Brinda Karat

New Delhi, Sept. 7: India’s drug regulators waived safety studies and ignored rules governing clinical trials while approving a drug named letrozole to treat infertility in women, documents released by the health ministry indicate.

The health ministry provided the documents to MP Brinda Karat in response to queries she had sent about the clinical trials that drug officials had conducted to approve letrozole for infertility.

The drug has been available as breast cancer treatment for post-menopausal women for several years in over 30 countries, including India.

But last year, India’s drugs controller-general cleared letrozole for infertility treatment — despite a warning by its original manufacturer Novartis that it should not be given to pre-menopausal women.

Drug officials had claimed, as reported in The Telegraph last year, that the approval for infertility treatment was given to an Indian company, Sun Pharmaceutical Industries, after mandatory clinical trials. But an independent expert who analysed the papers sent to Karat has said the trials disregarded rules.

The papers reveal that three doctors in Mumbai, Indore and Kochi gave the drug to only 55 infertile women in a Phase III trial during 2005-06, instead of including “at least 100 patients” as mandated by rules governing Phase III trials at the time.

The trial protocol papers do not provide evidence of Phase I trials to establish safety in healthy pre-menopausal women. They also do not establish the efficacy and dose of letrozole in Phase II trials for infertility approved by regulators elsewhere in the world.

“The permission has been granted in flagrant violation of Indian drug laws,” said Chandra M. Gulhati, the editor of Monthly Index of Medical Specialities, India, a journal on drugs.

This is the first time in India that a drug has been permitted for a disorder for which “it is not approved anywhere else in the world”, Gulhati said in a commentary on the approval.

Sun Pharmaceutical said it had fulfilled “all regulatory requirements for approval of the drug” in India. “We are not aware of any lapses in the procedure we have followed,” it said.

Drug officials said Phase I and II studies were considered “unnecessary” because of previous studies outside India on letrozole in infertility.

“The number 100 for Phase III is not sacrosanct. The actual number is decided on a case-by-case basis, depending on the drug and the illness,” a senior drug official said.

“Although one study in the past had raised safety concerns about letrozole, several subsequent studies have shown that it is safe and effective for infertility. The early concerns were unfounded,” the official said.

Novartis has said it recommends letrozole only for breast cancer in post-menopausal women and has issued warnings on its use in pre-menopausal women, after one of the largest clinical trials ever conducted among post-menopausal women.

“Studies investigating the use of letrozole for infertility are not supported, sponsored or condoned by Novartis,” a Novartis spokesperson said.

“It is shocking,” said Karat, who had sent the queries about the trial to the health minister. “There is a warning against the use of letrozole in pre-menopausal women. Yet, Indian officials approved it after a dubious clinical trial,” she said.

Letrozole first created controversy in India five years ago when Monthly Index of Medical Specialities, India had exposed its promotion for infertility by Sun Pharmaceutical without regulatory approval. Some doctors had offered the drug to infertile women in illegal clinical trials.

“In (ethics) training, we cite the case of letrozole as an example of how things can go wrong,” said Urmila Thatte, the head of pharmacology at Nair Hospital, Mumbai, and a member of an independent ethics committee.

In a letter written in January 2004, an Indian drug official had said “large, randomised controlled trials are needed to provide definitive evidence” of the efficacy of letrozole in infertility.

Letrozole was approved for breast cancer after trials on over 14,000 women. But Indian officials approved it for infertility after a trial on only 55 women, Gulhati said. “Is this the ‘large number’ that the regulators had sought?”

Gulhati and others who specialise in medical ethics believe that the letrozole case provides an example of how Indian drug regulators sometimes turn a blind eye to unethical or illegal clinical trials conducted on Indian patients.