people at the end of the trials.
Ethics in Clinical Research
Most basic and complex principle of clinical research ethics is informed
consent. An ethically valid informed consent has four key components:
disclosure, understanding, voluntariness, and competence. This creates
challenges for researchers in pediatrics, psychiatry, emergency and critical
care medicine. One can take surrogate consent or waived consent in the
following circumstances they are for example where a study of people at
risk for Alzheimer's disease, more than 90% thought that surrogate consent
was acceptable for minimal risk studies as well as randomized trials of new
medications. Whereas in case of intensive care and surgery patients their
consent is also informed consent, but in reality people are not aware of the
fact that they are in clinical trials. This is revealed in number of studies.
However, it is important to recognize that if surrogate consent were
eliminated, then it would virtually eliminate almost all critical care research
because many critically ill patients are incompetent or unable to make a
sound decision. Family members are frequently unavailable, may not know
the patient's wishes, or may not be specifically legally authorized to give
consent for the patient's involvement in research. Therefore, some have
questioned whether the concept of informed consent is even applicable to
research involving the critically ill.
For example in USA only certain emergency and resuscitation research can
be done without prospective informed consent. This is based on the 1996
US Food and Drug Administration (FDA) 'Final Rule' and the US Department
of Health and Human Services' parallel 'Waiver of Informed Consent'
regulations. These require community consultation, public notification, and
independent data and safety monitoring to allow exemption from informed
consent
These regulations further stipulate that they can only be applied to
emergency research for which human subjects can not give informed
consent because of their life-threatening conditions (for example,
unconsciousness); the condition requires immediate intervention; available
treatments are unproven or unsatisfactory; clinical equipoise exists; the
research might directly benefit the subject; the research intervention must
be administered before informed consent from the subjects' legally
authorized representative is feasible; and the responsible IRB concurs and
documents that these conditions had been met.
Other methods such as deferred consent, implied consent, or delayed
consent are no longer deemed acceptable, despite previous use in early
resuscitation research. However, in the 10 years since the release of the
Final Rule, investigators in the USA have reported variability in IRB
interpretation, and have called for standardization and refinement of the
rule. To address these concerns, as well as concerns from ethicists and
other stakeholders, the FDA recently announced a public hearing on
emergency research to be held on 11 October 2006. An updated FDA

guidance document is expected following this hearing that is intended to

assist IRBs, investigators, and sponsors in the development and conduct of
emergency research using exception from informed consent.
Informed Consent situations in India:
Experimental cancer drug tested without people's consent
In November 1999, 25 people with oral cancer who went to the
government-run Regional Cancer Centre in Thiruvananthapuram were given
an experimental drug, the chemical tetra-O-methyl nor-dihydro-guaiaretic
acid (M4N) or tetraglycinyl nor-dihydro-guaiaretic acid (G4N), though there
was an established treatment for their condition. They were not told that
they were taking part in an experiment or that they were being denied an
established treatment. Only later did it become known that the trial had not
been approved by the Drugs Controller of India (approval was obtained
retroactively). Further, the sponsor institution, the Johns Hopkins University
in the United States, had not given ethical clearance to the study, but
managed to release the money for research anyway.
Diabetes drug tested on humans before toxicology studies completed
In 2002, the multinational company Novo Nordisk conducted multi-centre
phase III clinical trials of a diabetes drug before receiving the results of
animal studies. The study report found that the drug, ragaglitazar, caused
urinary bladder tumors in rats -- and this should have been known before
the drug went for phase I trials, let alone phase II and phase III. Ragaglitazar
was developed by Dr Reddy's Laboratories, Hyderabad, and licensed to
Novo Nordisk which conducted the trials. The trials were conducted on 650
people from North America, 200 from Latin America, 100 from Australia /
New Zealand, 800 from the European Union, and 200 from non EU Europe-and 550 from Asia -- including 130 people from eight centers in India. Half
of these people received the experimental drug.
Drug promotion as "research"
In 2003, Mumbai-based Sun Pharmaceutical Industries Limited launched a
promotional-cum-"research" programme by getting private doctors to
prescribe the anti-cancer drug Letrozole to more than 400 women as a
fertility drug for ovulation induction. They then publicized the doctors'
reports to other doctors as "research", using their network of medical
representatives. As a result Off-label prescription of drugs was banned in
India, prompting the Indian Medical Association to launch a campaign to
permit off-label prescription.
Research in emergency situations
In 2003-2004 the drug company Santa Biotech ran a bioequivalence study
testing its version of the "clot-buster" streptokinase against the established
one. Streptokinase is given as emergency life-saving treatment to stroke
patients. While there were various controversies about whether the
company had taken the correct permissions to conduct the study, the
important questions are: could the patients have given their consent to
participate in the trial? After this In 2002, Dharmesh Vasava was among a
number of daily wage workers who were given a psychiatric drug as part of
a bioequivalence study sponsored by the Mumbai-based Sun
Pharmaceuticals. He developed pneumonia and died. The People's Union of
Civil Liberties, Vadodara, conducted an investigation into the death. PUCL
suggested that the participants were unlikely to have been able to give

their voluntary informed consent to participate. Second, was their health

checked properly before entering the trial, and monitored closely during it?
Incidentally, bioequivalence studies are conducted by drug exporters, to
prove that their product is as effective as the approved branded version.
They are not needed by Indian regulatory authorities.
These are the situations where the companies conduct clinical trails based
on informed consent. All these things are happening in these days where
media and communication are developed. Look at the situations in rural
areas where people suffers allot to get good food and shelter. Number of
multinationals is taking advantage of these situations for their business
purposes. Now it is the duty of ICMR to control unauthorized clinical trials in
India.
Conclusion:
As the medical research world becomes increasing globalized, there is a
need to make research both methodologically and culturally valid.
Conducting research on human subjects stretches the current norms of
medical ethics as well as stretching the current capabilities of international
law. To rely simply upon minimum standards of non-binding and vague
medical ethics instruments for conducting research on humans is both
nave and culturally insensitive.
Human lives are inherently complex and no single ethical framework,
including ours can claim to capture the complexity of research and
understand the ethical dilemmas that arise in these diverse settings. In
accordance with universal principals of justice, the "effective " participation
of oppressed populations in decision-making will be an instrumental step in
combating the social, economic and political forces of globalization that
constrain human capabilities. A law will not guarantee anything - look at
how the laws on transplants, on sex selection, are broken. But having a law
will help for those who are afraid of scrutiny, which are conscientious. The
group misusing the law will do so anyway. But with a law you can ask
questions, conduct an inquiry, and take action. To ensure that India
becomes a leading nation in Good Clinical Research, greater attention must
be paid to promoting clinical research.
The gap between the developed and developing worlds needs to be
narrowed in order to ensure global justice, particularly with respect to the
widespread availability of proven interventions in developing countries. The
emphasis is to ensure that Research ethics should be made an integral part
of all biomedical research. As such every stakeholder should consider
research participants as central players, who should be protected from any
harm for which an appropriate legislation should be in place to ensure the
above.

P. SREE SUDHA M.L., (Ph.D.,) is a Research Scholar, at Dr.B.R. Ambedkar College

of Law, Andhra University, Visakhapatnam, Andhra Pradesh, India.
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