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Vol. XXXVII
No. 36 September 08, |
Parliamentary Committee Indicts Clinical Trial Industry
Amit Sengupta
THE Seventy-Second
Report of the
Parliamentary Standing Committee on Health marks a strong
indictment of the way
in which clinical trials are being conducted in India. Before
discussing the
report, it is important to understand the underlying reasons for
the present
state of affairs.
OPEN INVITATION FOR
FOREIGN COMPANIES TO
CONDUCT CLINICAL TRIALS IN INDIA
The story dates back
to 2005 when the
Indian government revised a very crucial section of the Drugs
and Cosmetics
Act, which governs the use of medicines, vaccines and other
products that are
used to improve human health. The amendments in 2005 pertained
to the section
on clinical trials, ie, research done to prove that a product is
safe and
effective. All medical products, before being allowed to be
marketed, need to
pass through different phases of clinical trials.
The 2005 amendments
made it easier
for drug companies to do research that involved Indian
participants. The
governments rationale for easing conditions under which
research could be done
by foreign companies were that it would bring in foreign
investment (the
abiding mantra of neo-liberal policies!), that it would help
Indian science by
drawing more research activities into the country, and it would
help Indian
patients by promoting early introduction of new drugs. Within a
year, the
number of clinical trials being conducted jumped to over 500 per
year , from
less than 100 per year in the pre-2005 era. What followed was a
virtual free
for all unscrupulous trial sponsors and contract research
organisations
(CROs) milked the system and patients suffered. The regulatory
systems did not
have the capacity to deal with the sudden rise in the number of
trials. The
resulting confusion could well have been
termed a comedy of errors, except for the fact that the
consequences were
tragic, and in several instances, fatal.
SHIFT OF CLINICAL TRIAL LOCATIONS
TO DEVELOPING COUNTRIES
Traditionally the
United States has
been the major centre for conducting clinical trials. A vast
majority of
clinical trials used to be conducted in the United States and
Western Europe.
While even today a majority of trials are conducted in these two
regions, the
situation has started changing quite rapidly in recent years.
Given that most
pharmaceutical companies that develop new medical products are
based in the US
and Western Europe, it was logical that trials to validate these
products would
be conducted in these regions.
The shift of clinical
trials to other
countries has been driven by several factors. One major factor
that has
contributed to the globalisation of clinical trials is the rise
of contract
research organisations and the accompanying outsourcing of
clinical trials.
Unlike a few decades earlier, drug companies often prefer not to
directly
conduct trials but outsource them to CROs. The CRO industry has
grown
phenomenally its turnover grew from $1 billion in 1995, to $7
billion in
2005, and to an estimated $21.4 billion in 2010. CROs prefer
non-traditional
sites to conduct clinical trials because they are cheaper in
countries such as
India as compared to the developed world. What is left unsaid is
that the cost
of human lives is also cheaper. Most European countries have
regulations that
mandate compulsory insurance for human trial subjects that
includes no fault
liability ie, insurance coverage that covers the possibility
that the
research may result in adverse effects on subjects even if the
trials were
properly designed and executed. In India, we are just starting
to discuss the
issue of compensation for trial subjects who suffer adverse
effects. Also left
unsaid is that CROs prefer countries such as India because
regulatory capacity
is weak and laws and rules are yet not commensurate with
requirements. There is
clear evidence that trials are moving to places outside the US
and Western
Europe. This is clear from data from the European Medicines
Agency (EMA)
regarding number of trial participants involved in Phase III
trials (the largest
final phase of trials before regulatory approval) for which data
was submitted
for regulatory approval of different drugs in the EU. In 2005,
79.8% of trial
subjects lived in the EU or the US, but by 2011 this had
declined to 62.7%. The
largest increase was in Asia from 2.0% to 12.8%.
EXPLOITING THE VULNERABILITY
OF POOR PATIENTS
There is another very
important
reason why it is easy to enroll volunteers for clinical trials
in a country
like India. Theoretically all trial participants are volunteers,
and choose to
participate after they are clearly explained about the risks
involved. It is
important to recognise that all trials are experiments, and
hence carry a
theoretical risk. That is why there is a huge premium put on the
informed
consent process of clinical trials. In countries such as India
the entire
process of procuring informed consent from trial participants
has been
converted into a sham in a very large number of cases. First, a
bulk of trial
participants are drawn from underprivileged sections, many of
who do not have
the capacity to understand the consequences of participating in
a clinical
trial. Second, and perhaps most importantly, trial subjects are
vulnerable
because they are at the mercy of a non-functioning health
system. They are
vulnerable to pressure from their treating physicians who
could also be the
investigator in a clinical trial because participation in a
trial can often
be the only way in which a poor patient is able to afford
treatment for a
chronic or life threatening conditions. CROs exploit the
vulnerability of
patients to recruit trial patients and the tag of a volunteer
means very
little.
We discussed earlier
that it was
believed that by changing the regulatory norms in favour of less
restrictions
on clinical trials by foreign companies, Indian patients and
Indian science
will benefit. Neither has happened. Indian patients rarely
benefit as trials
conducted by foreign companies are used to generate data that
allows them to
get marketing approval in their home countries. These drugs are
patented and
sold in the global market at exorbitant prices, well out of the
reach of
virtually all Indian patients, and definitely not available to
poor patients
who form the bulk of trial participants in India. Nor has Indian
science
benefited. CROs today recruit both patients to participate in
trials and
doctors or scientists who conduct the trials. The latter are not
involved in
designing the trial, or in using the data to further their own
research. The
data generated flows back to the parent company and Indian
scientists are used
as mere conduits to generate and transmit data.
The horror story of
the Indian
clinical trial industry has now started unfolding and the
evidence has been so
compelling that the Supreme Court, in early 2013, stepped in to
put severe
restrictions on approvals to clinical trials. The Supreme Court,
in an interim
order that responded to a Public Interest Litigation (PIL) by
Swashya Adhikar
Manch and others, directed that the Drug Controller General of
India (DCGI)
would have to consult the health industry before allowing any
clinical trial in
the country. There are extensive reports of ethical violations
and of
multiplying severe adverse effects involving trial subjects.
THE GORY HISTORY
OF CLINICAL TRIALS
The gross and
repeated rights violation of trial subjects in India are grim
reminder that
when private capital stands to benefit, and when public scrutiny
is muted,
rights violations are the norm rather than an aberration. The
history of trials
on human subjects, has in the past, thrown up several such
instances. Two of
the worst instances of such violation
relate to the Auschwitz trials in Nazi Germany and decades of
violations of
human rights among the prison population and among people of
African origin in
the United States, who were coerced into participating in
clinical trials.
A
particularly horrendous tale in the US (among several others)
unfolded with
revelations in 1972 surrounding the Tuskegee Study of Untreated Syphilis in the Negro Male,
which was begun in
the 1930s and lasted 40 years. In it, several hundred mostly
illiterate men
with syphilis in rural Alabama were left untreated, even after a
cure was
discovered, so that researchers could study the disease.
In the late
1970s, other horror stories emerged. In 1979, the Philadelphia
Inquirer
reported that inmates in Holmesburg (Philadelphia Detention
centre) had been
used as guinea pigs to test whether mind-altering drugs were
useful as Army
weapons. In 1981, the paper reported that inmates had been dosed
with dioxin to
test the herbicide’s effects on human health. The centre was
later to gain
further notoriety as it became known that for twenty years,
tests involving
toothpaste, deodorant, shampoo, skin creams, detergents, liquid
diets, eye
drops, foot powders and hair dye were conducted on the prison
inmates, all
accompanied by constant biopsies and frequently painful
procedures. Finally in
1978, public opinion forced Congress to adopt legislation that
severely
restricted the use of prison populations for clinical trials. It
has been
conjectured that the move of clinical trials to developing
countries found its
early impetus in this change in the US law.
THE HPV TRIAL
IN INDIA
The story of the HPV
trials in India,
sponsored by a US based NGO called Program for Appropriate
Technology in Health
(PATH), appears to be a throwback to the dark ages of the
Auschwitz, Tuskegee
and Holmesburg trials. Instead of concentration camp, jail
inmates, or African
Americans, here the trial subjects were thousands of young
pre-adolescent
girls, many of them living in hostels, in rural areas of Andhra
Pradesh and Gujarat. PATH was given
approval for a trial that they
called a demonstration project. PATHs so called
demonstration project was
funded by the Bill and Melinda Gates Foundation and the
vaccines were provided
free of cost by the two giant vaccine manufacturers Merck
and Glaxo Smith
Kline (GSK). The trial involved vaccinating girls with a
vaccine that would
protect them against the Human Papilloma Virus (HPV). It is
believed that
infection by the HPV virus predisposes to the development of
cancer of cervix
(the last portion of the uterus). While only a fraction of
patients infected by
the HPV virus develop cervical cancer, almost all cervical
cancer patients are
found to harbour the virus. The two vaccines developed by GSK
(Cervarix) and
Merck (Gardasil), are available in many countries (including
the United States
where it has been extensively used since 2006) and is also
approved for
marketing in India. However the issue we pick up here is not
the efficacy and
safety of the vaccine (regarding which there are several
questions, which we
are not elaborating here) but of the way in which the trial
was designed and
executed.
There were
gross ethical
violations in which trial participants were recruited. In Andhra
Pradesh,
consent was not taken either from the girls or from their
parents or guardians.
Hostel wardens signed up to give consent for hundreds of girls
in their charge.
The district health systems were in no position to monitor the
health of the
trial subjects or to follow up on possible adverse effects. The
story broke
when four deaths were reported among trial subjects in Khammam.
Till this day
the cause of death and its possible link with the vaccine has
not been
established or disproved for the simple reason that there were
no systems in
place to follow up trial participants.
When the
issue was raised
by several health and womens organisations and was also raised
in parliament,
the ministry of health and family welfare promised to conduct an
enquiry. The
enquiry report agreed with the contention that there had been
several
violations of rights and of regulatory procedures, but remained
silent as
regards apportioning of blame and recommendation of punishment
for those
involved in allowing and in conducting such a trial.
PATH tried
to hide behind
its façade of being a non-commercial NGO and a self proclaimed
philanthropy. It
repeatedly tried to obfuscate the issue by claiming that it had
conducted a
demonstration project and not a clinical trial, and hence
rules governing
clinical trials did not apply to their project. This is a
blatant lie as
clearly any experiment conducted on human subjects (especially
one where a
medical product was administered), irrespective of the
nomenclature, is a
clinical trial. The DCGI provided approval for the trail when
the trail design
was flawed as it did not have proper protocols in place to
record informed
consent, or systems in place to effectively monitor the
vaccinated children.
The ICMR, the apex body in the country that develops guidelines
on clinical
trial ethics, was complicit participant and collaborator. In
fact the
Project Advisory Group (PAG), set
up for the project, included representatives from ICMR, PATH,
AIIMS,
governments of Gujarat and Andhra Pradesh, and the World Health
Organisation
(WHO).
SCATHING
CRITICISM OF THE
INDIAN
REGULATORY SYSTEM
Given
this context, the recent report of the Parliamentary Standing
Committee on
Health, comes as a timely corrective. The report has been
scathing in its
criticism of all those who were involved PATH, DCGI, ICMR, and
the inquiry
committee. In its report the Standing Committee has remarked: It is apparent the PATH has
exploited with
impunity the loopholes in our system as also the absence of a
nodal point or a
single window for maintaining a data bank of foreign entities
entering the
Country for setting up their offices. It further goes
on to say: Coming to the
instant case, it is
established that PATH by carrying out the clinical trials for
HPV vaccines in
Andhra Pradesh and Gujarat under the pretext of
observation/demonstration
project has violated all laws and regulations laid down for
clinical trials by
the Government. While doing so, its sole aim has been to
promote the commercial
interests of HPV vaccine manufacturers who would have reaped
windfall profits
had PATH been successful in getting the HPV vaccine included
in the UIP of the
Country. This is a serious breach of trust by any entity as
the project
involved life and safety of girl children and adolescents who
were mostly
unaware of the implications of vaccination. The violation is
also a serious
breach of medical ethics. This act of PATH is a clear cut
violation of the
human rights of these girl children and adolescents. It also
deems it an
established case of child abuse. The Committee, therefore,
recommends action by
the Government against PATH. The Committee also desires that
the National Human
Rights Commission and National Commission for Protection of
Children Rights may
take up this matter from the point of view of the violation of
human rights and
child abuse.
It is hoped that the government and concerned agencies
will act on the
parliamentary committee report expeditiously. At stake is not
just the
immediate case of the HPV trials but the entire perversity that
now permeates
the clinical trials industry in the country. Clinical trials are
necessary if
safe and effective medicines are to be developed. But by
allowing the
conversion of the clinical trials industry into the worst kind
of profit making
enterprise, we are doing gross disservice to both experimental
science and
health care.
