E-DRUG: Unethical drug trials in India
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The following article has appeared in the Indian
Journal of Medical Ethics, January-February 2004
issue:
Needed: Closer Scrutiny of Clinical Trials
How many people know that eight patients in Hyderabad
administered recombinant streptokinase to test its
efficacy and safety have died? According to the
Genetic Engineering Approval Committee (GEAC) the
trial was being conducted by the drug�s manufacturer
Shantha Biotechnics without its clearance. Not
surprisingly, the Company denies the allegation
claiming that it had taken permission from the Drugs
Controller General, India (DCGI). In this game of
passing the buck, no one is shedding any tears on the
lives lost or compensating the families of those whose
loved ones have died. Without any independent enquiry,
the death of �trial subjects�, as they are
impersonally called, has been attributed to �causes
other than the use� of the drug!
Not long ago Dharmesh Vasava, a 22-year-old healthy
�volunteer� from Bharuch in Gujarat had died while
participating in tests on citalopram, an
anti-psychotic drug sponsored by Mumbai-based Sun
Pharmaceuticals. According to another participant of
the same trial, the subjects were lured with money by
agents working for the Company. Needless to say such
exploitative inducements are both unethical and
illegal.
More recently, over 400 unsuspecting young women have
been used as guinea pigs by self-styled researchers to
test if an anti-cancer drug Letrozole can help
ovulation. The trials have been conducted illegally
without permission from the DCGI predominantly at
private clinics not recognized as research centres. At
least one �investigator� with just a diploma in
gynaecology could hardly claim to be qualified or
competent enough to try untested drugs. Strangely
enough, based on documents submitted by the innovator
of the drug Novartis, both the USFDA and the British
Authority (MHRA) have labeled Letrozole as
embryotoxic, fetotoxic and teratogenic at miniscule
doses! The results of the apparently sponsored trials
were extensively used by a Mumbai-based company to
illegally promote Letrozole for ovulation induction.
It may sound incredible but animals subjected to
experiments in the United States enjoy more protection
than humans in India. Any trial done on animals
without authority of the Ethics Committee is fined Rs.
120,000 (US$ 2,500) under Animal Welfare Act. In
India, more than 400 young women have been treated
worse than animals in America.
Such unethical and illegal trials are conducted
without any fear because regulatory authorities,
either by design or default, fail to take action. A
couple of years ago, new chemical entities called M4N
and G4N discovered in the United States were
unlawfully tested on 26 oral cancer patients at the
Regional Cancer Centre (RCC) at Thiruvananthapuram.
Under unrelenting pressure from the media and NGOs, an
unwilling Government was literally dragged to take
action. Instead of penalizing the guilty, further
research on M4N and G4N was merely suspended for six
months! In such cases, the law provides for three
months imprisonment for the guilty.
Legally all clinical trials require DCGI permission
and approval by the concerned Hospitals� Ethics
Committees. Research can only be conducted at
recognized centres by duly qualified and experienced
investigators. In practice DCGI approves clinical
trials the same way as ration cards are issued by food
inspectors. Some examples:
 As per rules, trials of foreign drugs are
permitted in India at one step below the Phase
completed abroad. Yet DCGI approved Phase III trial of
Pfizer�s Zoniporide even when Phase II trials had not
been completed in USA. Furthermore carcinogenic and
reproductive studies on animals mandated by Indian law
had not been completed.
 Cilansetron, a new molecule of Solvay
Pharmaceuticals not approved anywhere in the world was
cleared for Phase III trials even though only Phase II
trials had been conducted abroad.
 Cilostazol, a product of Otsuka, was cleared
by DCGI based on incomplete, inadequate information on
adverse effects. Common serious side effects such as
angina and myocardial infarction were not even
mentioned. Needless to say such omissions can be
life-threatening in study subjects.
 The protocol of the drug Tacrolimus submitted
by Panacea Biotec and cleared by DCGI was not only
vague but deficient and defective beyond imagination.
It did not even state the Phase of the trial, an
elementary requirement, and omitted all important
serious adverse effects such as malignancies,
cardiomyopathy, lymphoproliferative disorders etc.
It appears that some protocols and accompanying
documents such as Investigator�s Brochures are not
even read by DCGI. Otherwise how does one explain
approval of patently defective clinical trials? This
perception is strengthened by the super speed with
which some proposals are cleared: a voluminous
protocol on trastuzumab sponsored by Roche was
approved within 5 working days. It is humanly not
possible to read and analyze the bulky documents in
such short period.
Most of the clinical trials in India are conducted
without any arrangement for compensation in case of
study-related injury, disability or even death in
human subjects. ICMR Guidelines specifically require
that each research �shall include in-built mechanism
for compensation for the human subjects�to cover all
foreseeable and unforeseeable risks.� Despite this
clear requirement, DCGI routinely approves trials
where no such undertaking is given by the sponsors.
The investigators for clinical trials, particularly
when drugs are to be tested, are chosen by sponsoring
companies. All manufacturers want that their products
should be found to be safe and effective. There cannot
be a better way to ensure positive results than to
select friendly, obliging and ever willing
investigators to do the bidding.
Many investigators that conduct clinical trials are,
or have been, beneficiaries of largesse from the
pharmaceutical manufacturers. The financial ties
include paid speaking engagements, equity of the
sponsoring companies, expensive gifts such as cars,
refrigerators, air conditioners, medical equipment,
attendance at sponsored scientific conferences, paid
consultancy work, authoring �ghostwritten� scientific
articles and travel grants for domestic and foreign
travel. Last year a Mumbai-based company marketing
erythropoietin had obliged some 300 senior most
nephrologists to visit Singapore on an expense paid
jamboree, an effective strategy not only to garner
more prescriptions but ensure positive results of
future clinical trials. Neither the regulatory
authorities nor the Ethics Committees seek conflict of
interest information from investigators.
Another important area concerns the right to publish
the results of trials. For obvious reasons no sponsor
would like to publicize unfavourable results. With few
exceptions, most protocols bind the investigators to
seek prior permission before publishing the trial
results. This practice needs to be curbed. The rules
on clinical trials should be amended to insert a
clause to make �Freedom to Publish� an essential
criteria for approving trials. World�s top medical
journal editors have already decided that trials which
restrict investigators freedom to publish will not be
accepted.
It is often argued that India should not be left
behind in what is grandiosely described as
�cutting-edge technology� of drug development. If at
all India is to become a big player, it will have to
actually discover or synthesize new drugs. Testing
them in humans hardly involves any advanced
technology. There are preset procedures that can be
found in any good book on human trials. No wonder
American companies have found doctors in Vietnam as
competent as those in India in this field.
Unless laws are honestly implemented by regulatory
authorities, the current unsupervised, unethical and
often illegal clinical trials will pave the way for
similar trials in gene therapy that will leave many
Indians diseased, deformed and even dead.
The way things are going on, the regulators officially
designated as public servants are in imminent danger
of becoming servants of the industry. WHO calls this
phenomenon as �Regulatory Capture� i.e. the authority
is seized by the very interests it is supposed to
regulate.
Dr. Chandra M. Gulhati
India
e-mail: seeemgee@yahoo.co.uk
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