Shashank R Joshi*, SM Sapatnekar**
“The Physician … must have two special objects in view with regard to
disease, namely, to do good or to do no harm(Primum Non Nocere) “1 … Hippocrates
Are we not too familiar with
this quote by the Father of
Modern Medicine? But then, familiarity does breed contempt. Or else, practicing
clinicians would have paid heed to this basic principle medical practice. Then
Drug Related Problems (DRP) would not have resulted in 8.1 million hospital
admissions in USA in 1992.1
Johnson and Bootman’s decision-analytic model shows three types of incorrect or
inappropriate attention by physicians; viz., Adverse drug reactions, Drug
interactions, Drug use without indication. Even this oft quoted study of 1995
has not made the medical profession any wiser or practise their art more
responsibly. Overall, the cost of drug- related morbidity and mortality
exceeded $ 177.4 billion in 2000. Hospital admissions accounted for nearly 70%.2 This pandemic is ascribed
to unnecessary prescribing, imprecise diagnosis, the uncritical application of
evidence-based medicine, the outstanding development of new drugs and their
unjustified promotion.3
The last aspect is particularly worrying. While the procedures for Drug Trials
– often referred to as Clinical Research have evolved, been standardized and
carry statutory obligations can one say that the Drug is safe? The license to
market a new drug by Food & Drug Authority gives a legal authority to the
manufacturer. Alas, it also gives a false sense of security to the Medical
Profession. What ought to be remembered is that we are playing with laws of
probability and taking calculated risks while permitting a new drug to be
marketed. Even with all protocols, procedures and laws, we do not know if the
new compound is safe for humans. At best it is “not unsafe” and
may be tested further with
extreme caution.
Phase 1 trials
try to determine dosing, identify acute side effects in about 20-80 healthy
volunteers. Phase 2 trials include about 100-300 volunteers to seek preliminary
evidence of the drug’s efficacy. If the benefits and risks are considered
acceptable, the drug moves to Phase 3, where 1000 to 3000 subjects are enrolled
in the study, testing the product’s effectiveness, monitors side effects, and
compares the product’s effects to a standard treatment. As more and more
participants are tested over longer periods
*Endocrinologist, Joshi
Clinic, Lilavati and Bhatia Hospital, Mumbai, India. **Director and Dean,
Clinical Research Education & Management Academy, Mumbai 400 059.
of time, the less common
side effects are more likely to be revealed.5 This goes to show that a marketed drug has taken care to ensure that
the common side effects to this new drug are not serious. But then, the
corollary is that we are not aware about the rare side effects of this new drug
and we do not know if these are occurring, how often and are these going
unreported. The only way to find out such occurrences is to be on active
lookout for adverse events over a long tome horizon in large population and in
different host conditions with regard to ethnicity, age, gender, and
physiological state. We know that each one can alter the response to a drug.
Year
|
Drug
|
Toxicity
|
Remarks
|
1950
|
Chroramphenicol
|
Aplastic anemia
|
Still its use
|
continued
|
|||
1961
|
Thalidomide
|
Phocomelia
|
National disaster
|
1970
|
Clioquinol
|
SMON
|
After 30 years of
|
use
|
|||
1970
|
Diethylstilbestrol
|
Adenocarcinoma
|
In utero
|
of the cervix and
|
exposure.
|
||
vagina
|
Manifestation
|
||
after 20 years
|
|||
1975
|
Practolol
|
Oculo-mucocutan-
|
5 years after
|
eous syndrome
|
marketing
|
||
1976
|
Zomepirac
|
Anaphylaxis
|
|
(NSAID)
|
|||
1980
|
Ticrynafen
|
Deaths from liver
|
|
disease
|
|||
2004
|
Vioxx
|
Sudden cardiac
|
5 years after
|
deaths
|
suspecting
|
Based partly on Pharmacoloepidemiology by Brian L. Strom
The need for
conscious vigilance was perceived as early as late 1960’s. The World Health
Organization offered guidelines for International Drug Monitoring6 defining the role of
National Centre in 1972. Previously new drugs used to be introduced in the
Indian market several years after they were launched in other countries. The
regulatory bodies in India approved drugs based on the data generated in the
countries where these products were earlier approved and marketed. India’s
regulatory agencies and drug companies based their safety assessments on Data
derived from long-term drug use in US, European and Japanese markets. India did
not have a formal Pharmacovigilance system in the past to detect adverse
reactions of marketed drugs as very few new drugs were discovered in India.
It was on
November 23, 2004, The Central Drugs Standard Control Organization (CDSCO) of
Govt. of India launched
© JAPI • VOL. 56 • DECEMBER 2008 LearnLync 933
a
formal National Pharmacovigilance Program7 (NPP) that became functional from January 1, 2005, with a nationwide
network with 25 peripheral centers, 5 regional centers, and 2 zonal centers was
established, in a hierarchical fashion, with predefined tasks and
responsibilities allocated at each level. The National Pharmacovigilance
Program at CDSCO aims to: (1) monitor the adverse drug reactions of medicines
to identify unexpected adverse drug reactions.
(2) review Periodic Safety
Update Reports (PSURs) submitted by pharmaceutical companies for all new
chemicals drugs for 4 years. (3) maintain contacts with international
regulatory bodies. (4) assess the regulatory information relating to safety.
& (5) provide information to end-users through adverse drug reaction news
bulletins, drug alerts and seminars.8
Thus, the
Physician has most important role to play in Pharmacovigilance. Not merely
because he is the first person to whom the patient will come with symptoms; but
also to suspect an ADR. By their training the Physicians have the abilities to
suspect and detect; they need to augment this by inculcation of intuitive
skills. A drug rash or nausea is always at the front of our mind as ADR; but
not the tinnitus or neutropenia. The diagnosis in such cases is invariably
missed or is at advanced stage of complications. Quite often the diagnosis is
in hindsight. This does not help the patient. Merely the history of years of
use of a drug in millions of patients with an established drug also is not a
guarantee of its safety. Chloramphenicol continued to be prescribed in spite of
knowing that it might cause Aplastic anemia in 1950 till an effective
alternative was available in the 1980’s. The physicians therefore ought not to have
a false sense of security with license issued by FDA or by traditional large
scale use of a drug. WHO (1972) offered its definition of ADR as ”A response
which is noxious and unintended and which occurs at doses normally used in
humans for the prophylaxis, diagnosis or therapy of disease, or for the
modification of physiological function”. Such a reaction may lead to an Adverse
Event that is defined as “Any untoward medical occurrence that may present
during treatment with a pharmaceutical product but which does not necessarily
have a causal relationship with this treatment.” Rawlins and Thompson
classification is easy in routine clinical practice. Therein the following
types are described. Type A (augmented) two subclasses; viz., Exaggerated
Desired Effect or an Undesired Effect. Type B (bizarre) adverse event are
called pharmacologically unexpected, unpredictable, or idiosyncratic adverse
reactions; with two subclasses; viz., Immunologic or Idiosyncratic. There are
many other classifications that have higher level of clarity and complexity.
One such classification is by JK Aronson and RE Ferner.9
Several
attempts of pharmacovigilance are now done by various regional centers and we
encourage physicians to manually or e-report ADRs. We encourage physicians to
share ADRS though not only medical journals but also through the national
centers of pharmacovigilance. In this issue of JAPI Ramchandran et al report
the first Indian
case of
Exenatide pancreatitis.10
The GLP – 1 analogue like Exenatide are incretins which have novel new axis of
pharmacointervention for diabesity. This pancreatic ADR is a new ADR of which
little is known. We have postulated a cholinergic hyperstimulation pancreatitis
as a mechanism. Seven deaths due to hemorrhagic pancreatitis have been reported
in the US recently. A direct cause effect relationship with the drug and
pancreatitis has not yet been established but we need to be vigilant and use
the drug with care and caution. Rimonabant a novel weight loss compound was
recently suspended in the EU and failed US FDA though is available in India due
to serious Neuropyschiatric ADRs including suicidal ideation. More than 2.5
billion US$ have been spent on the CB-1 pathway which is now closed globally.
There
is an element of inevitability in occurrences of Adverse Drug Reactions (ADRs);
particularly for new drugs. The sponsor has invested millions of dollars in
drug discovery and development. There is the urge to market the drug as soon as
the permission to do so is obtained. Any report of ADR is construed as a speed
breaker and is likely to be neglected. There may be conscious efforts to
neglect what is suspected or there might be an innocent omission to value a
danger signal. In either case, it is the life and welfare of human beings at stake,
and the primary responsibility of a physician is to safeguard these. The
physician therefore has a role to play in terms of constant vigilance in mind
and due diligence in practice. He will suspect uncommon and detect the rare. He
will report ADR and deport dangerous drugs. He will do this not for any award;
but for the reward of making the world safer for humankind to live and thrive.
REFERENCES
1. Hippocrates; Epidemics;
http://ancienthistory.about.com
2. Johnson JA, Bootman JL.
Drug-related morbidity and mortality. A cost-of-illness mode. Arch Intern Med
1995;155:1949-56.
3. Frank R Ernst. J Am Pharm Assoc
2001;41(2):192-199,
4. Hugh McGavock; Journal of
Evaluation in Clinical Practice; Volume 10 Issue 4, Pages 491 - 497
5. Carol Rados. Inside Clinical
Trials; Testing Medical Products in People; FDA Consumer magazine; Sept.-Oct.
2003 Issue
6. WHO Technical Report Series No.498.
7. Pharmacovigilance Official
website www.pharmaco vigilance.co.in/ home.html
8. CDSCO official website http://cdsco.nic.in/
9. Aronson JK, Ferner RE; Joining the DoTS: new
approach to classifying
adverse drug reactions; BMJ 2003; 327: 1222 -
1225.
10. Tripathy NR, Basha S, Jain
R, Shetty S , Ramachandran A. Exenatide and Acute Pancreatitis. J Assoc
Physician India 2008;56:987-8.
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