E-DRUG: India: Illegal approval to market letrozole for infertility
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The following editorial has appeared in MIMS (Monthly Index of
Medical Specialities, New Delhi) dated August 31, 2008.
Illegal Approval to Market Letrozole for Infertility in India
Letrozole, a research molecule of Novartis, is indicated for use in
cases of breast cancer in postmenopausal women all over the
world. Its use in women of child bearing age is strictly prohibited
because, based on animal studies, such a use can lead to (a)
estrogen deprivation, (b) ovarian atrophy, (c) uterine atrophy, (e)
increased incidence of foetal malformations, foetal resorption and
foetal death.
Permission to use letrozole for breast cancer in older women was
given in the United States, Britain and other countries after
reviewing the results of at least four very large double blind,
randomised, placebo-controlled clinical trials involving 14,105
female subjects.
Despite this mass of scientific evidence precluding its use in
pre-menopausal women, the Drugs Controller General, India
(DCGI) has approved the application by Sun Pharmaceuticals to
market letrozole to treat sub-fertility in young menstruating
women. This is the first time in the history of independent India
when a drug has been permitted for a disorder for which it is not
approved anywhere else in the world.
Permission has been granted in flagrant violation of Indian safety
laws. As per Drugs and Cosmetics Rules, even an old drug when
used for a new indication is deemed to be a "New drug" and must
undergo a series of safety and efficacy studies both in animals
and humans before its use in general public is allowed. These
tests are:
- If the drug is intended for use in young women of child bearing
age, Reproductive studies including Fertility studies,
Teratogenicity studies and Perinatal studies must be performed
in two female animals such as mouse, dog or rabbit. None of
these studies were performed by the applicant.
- The drug must also undergo Phase I clinical trial in about 10
healthy volunteers (pre-menopausal women over 18 years of
age) to determine the maximum tolerated dose and document
preliminary side effects. This legally mandatory study was not
done.
- Exploratory Phase II studies to determine the therapeutic use,
dose and safety of the drug are to be conducted in 10-12 patients
in each of 3 to 4 research hospitals. These studies were not
done.
None of the above studies were conducted by Novartis or any
other company anywhere in the world since the drug was never
intended to be used in women of childbearing age. Consequently
without going through preliminary, scientifically essential animal,
Phase I and II safety and efficacy studies, the drug was
unethically tried on Indian women in Phase III studies. Moreover
the trial involved just 55 patients, too small to arrive at any
conclusion. As per Indian rules, the drug should have been tested
on a minimum of 100 patients. Other countries require far larger,
broad based trials to make sure that the drug is really safe and
effective. Strangely the Joint Drug Controller in letter F. No.
4-122/2003-DC dated 28th January 2004 had himself stated that
"large, randomised, controlled trials are needed to provide
definitive evidence (on safety and efficacy of letrozole)." What
made him change his mind and accept such a ridiculously small
study to approve a new drug? Still worse, the trial was conducted
by private practitioners in personal clinics while such studies
should be conducted by independent, experienced investigators
in large, research hospitals attached to medical colleges. The
close nexus between drug companies and private practitioners in
India is too well known to trust such company-sponsored clinical
trials in private establishments. The rules governing clinical trials
also require that to protect patients from unethical acts of
investigators with vested interests the trial must have prior review
and approval from the concerned Hospital's Ethics Committee.
Needless to say that there simply cannot be independent Ethics
Committees in solo private practices. Thus letrozole trial was
conducted in violation of the rules. Patients were put to
unacceptable risks.
Strangely the Principal Investigator of the trial, a Mumbai-based
gynaecologist was the same who was caught red handed in the
year 2003 along with a dozen other gynaecologists for having
conducted illegal trial on the same drug, letrozole, sponsored by
the same company, Sun Pharmaceuticals. A complaint against all
the self-styled "researchers" for indulging in illegal activities and
professional misconduct is pending in the Medical Council of
India. In the same year the company was also caught illegally
promoting letrozole for infertility. In the face of media outcry, the
Drugs Controller General, India (DCGI) had little option but to
issue warning letter vide reference F. No. 12-15/97-DC on
November 25, 2003 to Sun Pharmaceuticals. Instead of
blacklisting the company, its application dated 17th October 2003
requesting permission to conduct clinical trials was accepted.
Ultimately the offending company was rewarded with an
unprecedented permission to market a globally prohibited drug in
young females in India.
Dr. Chandra M. Gulhati
Editor, MIMS
(Monthly Index of Medical Specialities)
e-mail: indianmims@yahoo.co.in or seeemgee@yahoo.co.uk