In addition to monitoring trials abroad, which it does not really do, the F.D.A. is responsible for inspecting drug-manufacturing plants in other countries, which it also does not really do. In 2007 and 2008, hundreds of patients taking the blood thinner heparin, which among other purposes is used to prevent blood clots during surgery and dialysis, developed serious allergic reactions as a result of a contaminant introduced at a Chinese manufacturing facility. It took months for the F.D.A., its Chinese counterpart, and Baxter International, the pharmaceutical company that distributed the drug, to track the source of contamination to Changzhou, a city of 3.5 million on the Yangtze River.
The delay was perhaps understandable, given the manufacturing process. The raw material for Baxter’s heparin comes from China’s many small pig farms. To be precise, it’s derived from the mucous membranes of the intestines of slaughtered pigs; the membranes are mixed together and cooked, often in unregulated family workplaces. By the time the source of the contaminant was pinpointed, many more patients in the United States had experienced severe reactions, and as many as 200 had died. It later turned out that the F.D.A. had indeed inspected a Chinese plant—but it was the wrong one. The federal regulators had confused the names.
The good news was that, in this instance, the F.D.A. at least knew which country the heparin had come from. The bad news is that it does not always know where clinical trials are being conducted, or even the names or types of drugs being tested, or the purpose for which they will be prescribed once approved. Companies may withhold the foreign test data until they actually submit the application to the F.D.A. for approval. By then the agency has lost the ability to see whether the trials were managed according to acceptable standards, and whether the data collected was manipulated or fabricated.
If the globalization of clinical trials for adult medications has drawn little attention, foreign trials for children’s drugs have attracted even less. The Argentinean province of Santiago del Estero, with a population of nearly a million, is one of the country’s poorest. In 2008 seven babies participating in drug testing in the province suffered what the U.S. clinical-trials community refers to as “an adverse event”: they died. The deaths occurred as the children took part in a medical trial to test the safety of a new vaccine, Synflorix, to prevent pneumonia, ear infections, and other pneumococcal diseases. Developed by GlaxoSmithKline, the world’s fourth-largest pharmaceutical company in terms of global prescription-drug sales, the new vaccine was intended to compete against an existing vaccine. In all, at least 14 infants enrolled in clinical trials for the drug died during the testing. Their parents, some illiterate, had their children signed up without understanding that they were taking part in an experiment. Local doctors who persuaded parents to enroll their babies in the trial reportedly received $350 per child. The two lead investigators contracted by Glaxo were fined by the Argentinean government. So was Glaxo, though the company maintained that the mortality rate of the children “did not exceed the rate in the regions and countries participating in the study.” No independent group conducted an investigation or performed autopsies. As it happens, the brother of the lead investigator in Santiago del Estero was the Argentinean provincial health minister.
In New Delhi, 49 babies died at the All India Institute of Medical Sciences while taking part in clinical trials over a 30-month period. They were given a variety of new drugs to treat everything from high blood pressure to chronic focal encephalitis, a brain inflammation that causes epileptic seizures and other neurological problems. The blood-pressure drugs had never before been given to anyone under 18. The editor of an Indian medical journal said it was obvious that the trials were intended to extend patent life in Western countries “with no consequence or benefit for India, using Indian children as guinea pigs.” In all, 4,142 children were enrolled in the studies, two-thirds of them less than one year old. But the head of the pediatrics department at the All India Institute maintained that “none of the deaths was due to the medication or interventions used in clinical trials.”
For years, American physicians gave anti-psychotic medicines to children “off label,” meaning that they wrote prescriptions based on testing for adults, sometimes even for different conditions. That didn’t work out so well for the children, who, when it comes to medicine, really are not just little adults. To provide the pharmaceutical industry with an incentive to conduct clinical trials on children’s versions of adult drugs, Congress in 1997 enacted legislation, known as the Pediatric Exclusivity Provision, extending the patent life of certain drugs by six months. It worked so well that the industry has, in the ensuing years, been able to put younger and younger children on more and more drugs, pocketing an extra $14 billion. Between 1999 and 2007, for instance, the use of anti-psychotic medications on children between the ages of two and five more than doubled.
A study of 174 trials under the Pediatric Exclusivity Provision found that 9 percent of them did not report the location or number of sites of the clinical trials. Of those that did, two-thirds had been conducted in at least one country outside the United States, and 11 percent were conducted entirely outside the United States. Of the 79 trials with more than 100 subjects participating, 87 percent enrolled patients outside the United States. As is the case with adult studies, many children’s trials conducted abroad are neither reported nor catalogued on any publicly accessible government database. There is no public record of their existence or their results.
In the mid-90s, Glaxo conducted clinical trials on the antidepressant Paxil in the United States, Europe, and South America. Paxil is a member of a class of drugs called selective serotonin re-uptake inhibitors. The class includes Zoloft, Prozac, and Lexapro. In the United Kingdom, Paxil is sold as Seroxat. The clinical trials showed that the drug had no beneficial effect on adolescents; some of the trials indicated that the placebo was more effective than the drug itself. But Glaxo neglected to share this information with consumers; annual sales of the drug had reached $5 billion in 2003. In an internal document obtained by the Canadian Medical Association Journal, the company emphasized how important it was to “effectively manage the dissemination of these data in order to minimize any potential negative commercial impact.” The memo went on to warn that “it would be commercially unacceptable to include a statement that efficacy had not been demonstrated.” After the document was released a Glaxo spokesperson said that the “memo draws an inappropriate conclusion and is not consistent with the facts.”
It may be just a coincidence, but as controversy swirls around new drugs, and as the F.D.A. continues to slap medicines with new warning labels—especially the black-box warnings that indicate the most serious potential reactions—most of the problematic drugs have all undergone testing outside the United States. Clinical-trial representatives working for GlaxoSmithKline went to Iaşi, Romania, to test Avandia, a diabetes drug, on the local population. Glaxo representatives also showed up in other cities in Romania—Bucureşti, Cluj-Napoca, Craiova, and Timişoara—as well as multiple cities in Latvia, Ukraine, Slovakia, the Russian Federation, Poland, Hungary, Lithuania, Estonia, the Czech Republic, Bulgaria, Croatia, Greece, Belgium, the Netherlands, Germany, France, and the United Kingdom. That was for the largest of the Avandia clinical trials. But there have been scores of others, all seeking to prove that the drug is safe and effective. Some took place before the drug was approved by the F.D.A. Others were “post-marketing” studies, done after the fact, as the company cast about for ways to come up with more positive results so it could expand Avandia’s use for other treatments. Based on the initial evaluations, Avandia was expected to—and did—become another Glaxo multi-billion-dollar best-seller.
While sales soared, so, too, did reports of adverse reactions—everything from macular edema to liver injury, from bone fractures to congestive heart failure. In 2009 the Institute for Safe Medication Practices, a Pennsylvania-based nonprofit group that monitors the prescription-drug field, linked the deaths of 1,354 people to Avandia, based on reports filed with the F.D.A. Studies also concluded that people taking the drug had an increased risk of developing heart disease, one of the very conditions that doctors treating diabetics hope to forestall. The risk was so high that worried doctors inside and outside the F.D.A. sought to have the drug removed from the market, an incredibly difficult task no matter how problematic the medicine. As always, the F.D.A. was late to the party. In 2008 the American Diabetes Association and the European Association for the Study of Diabetes had warned against using Avandia. The Saudi Arabian drug-regulatory agency yanked it from the market, and the Indian government asked Glaxo to halt 19 of its Avandia trials in that country. In September 2010 the European Medicines Agency pulled Avandia from the shelves all across Europe. The F.D.A. still could not bring itself to take decisive action. This even though the F.D.A. knew that Glaxo had withheld critical safety information concerning the increased risk of heart attacks, and the F.D.A. itself had estimated that the drug had caused more than 83,000 heart attacks between 1999 and 2007. The agency settled for imposing new restrictions on the availability of the drug in the United States. Glaxo released a statement saying that it “continues to believe that Avandia is an important treatment for patients with type 2 diabetes,” but that it would “voluntarily cease promotion of Avandia in all the countries in which it operates.”