Just as clinical trials in developing countries become increasingly important for testing new drugs and getting them to market, drugmakers are encountering more questions about their practices,The Wall Street Journal writes.
Last month, for instance, authorities in India halted a 350-participant study of a new Wyeth vaccine after a baby died. The Drugs Controller General of India is now investigating whether the infant was screened properly and if rules were bent to enroll babies in the study. A conclusion is expected shortly (back story).
Last year, two elderly patients died after Polish investigators enrolled them in a study of a bird-flu vaccine being developed by Novartis, even though they should have been excluded based on age. The deaths and other problems with participants in Poland, one of 10 countries involved in the 3,000-patient study, led to a delay of at least a year in approval of the vaccine by European authorities, according to Novartis.
The drugmakers and their experimental vaccines have not been implicated in either case, but the investigations illustrate the pressures to provide effective oversight of clinical trials to ensure that medical and ethical practices are followed in developing countries, The Journal writes. A similar case arose recently in Argentina, by the way, where Glaxo has been testing a pediatric pneumonia vaccine (back story).
"There are standard ways of conducting clinical trials," Sonal Singh, an assistant professor of medicine at Wake Forest University who studies clinical-trial regulation, tells the Journal. "The question is: Are they being adhered to?"
Drugmakers have conducted trials in some developing countries for more than a decade but have faced questions from the start about ethical treatment of study participants and the integrity of the data generated abroad. Though pharma and regulators have attempted to address these concerns and monitor trials closely, these latest incidents underscore that concerns remain, the Journal writes.
About 40 percent of trials sponsored by big pharma in 2005 were conducted in low- and middle-income countries, according to a recent report by the Centre for Research on Multinational Corporations, or SOMO, a European industry watchdog group based in the Netherlands. That figure is almost certainly rising. India has approved some 450 clinical trials this year, up from about 100 in 2005. Wyeth says about 45 percent of its mid- and late-stage trial participants come from outside the U.S. and Western Europe.
Trials in lower-income countries cost less than half of the millions of dollars for of a late-stage trial in the US and Europe because of lower salaries for doctors and clinical personnel. Patient recruitment is faster in countries such as India, China and in Eastern Europe, where populations are larger or competition for patients is less intense. Patients outside the US or Western Europe are also far less likely to be taking other medicines, important for trials requiring "drug naive" patients. And in countries where access to medical care is poor, people are often desperate to participate in trials.
Another worry is locals who carry out the work, the Journal writes. They may feel pressure to cut corners to boost enrollment or reconcile questionable data in order to impress drug-company sponsors, which brings them prestige and money, according to Francis Weyzig, a researcher at SOMO and co-author of the recent report on ethics for drug testing in lower-income countries.
Critics also complain that drugmakers ask people from poor countries to be guinea pigs for drugs they can't later afford when they reach the market. Glaxo faced such allegations earlier this decade on trials of AIDS drugs in Africa and a hepatitis E vaccine study in Nepal, the Journal reports.
Big drugmakers say they use the same study protocol regardless of where meds are tested, routinely monitor international sites and try to use only investigators who have experience conducting clinical trials and who are often trained in the West. Glaxo, Wyeth and others say they seek regulatory approval in each nation in which they conduct a trial. In addition, drugmakers say they try to ensure that study participants can stay on meds, or a suitable alternative after the trial ends.
In the Wyeth study, which is testing a new pneumococcal vaccine called Prevnar-13 against the widely used Prevnar, the question is whether local investigators took shortcuts or made mistakes in screening procedures requiring only healthy babies be allowed to participate.
One of the approximately 250 infants that had been enrolled died on October 18, within a week of receiving the third dose of the Prevnar vaccine - not the experimental version. That prompted the Indian drug regulator to look into the incident, according to Emilio Emini, head of Wyeth's vaccine division.
A.B. Ramteke, deputy drugs controller general for India, tells the Journal his office received reports the baby had a pre-existing cardiac disorder that should have precluded participation in the trial. But he says evidence wasn't conclusive and the investigation is intended to determine whether screening was thorough and accurate. Wyeth says records show the infant was screened and considered healthy at enrollment, and it monitors and documents all aspects of its clinical trials carefully, according to Emini.
The study was designed to assess the tolerability and safety of Prevnar-13 when used in conjunction with local vaccines administered to Indian children, a standard type of vaccine study that Wyeth is currently conducting in more than a dozen other countries, Emini tells the Journal. As soon as the infant's death was noted, the company informed all other countries in which Prevnar-13 trials were being conducted and none decided to suspend their studies, he adds.
"It's our trial; it's our responsibility," Emini tells the paper. "We look to make sure (the study) is being done appropriately. We keep the regulatory authorities in the country fully informed."
Ramteke acknowledged other countries testing the Wyeth vaccine had allowed the trial to continue. "Our decision to suspend the trial was because of the death. We felt we needed to investigate the cause before admitting more patients," he tells the Journal.
In the Novartis case, the drugmaker looked into conduct of its study after noticing "irregularities" in data from Polish investigators. After finding evidence that clinicians had recruited participants from an elderly home and a homeless shelter, the drugmkaer notified the European Medicines Agency and the Polish Police, Joerg Reinhardt, head of its vaccines and diagnostics division, tells the paper.
Polish prosecutors launched an investigation and as of July hadn't found any link between the deaths and the vaccine. A criminal probe of some of those who enrolled patients is continuing, Reinhardt adds. The quality of the trial "depends on the integrity of the investigators running these studies," Reinhardt, the drugmaker's chief operating officer, tells the Journal.
Ultimately, Novartis decided it couldn't rely on the accuracy of the 300 Polish participants' data and threw them out. As a result, the EMEA declined to approve the vaccine and asked the company do another 3,000-patient study, delaying approval by at least a year, he says, adding that such problems "very rare," while insisting that monitoring of international trials has substantially improved over the past decade.