“Survival of
the fittest” as coined by the British philosopher of the Victorian era,
Herbert Spencer, explains the evolutionary trend of life, which can also be
seen even in our man defined world of medicines. In order to treat a disease, several molecules are created after identifying the target. These discovered
molecules have to be tested before bringing it into the market for human use.
“Don't count
your chickens before they hatch” - These discovered molecules cannot be as
such prescribed to the needy without enough evidence that the molecules show enough efficacy in parallel with its safety. Hence, to prove this, the
molecules are made to go through a lengthy process of verification. This process
is termed as Clinical trials.
What led to the birth of stringent clinical trials?
To understand this we have to go back to early 1900s. Sulfanilamide, a drug
used to treat streptococcal infections (bacterial infections), had been shown
to have a promising curative effect in tablet and powder form. In 1937, there
was a demand for the drug in liquid form. On experimentation it was found to
dissolve in diethylene glycol, a solvent, which was lab tested for flavor,
appearance, and fragrance giving satisfactory results. Immediately,
the drug was compounded in liquid form using diethylene glycol without testing
for its toxicity. At that time the food and drugs law did not require safety studies to be done on new drugs. Selling toxic drugs was, undoubtedly, bad
for business and could damage a firm's reputation, but it was not illegal.
Because no pharmacological studies had been done on the new Sulfanilamide
preparation, one characteristic of the solution was left unnoticed. Diethylene
glycol, a chemical normally used as antifreeze, is a deadly poison. At least
100 deaths were blamed on the medication. This led to the passage of the 1938
Food, Drug, and Cosmetic Act, which increased FDA's authority to regulate
drugs.
Another example is the unforgettable Thalidomide
tragedy. Thalidomide first entered the German market in 1957 as an
over-the-counter remedy, the only non-barbiturate sedative known at the time,
gave the drug massive appeal. Sadly, tragedy followed its release, catalyzing
the beginnings of the rigorous drug approval and monitoring systems in place at
the United States Food and Drug Administration (FDA) today. The product was
advertised as “completely safe” for everyone, including mother and child, “even
during pregnancy,” as its developers “could not find a dose high enough to kill
a rat.” By 1960, thalidomide was marketed in 46 countries, with sales nearly
matching those of aspirin. Around this time, the drug was also found to be a
possible curative for morning sickness. In 1961, this so-called harmless
compound showed severe birth defects in the babies whose mothers took the drug
during pregnancy. The drug interfered with the babies' normal development,
causing many of them to be born with phocomelia, resulting in shortened,
absent, or flipper-like limbs. A German newspaper soon reported 161 babies were
adversely affected by thalidomide, leading the makers of the drug—who had
ignored reports of the birth defects associated with the it—to finally stop
distribution within Germany. Other countries followed suit and, by March of
1962, the drug was banned in most countries where it was previously sold.
Clinical trials can be defined as a set of medical research and drug development that generate safety and efficacy data (or more specifically, information about
adverse drug reactions and
adverse effects of other treatments) for health interventions (e.g., drugs,
diagnostics, devices, therapy protocols). These studies are conducted only
after sufficient satisfactory information has been gathered from the
nonclinical studies on safety and grant of approval from the health authority/ethics committee in the country
where approval of the drug or device is sought.
Clinical trials are of five types – prevention, screening,
diagnostic, treatment, and quality of life. Trials can also be comparative type
which has come up in recent times to prove the molecule as an alternative to an
already existing marketed molecule. These trials are initiated by the
sponsor(s) and he is the one who is answerable about the outcome of the trial
to the regulatory authorities. The sponsor has to select an experienced,
qualified investigator having the capability of recruiting the subjects and
site where the study can be conducted. For a given study, the number of sites
can range from one to many spreading across many countries and races.
The road-map to success for the trial which is the protocol
has to be prepared by the sponsor carefully taking care of the trial design. This
document gives information on the objective, methodology and statistical
analysis for the procedures used in the trail. In order to void bias, randomization,
blinding technique is used so that the values are not altered. Prior to the
start of the study, this prepared document, the protocol needs to have an
approval from the regulatory bodies.
The clinical trial of new drugs is commonly classified into
four phases. Each phase is treated as a separate study for its approval. The
patient population is directly proportional to the type of product and the
stage of its development – small scale, pilot (medium) and large scale. In
order to determine the therapeutic window (the effective safe and effective
drug range) of the molecule, phase one and phase two trials are conducted
separately (the later is conducted only after success of former). In the phase
one the safety the molecule is tested in healthy volunteers of population size
of less than 100. After gathering enough positive data the study is taken to
the next level of phase two where less than 500 subjects, both healthy and
diseased, are taken for determining the safety and efficacy respectively. Only
after the success of the phase two, phase three is conducted by increasing the
population size to about 10,000. Here, in this phase, the efficacy of the
molecule is studied closely keeping an eye on the side effects or the adverse events
of the molecule. Once the trial is said to have achieved its goal, NDA i.e New
Drug Application is sent to the regulatory bodies such as US FDA along with the
data that was obtained from the trial for obtaining the approval of marketing
the molecule.
The molecule is all set to enter the market. Post marketing
surveillance or phase four is carries out in order to keep a check on the
treatment’s benefits and risks and optimal use. This phase is mainly helps us
in understanding or discovering the long term side effects, if any seen.
In the struggle for success, initial molecules of around
10,000 get filtered to less than 250 in preclinical study, out of which less
than 5 molecules enter the clinical study. From a group of less than five, one
molecule could be given an approval by the health authorities for human usage.
Hence, in this scientific world of medicine, a drug with benefits clouding the risks is the one rewarded as the fittest!!!
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Written by
Vindhya Marpalli
vindhya.marpalli@clinzen.com
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