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Jan-Mar2004-12(1)
DISCUSSION
Are all new drugs 'healthy'?
Sujith J Chandy, Atiya R Faruqui
Sujith J Chandy, Atiya R Faruqui
The race for the launch of new drugs, brands and
combination drugs has resulted in nearly 50-80 new entries in the market in the
year 2002 alone. Is it 'healthy' to have such a flooding of the market with new
drugs? Do these new drugs really have benefits over their older congeners as
most of them claim to have? To answer these questions, we need to look at two
important aspects in the field of new drug marketing: safety and claims of
superiority.
Safety of new drugs
The health sector is faced with the issue of safety
of all new drugs. In the present system, before a new drug is introduced into
the market, it is mandatory to go through different stages of laboratory and
clinical trials. These are aimed at establishment of therapeutic efficacy as
well as the safety profile of the new drug. The various phases of the clinical
trial are (1):
Phase I trials test the drug on a sample of 25-50
healthy volunteers to establish its safety. Phase II trials test 50-300 patients
for the drug's therapeutic effect. In Phase III trials, between 250 and 1,000
patients participate in a randomized clinical trial comparing the drug with a
placebo to confirm the drug's efficacy. Phase IV 'trials' are post-marketing
surveillance of the drug's safety in the general population and can cover
between 2,000 and 10,000 people.
From these figures, one can see that the number of
people actually exposed to the drug in the first three phases are few (a maximum
of 1,350). If there are no serious adverse effects at this point, the drug is
approved for marketing.
Is a number of 1,350 enough to detect a rare
adverse effect? Let us examine this issue by looking at the following situation:
In a case where the adverse drug reaction to a particular drug has an incidence
of 1 in 1,000 (occurs in 1 patient out of 1,000 treated), we would need to
screen a minimum number of 3,600 patients for the confirmation of its absence
(2).
As 3,600 people are usually not involved in the
first three phases of a clinical trial, it is possible that a drug with a rare
but fatal adverse reaction could be used by the general population. The process
of monitoring for safety should thus continue. This monitoring is done in Phase
IV, termed as 'post-marketing surveillance'. The spectrum of adverse effects of
any drug range from the common (detected during these trials and documented), to
the rare (unidentified in early studies and yet important). It is these rare
side-effects, usually undocumented in trial settings, which may subsequently
have serious consequences for the population taking that drug. This makes the
post-marketing surveillance an even more important tool to get the entire
spectrum of the drug's activity.
It takes some time before such large numbers of
patients get treated and observed. Thus, we see a delay of many years before
such significant reactions are reported. The risk of 1 in 1,000 went undetected
for 3-7 years in the following instances: pulmonary embolism due to oral
contraceptives, halothane-induced jaundice, lincomycin-induced colitis
(2).
In many occasions, the incidence of a potentially
fatal adverse reaction may be smaller than this. This therefore means that it
may be even more difficult to detect them in the population and would need a
larger number of patients on the drug, and a more intensive surveillance
programme.
There are a few other issues to be highlighted
regarding post-marketing surveillance. The first issue, that of who conducts the
surveillance and who are the subjects, is an important one with respect to its
credibility. In most of the cases, these are conducted by pharmaceutical
companies, and therefore the issue of potential bias comes into play. The other
aspect is that the surveillance done in western countries for adverse effects is
often extrapolated to the Indian population. Considering the genetic differences
as well as diet and nutrition, the extrapolation of such reports may not give
the true picture in the Indian setting.
Claims of superiority
Post-marketing surveillance is not only about
reporting adverse effects. It is also done to see the performance of these drugs
as compared to the existing ones. Often, doctors are exposed to various claims
of pharmaceutical companies that their drug is 'superior' to existing drugs,
with the standard phrase being 'the initial results are very promising'. Hence,
it is essential to consider the factors affecting the feedback from the case
reports of patients receiving any new drug. One of the most important factors
emerges when post-marketing surveillance is subject to an effect called the
Weber Effect (3). This phenomenon, first described by Dr Peter Weber, denotes
the combined effects of rapid increase in the use of, and interest in, a new
drug, leading to a high rate of reporting. However, comparisons with older drugs
with stable reporting can be misleading. Therefore, both the general
over-reporting, for the new drug, combined with the Weber Effect, should be
considered when comparing new drugs with drugs already existing in the market.
A possible solution
In the Indian scenario, general practitioners, with
an outpatient base and limited facilities for adverse drug reaction (ADR)
monitoring tend to be among the first ones to use these 'latest' drugs. Even the
patients seem to prefer these 'new' drugs for their treatment without realising
the risk that they are putting themselves through.
The solution to most of the above problems
associated with the use of new drugs can be derived from the example of the
policies of the Japanese health ministry (4). In their set-up, the
pharmaceutical companies are required to provide their product to a limited
number of medical institutions for a period of three months following the launch
of a product and conduct focused post-marketing surveillance. After inspection
of the results of this surveillance, the companies are then allowed to expand
the number of medical institutions using the product. Requiring companies to
limit sales to a small number of medical institutions and collecting information
in this way makes it easier to respond to adverse drug reactions of newly
approved products. It needs to be examined whether this practice can be
transcribed to the Indian situation.
It is imperative that the drug control authorities
and other governmental agencies strengthen the post-marketing surveillance
programme in India. They need to look at ways of minimising risk to the
population due to rare adverse events when new drugs are introduced into the
market. Any doctor or hospital, when deciding on the use of a new drug, should
objectively compare it to the existing drugs. A balanced judgement needs to be
made without blindly following the tall claims of superiority made by drug
manufacturers.
In conclusion, an awareness of the importance of
post-marketing surveillance is the need of the hour, at all levels, whether it
be the government, the health professional or the patient. An official
surveillance programme needs to be initiated and subsequently evaluated. Till
then the question remains, 'Are all new drugs 'healthy'?'
References
1. Laurence DR and Bennet PN. Clinical
Pharmacology. 7th ed. Edinburg,UK: Churchill Livingstone, 1997:42.
2. Ferner RE, Hazards, risks and reality.
Br J Clin Pharmacol 1992;33:125-8.
3. WHO international drug monitoring:
cerivastatin and gemfibrozil. WHO Drug Information 2002;16:8-11.
4. Postmarketing system to be revised. WHO
Drug Information 1999;13:240.
SUJITH J CHANDY*, ATIYA R FARUQUI**,
*Reader and **MD student, Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore 632004, India. e-mail:clinpharm@cmcvellore.ac.in
*Reader and **MD student, Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore 632004, India. e-mail:clinpharm@cmcvellore.ac.in