The Hindu : National : Infertility drug cleared without proper tests

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Wednesday, Nov 07, 2007
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Infertility drug cleared without proper tests

Sarah Hiddleston

Authorisation to market Letrozole for infertility treatment issued despite adverse toxicity indications

Drug inhibits the enzyme responsible for producing oestrogen
It has been approved despite a 2005 warning issued by Novartis

CHENNAI: Women in India being treated for infertility with Letrozole could be running the risk of damaging themselves and their babies. Authorisation to market the drug was issued to Sun Pharmaceuticals by the regulatory authority on April 10. But Letrozole has not been put through proper tests to demonstrate that it is a safe and effective treatment for infertility.

Letrozole, developed by Novartis and sold under the brand name Femara, was approved in 1998 as a treatment for breast cancer in post-menopausal women only. The drug inhibits the enzyme responsible for producing oestrogen. When administered to women of child-bearing age, it stimulates follicular development and could be exploited to induce ovulation.

Letrozole’s use as a fertility treatment has been registered as an additional indication of a known drug. It has, therefore, undergone only phase III trials and skipped the phases that establish safety, determine side effects, dose and regimen.

Under India’s Drugs and Cosmetics Act Section 122E(b), if a drug is found to have a new indication, it should be considered new and subjected to the gamut of clinical trials. But, if the dosage form is the same, the drugs regulator can waive previous phases provided that drug safety and concept are properly proven.

Drugs Controller-General of India M. Venkateswarlu, told The Hindu that no new toxicity studies were necessary because “in the opinion of experts,” that is, the five gynaecologists who approved the trials, “this is a short-term course [three-five days] and the dosage [2.5mg] is the same. The toxicity information generated from the cancer trials is sufficient.”

But toxicity information generated from cancer trials and contained in Novartis’ prescribing information shows that Letrozole is embryotoxic and foetoxic.

Under the heading “warnings,” the company states: “Femara [Letrozole] may cause foetal harm when administered to pregnant women.”

Administration of the drug to animals brought “intrauterine mortality, increased resorption, increased post-implantation loss, decreased numbers of live foetuses” and foetal anomalies, including incomplete ossification of skull, forelegs and hind legs. Repeated doses at the equivalent dose to humans and less “caused sexual inactivity in females and atrophy of the reproductive tract in males and females.”

The drug has been approved despite a 2005 warning issued by Novartis to regulators worldwide against the use of Letrozole in fertility treatment.

Acknowledging receipt of the Novartis advisory, Dr. Venkateswarlu said that it was based on a 2005 study at the Montreal Fertility Centre, Canada, published in the journal Fertility and Sterility, but that a 2006 study at the same centre found that the drug had nothing to do with the deformities observed in babies in the initial study.

“We rely on the opinion of our experts,” Dr. Venkateswarlu said.

Off-label studies

Health Canada, the Canadian Health authority, maintains that Letrozole should not be used for infertility treatment, despite such off-label studies. A copy of the Novartis advisory was sent to all its gynaecologists on November 22, 2005, and is still displayed on their website. Market approval to treat infertility has not been given in the U.S. or the United Kingdom.

When market application is sought, the onus is on the manufacturer to prove that the drug is effective. Prescribing information from Sun Pharmaceuticals indicates that approval has been given based on a collation of separate studies by foreign research institutes and one multi-centric study conducted on 55 women in India. The tiny number of women involved in India’s only trial does not conform to the required Schedule Y figure of 100 people, even if the drug has been approved in other countries. None of the foreign studies meet the standard highly controlled, randomised, double-blind trials of thousands of women needed for market approval for this indication in developed countries. Under Schedule Y, if the drug has not been approved elsewhere, trials must be undertaken on 500 people in 10-15 centres and data on adverse drug reactions should be collected in 1,000-2,000 people.

“We have submitted the necessary information required for the approval of the drug and based on that we have been given marketing approval,” a spokesperson for Sun Pharmaceuticals said.

In 2003, Indian generic companies, including Sun Pharmaceuticals, were caught illegally promoting the drug as an infertility treatment under the brand Letoval, for which they were conducting unlawful trials through private clinics. In the wake of the media storm this created, the drugs regulator warned companies against the promotion of the drug to treat infertility. Now the same authority has approved it based on the Sun Pharma’s submissions.

‘Contraindicated’

A spokesperson for Novartis India told The Hindu that “Femara [Letrozole] is not approved for use in the treatment of infertility and Novartis does not promote Femara for this indication.” The 2005 Novartis advisory states: “Femara is contraindicated and should not be used in women who may become pregnant, during pregnancy and/or while breastfeeding, because there is a potential risk of harm to the mother and the foetus, including risk of foetal malformations.”

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