Clinical trials are an essential part of
advancing medical science.
HOW do
you know that the drug you are ingesting, being injected with or applying to
your body is safe?
After
all, we call both aspirin and cocaine drugs. But obviously, one is medicinal in
nature (and legal), while the other is not.
A
further difference would be that medicinal drugs – especially those discovered
in the past couple of centuries – would have most likely undergone clinical
trials to establish their safety and efficacy.
According
to the World Health Organization, 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”.
As
Universiti Malaya (UM) Faculty of Medicine senior lecturer Dr Muhammad Muhsin
Ahmad Zahari explains: “Usually, clinical trials are a reference to
pharmacological trials.
“But
medical research is very wide; clinical trials can be about investigating
prevention, diagnostics or treatment for patients.”
This
can include methods like surgical or radiological procedures, blood tests, and
behavioural modification, among others.
As the
cost of discovering and testing these new substances or procedures can run up
to billions of (US) dollars, clinical trials are usually financed by
pharmaceutical companies.
Other
bodies such as government agencies, academic institutions, non-governmental
organisations, and even, private individuals, also do provide grants for
clinical trial research, especially in developed nations.
However,
the limited number of such grants make them highly competitive to obtain, and
are likely to be insufficient to cover the entire cost of the study.
Clinical trial phases
The
clinical trial aspect of medical research is actually the third stage out of
four for drug development. (See Drug development)
Explains
Dr Muhsin: “When we talk about clinical trials, it has to be backed by
(scientific) literature to suggest that this is the best way (to treat the
disease), or show that it can do more good, or less harm, than the current
method.”
Interventional
cardiologist Dr Rajesh P. Shah says: “It’s usually a pharmaceutical company
with a particular molecule that they have tested out at the pre-clinical
stage.”
Pharmaceutical
companies usually have a “library” of unique molecules that have different
properties, which may lend themselves to treating or diagnosing various
diseases.
Based
on the initial research results, scientists will then further explore the
safety, efficacy and bioavailability (the proportion of the molecule that
actually reaches the targeted cells in the body) of the molecule via laboratory
and animal studies.
Only
when the drug has been established as safe and effective in animals does the
research move onto human subjects, ie the clinical trial stage.
“Clinical
trials can be divided into four phases: I, II, III and IV,” explains Dr Muhsin.
“In
phase I, a few healthy people will be carefully selected to receive the
product, to determine how safe it is to be used in humans. So, it is a very
meticulous process.
“Sometimes,
for phase I patients, they need to stay in the hospital for up to five days,
and we monitor all their vital functions and do regular blood tests on them.”
Once
the safety of the product, including the safe dosage range and side effects,
has been established, then the research can move on to phase II of the clinical
trials.
According
to Dr Muhsin, this second phase delves deeper into the effectiveness and
mechanics of how the product actually works and reacts in human beings.
The
number of participants involved in this phase are increased, and consist of
patients with the condition the new product is meant to affect.
Phase
III is the stage where the numbers are increased to thousands of patients, and
the study is frequently expanded to multiple medical centres across several
countries.
In this
phase, the new product is compared to either the current standard treatments or
tests, or a placebo.
The
results are then analysed statistically, and have to show a statistically
significant difference in outcome in order to prove the new product’s
superiority over what it was compared against.
Phase
IV is when the product has already been rolled out and is available on the
market. This phase is also known as the post-marketing phase, says Dr Muhsin.
Among
the areas monitored in this phase are any common side effects of the product,
as well as its interaction with other drugs or products for patients on
multiple medications.
Regulations and ethics
Because
of the potential danger in introducing a new chemical substance or mechanical
device into humans, clinical trials must undergo stringent regulatory and
ethical approval procedures.
Pharmaceutical
company MSD’s Southeast Asia Global Clinical Trial Operations director and lead
Dr Nazrin Azli explains that there are two big regulatory agencies in the
world: the US Food and Drug Administration (FDA) and the European Medicines
Agency.
“Before
we start any study, we usually consult them first, because every regulatory
authority in the world will follow them,” he says.
In
Malaysia, all clinical trials involving humans that are conducted at Health
Ministry hospitals or clinics, have to have their applications approved by the
ministry’s Medical Research and Ethics Committee (MREC). These applications
have to be submitted via the online National Medical Research Register (NMRR).
Clinical
trials conducted at places like university hospitals and private hospitals also
have to be reviewed and approved by each institution’s or hospital’s ethics
committee.
So, for
example, any clinical trials Dr Muhsin wishes to run, have to first be reviewed
by the UM Medical Centre Medical Ethics Committee.
These
ethics committees are responsible for ensuring that the clinical trials are run
in accordance to the Malaysian Guidelines for Good Clinical Practice, and
usually comprise of both physicians and laymen.
Researchers
are also ethically governed by the Declaration of Helsinki, which is “a
statement of ethical principles for medical research involving human subjects,
including research on identifiable human material and data” developed by the
World Medical Association, and the Nuremberg Code, a set of medical research
principles that grew out of the World War II Nazi experimentation on Jews and
other minorities, among others.
There
are, however, no specific legal provisions governing the conduct of clinical
trials in Malaysia.
While
the National Pharmaceu-tical Control Bureau (NPCB) is the sole regulatory body
overseeing clinical trials in Malaysia, they draw their authority from the laws
that regulate the sale and control of drugs alone.
Doctors and patients
Most of
the clinical trials conducted in Malaysia are phase III trials, which are
nowadays run as international multi-centre trials.
Physicians
with an established reputation and track record are usually approached by the
pharmaceutical company organising the trial to help run it in their respective
medical institutions.
Says Dr
Muhsin, who has been involved in several psychiatry-related clinical trials at
UM Medical Centre: “They will appoint a principal investigator (PI), who leads
the research at that particular place.
“We
also have co-investigators, research assistants (RA), and clinical research
associates (CRA), who help run the trial.”
However,
as Dr Shah, who practices at a private hospital in Penang, shares, the scenario
in the private sector can be quite different.
“I am
the only doctor seeing the patients. I do everything, including filling out all
the paperwork,” he says.
While
public hospitals have a large pool of patients to select from for a clinical
trial, the choices in private practice are definitely less.
In
addition, Dr Shah shares: “People say, ‘I’m coming to a private hospital; I’m
paying so much money, and you want me to be part of a trial?’
“I’ve
had so many rejections because of this.”
But he
always explains to his patients that the drug has passed the “guinea pig” stage
by this phase of the study, and that this is an opportunity to contribute to
the body of knowledge that can benefit patients like themselves worldwide.
“As I
see patients daily, I will check them against the inclusion criteria of the
trial.
“After
I select the patient, I will tell them about the trial, try to convince them to
participate in it, and give them some literature on it.
“After
one week, they come back with lots of questions, which I will answer, and tell
them everything they want to know. There’s no hiding of anything.
“It is
very important that they go through the whole informed consent process. I tell
them that they can opt out at any time, but that I hope that they won’t,” he
explains. (See Questions to ask)
Following
the patient’s agreement, there is usually a short period of about two weeks,
where the patients are given the new drug, and monitored closely to see if they
can tolerate it.
If all
goes well, then the patients are subsequently randomly selected (by a software
programme) to receive either the placebo or current standard treatment, or the
new drug.
As most
studies are double-blind, this means that not even the doctor knows which
patient is receiving which treatment, in order to eliminate any bias in the
trial.
Dr Muhsin
says that he usually informs suitable patients that there is an optional
treatment available under study, which, while they are not obliged to take it,
will benefit the rest of mankind, if they do.
He adds
that clinical trials also offer an option for treatment for patients who have
exhausted all conventional therapies.
At the
end of the day, Dr Shah shares that he always shows his patients the published
results of the clinical trial they participated in, and reminds them of their
contribution – no matter how small – to it.
“They
are usually very happy to feel that they are a part of medical advancement, and
some of them even ask me if there are any more trials to participate in,” he
says.
TAN
SHIOW CHIN
The
Star
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