New Delhi, Nov 25: Three hospitals in India violated clinical guidelines while testing a drug on patients with heart disease in a trial that a medical expert said also illustrates how India's lax regulatory watchdogs allow foreign drug companies to use Indian patients as "guinea pigs".
A review by the US Food and Drug Administration has observed that Janssen Pharmaceuticals, the US-based sponsor, had detected violations at hospitals in Bangalore, Hyderabad and Mangalore ' three of more than 40 sites across India that joined the trial.
The trial, managed by Bayer Pharmaceuticals in India, was aimed at evaluating the efficacy of a blood-thinning agent called rivaroxaban in preventing cardiovascular events (heart attacks or strokes triggered by blood clots) among patients who already had a history of heart disease.
An Indian pharmacology expert has questioned the decision by drug regulators in India to approve the trial which involved giving one group of patients rivaroxaban and another group a placebo (sham tablets), while both groups received standard heart-protective medication such as aspirin.
While Indian drug laws do not require showing efficacy by comparing a drug with a placebo, such trials are required by the US FDA, Dr Chandra Gulhati, a pharmacology expert and the editor of the Monthy Index of Medical Specialities, India, has said in a commentary to appear in the journal this week.
"Why did our drug regulators approve a clinical trial that was not required at all under Indian law? This appears to be a classic example of Indian patients offered as guinea pigs to generate data to satisfy foreign regulators' requirements," Gulhati told The Telegraph.
The rivaroxaban trial, which recruited 15,526 patients at more than 760 sites scattered across 44 countries, including the US, was conducted between November 2008 and September 2011. The US FDA, which reviewed the results earlier this year, did not approve rivaroxaban for use in patients with heart disease.
A spokesperson for Janssen Pharmaceuticals said the company "takes its commitment to safety very seriously," and its clinical trials are guided by a code of ethics and good clinical practice guidelines. "All patients in the trial received the current standard of care treatment for their heart condition, while some received rivaroxaban as additional drug," Charlotte Rodrigues, a spokesperson speaking on behalf of the company, told The Telegraph.
She said Janssen excluded efficacy data from the three sites based on audits of the sites' practices.
The audit first detected clinical guidelines issues at a hospital in Mangalore and reported them to the US FDA in December 2010. It observed missing electrocardiograms (ECG) and missing laboratory reports, making it difficult to say whether patients recruited to join the trial were indeed eligible according to the parameters set for the trial. The audit also found ECG tracings lacking dates and discrepancies in dated signatures on informed consent documents and missing investigational drug.
The company told the US FDA about similar concerns at a hospital in Hyderabad and Bangalore in April 2011. The review by the US FDA does not name the sites (hospitals), but merely lists them by the codes assigned to them for this trial ' 091001 in Mangalore, 091019 in Bangalore, and 091026 in Hyderabad.
Each of these three cities had more than one hospital involved in the trial. Altogether 1469 patients at about 40 sites (hospitals) in nearly 25 cities across India volunteered for the trial. The three problem sites made up about 184 patients.
Gulhati, who has been tracking clinical trials in India for the past decade, said in his commentary: "Hopefully, western drug regulators will learn a lesson and think twice before accepting data generated in India since there is no local monitoring, assessment, or evaluation."
The journal has also questioned discrepancies between the number of deaths in rivaroxaban trials in India as reported by the Union health ministry to Parliament in August 2011 and the number of deaths reported by the company to the US FDA.
The health ministry had said the pharmaceutical company had compensated next of kin of five patients who had died in clinical trials involving rivaroxaban in India. But data submitted by the company to the US FDA suggests that seven patients participating in this trial alone had died after cardiovascular events ' one patient had received 2.5 mg of the drug, four had received 5 mg of the drug, and two patients ' one in Mangalore and one in Hyderabad ' had received the placebo pills.
Gulhati claimed that an investigation by MIMS India suggests that three out of five deaths reported to Parliament took place in a different trial that was aimed at proving that rivaroxaban was not inferior to another blood-thinning agent called warfarin.
"Such an inferiority trial is also not required under Indian drug laws," Gulhati said.
India's drugs controller general of India Gyanendra Nath Singh said the trial of rivaroxaban for heart patients had been approved before he occupied his current position. "Things are going to change dramatically ' we're tightening the processes through which trials are approved," Singh told The Telegraph.
"Clinical trials here should help Indian patients ' otherwise we'll bluntly say: no," Singh said.
Experts in medical ethics have long campaigned for rigorous enforcement of clinical trials guidelines.
"The problems documented at the three hospitals could be viewed as the tip of an iceberg or an aberration," said Amar Jesani, a physician and director of the Centre for Ethics and Rights, Mumbai. "The industry will say it's aberration, activists will say it's an example of what lies hidden."
An industry executive told The Telegraph that it is unfair to portray Indian patients as guinea pigs when they participate in global clinical trials. "Most of the drugs used in India today, from paracetamol to cancer drugs, were based on clinical trials in patients in North America or Europe," the executive said.