Case Study 2.2: Testing Drugs in the Developing World Any drug marketed within the United States has to be approved by the FDA, a government agency charged with ensuring the safety of the food supply and medicines. Before the FDA will allow a drug company to market a newly discovered drug within the United States, however, it requires the company to test the drug on animals and then on humans. The FDA-mandated tests on humans are called “clinical trials" and have three “phases.” In Phase 1, the new drug is tested on 20 to 100 people in order to evaluate its safety and its most frequent side effects. In Phase 2 the drug is tested on several hundred people to determine how effective it is in treating a certain disease or condition and what doses are required to treat it. In Phase 3, the drug is tested on 200 to 3,000 people to confirm its effectiveness and safety compared with other drugs, study different dosages, and identify additional side effects.’ U.S. law requires that everyone participating in a clinical trial must sign a “consent form,” which states that they understand the nature of the clinical trial and its risks and have consented to participate in the trial. Generally, the consent form will contain several pages explaining the clinical trial and its risks, and the subject is expected to read them before signing the form. Until 1980 all clinical trials had to be conducted within the United States on people living in the country, and were usually conducted in medical schools and hospitals. That year, however, the FDA began to allow drug companies to test their new drugs ‘on people in other countries. A key reason for this change in FDA policy was the fact that average Americans are reluctant to enter clinical trials, knowing that they often carry high risks. New drugs “are tested on humans because no one knows their side effects: “which might range from fairly benign effects such as a temporary ‘ fash bye ‘a headache, to more serious Natsses ‘such as Parnerparalysis, organ failure, or death. Before the FDA began ae ing foreign clinical trials, American drug companies hag foung increasingly difficult and more time-consuming to fing the ta, numbers of U.S. volunteers they needed to Complete the, Phase 1, 2, and 3 trials. Time was important to the Compan, iid since each year a company spent looking for volunteers to tes, iy drug was a year of lost sales. Time pressures and the difficuty o finding volunteers led the companies to look for alternatives, ar their lobbying efforts eventually convinced the FDA to allow them to look for test subjects in other countries. In the following decades, the number of clinical trials Con. ducted outside the United States exploded. By 2015 American, drug companies were testing a large proportion of their New drugs on the citizens of foreign countries, Particularly those living in poorer parts of the world, such as India, Africa, the Middle East, eastern Europe, and Latin America. Finding the numbers of people required for their clinical tests was much easier when the drug companies began conducting their clinical trials in poor countries. Poor people in less developed nations have little access to medical personnel, and so they are attracted by the opportunity to be examined by health care profes- sionals even if the examination is part of a drug experiment. Mary People in less developed nations, in fact, believe they are beng treated for a disease when they take part in a clinical trial. Requa tions in foreign countries can be less stringent than those of the United States, making it easier for the drug companies to operate The drug companies not only found more people in poor nations who were wiling to enter a clinical trial but also substar- tally lowered the costs of their clinical trials, Clinical trial patch pants are compensated, and the compensation required © Convince most Americans to acespt the inconveniences and "= Of drug testing are higher than the compensation required to Co" vince a chtizen Of & poor nation to accept the same. Moreover for Poor People in developing nations, the compensation the 04 companies provide is often more than they make in a month. 8p,d products are Conducted outside of the United States,."12 According to critics, one of the main reasons it is easier to find clinical trial participants in Poor nations is because they can be poorly educated, Sometimes even illiterate Consequently, they May not understand the consent forms they are asked to sign and are not aware of, or do not understand, the nature of a Clinical trial and its risks. GlaxoSmithKline, for example, developed a vaccine for hepatitis E and began testing it during the early part of this century, World Health Organization estimates that each year, about 20 million People are infected with hepatitis E, and about 56,600 people die of the liver disease the virus causes. '° The virus is transmitted Mainly through Contaminated drinking water, and most infections and deaths occur in poor nations where people have limited access to clean drinking water, GlaxoSmithKline decided to test the vaccine in Lalitpur, Nepal, where hepatitis E is endemic and where much of the pop- Ulation lives in extreme poverty.'* GlaxoSmithKline did not expect to market the drug in poor countries such as Nepal, since their citizens would not be able to afford the vaccine. Instead, the Company had thought it might market the drug to people in the developed world who planned to travel to a region where the dis- ase is common, or to the U.S. military whose soldiers often were deployed to such countries.’ Critics suggested that this approach could be seen as a form of exploitation since “In clinical research, exploitation involves asking others to bear risk while benefits accrue to persons not exposed to those tisks . . . [so that] the rich and advantaged gain at the expense of those who re neither."'6Before GlaxoSmithKline could begin its tests, however, a local Nepalese NGO, Lumanti, protested against the tests, argu- ing that the majority of the population of Lalitpur, Nepal, was illit- erate, highly vulnerable, and likely unable to understand what the tests involved. Faced with this opposition, GlaxoSmithKline turned to the government, who agreed to provide 2,000 soldiers from the Royal Nepalese Army as test subjects. However, the soldiers were also largely poor and illiterate. Moreover, critics argued, as soldiers their participation would likely not be volun- tary since they would feel they were being ordered to participate by their officers.” Nevertheless, GlaxoSmithKline went ahead and carried out its clinical trial on the Nepalese soldiers. In 2008, GlaxoSmithKline carried out another clinical trial in the Argentinean province of Santiago del Estero, one of Argenti- na’s poorest regions. This clinical trial was for Synflorix, a vaccine developed to prevent pneumonia and ear infections.'® The trial was designed to test whether the vaccine was safe to use on babies. Many of the parents of the babies used in the clinical trial were illiterate, however, and did not understand that they were allowing their babies to be used in a medical experiment. The par- ents were persuaded to enter their babies in the clinical trial by local doctors, who received about $350 from GlaxoSmithKline for each baby a doctor enrolled in the trial. At least 14 babies died during the trial. The two principle investigators running the clinical trial as well as GlaxoSmithKline were fined. However, the company insisted that the mortality rate of the infants participating in the tria was comparable to the morality rate of the local population. i ie aah 1 AMaBinThe practice of paying local doctors to provide test subjects is widespread. A psychiatrist in Budapest stated: “Drug compa- nies make us offers they know turn our heads.” Although at the time he was earning $178 a month in salary, he said, the drug companies would offer him as much as $1,000 and $2,000 for each test subject he recruited.’9 A site that several American and European drug compa- nies have chosen for many of their clinical trials is Maharaja Yeshwantrao Hospital, which is located in Indore, India. Its patients are often inducted into clinical trials. However, accord- ing to the BBC, patients do not always know that they have been enrolled in a clinical trial. Chandrakala Bai’s daughter-in- ple, b ht:her to ospit h om-In Poland, Wojclech, a 24-year-old homeless man, was Standing outside a church-run shelter in Warsaw when he was approached by three men who asked him and other homeless People if any of them wanted to test a new flu vaccine for 50 PLN in cash (about $20 at the time).2" Wojclech agreed and a few days later went to a clinic to begin the clinical trial. There, he was asked to sign a lengthy form: | did not really understand it, it was around 50 pages long and the language was difficult to understand. | asked the trial officials some questions about it but they said explaining everything would take too much time.22 He nevertheless signed the form, got the vaccine, and was Paid. When asked why he did it, he said: “All | care about is mak- ing easy money. | did what | had to do and got paid.”25 Mrs.-Liu, the wife of a poor peasant farmer living in a village south of Beijing, China, was diagnosed with lung cancer. Three years later, when she began getting headaches and vomiting, she borrowed money from her son and journeyed to Beijing to see a doctor who told her the cancer had moved to her brain. When she told the doctor her family was too poor to pay for any treatment, the doctor offered to enroll her in a trial of a drug that, he said, would help shrink her tumor. She later said: | didn’t really understand anything but he said | could have the treatment for free which was a good thing. | do not really under- stand what a clinical trial means, but we are poor farmers and the most important thing for us is saving money .. . We didn't ask the doctors anything. | didn’t think about any risks, | just wanted the free benefits and to save some money. They didn't ask me to sign anything.?*Although Mrs. Liu took the drug, it did not help her condi- ton. Later her husband said, “if we were a rich family we would Not have to take part in these clinical trials."2° The Problem of Finding Ways to Test Drugs In 1996 a meningitis epidemic broke out in the city of Kano, in northern Nigeria; scores of people were soon dying. Doctors Without Borders, an organization of doctors dedicated to caring for the sick for free anywhere in the world, quickly arrived and set up a treatment tent on one side of a hospital compound. They were soon administering an antibiotic that is a standard treat- Ment for curing meningitis, a disease that is caused by certain bacteria. On the other side of the world, researchers at Pfizer Inc, a major American drug company, heard about the mening! tis epidemic. Pfizer at the time was trying to get the FDA to approve Trovan, a new antibiotic the company had recently developed. The drug had never been tested on children, and Pfizer's researchers saw the Nigerian epidemic as an opportu- nity to test an oral form of their drug on children with meningitis. The company therefore quickly organized a team that flew into Kano and set up their clinical trial on the other side of the same hospital compound that Doctors Without Borders was using. There they began treating sick children with their new experi- mental drug. When parents brought their sick children into the hospital, they were generally steered toward the Pfizer team. Most of the families were illiterate, and so could not understand the consent forms they were given. Instead, local nurses talked to the families, saying that they were administering a new medi- cine for treating their child's disease, and they had a right to say no. They failed to tell them that there was an alternative available for their children: walking over to the Doctors Without Borders. tent and taking the standard known and well-tested treatment for meningitis. Several of the children treated with Trovan died, although it is not clear whether the death rate was lower than the death rate of those treated by Doctors Without Borders. The Pfizer team left Nigeria two weeks after it had arrived, without providing the follow-up exams that are called for by U.S. medicalProviding the follow-up exams that are called for by U.S. medical guidelines. However, one of the physicians from Doctors Without Borders later saw several of the children who had been treated with the Pfizer drug and who had returned for follow-up exams. He said: “All those patients and their families came back saying that they had never been informed that they were used in exper- imentation.with an unproved medicine."26 Eventually Pfizer’s Trovan was approved for adults, but the FDA refused to approve it for children. In Europe regulators spe- cifically ruled that Trovan should not be administered to children. About 16 months after Trovan began to be used in the United States, the FDA discovered that the drug had injured the livers of 140 patients, some of whom had died as a result. The FDA restricted its use to patients with serious diseases, while European regulators ruled that the drug could no longer be sold in Europe. While many have criticized the drug industry's growing tendency to conduct their drug trials in poor countries, industry representatives defend the practice. Bert Spiker, a spokesman for the Pharmaceuti- ch and Manufacturers of America pointed to the enormous cal Resear een benefits drug trials produce by enabling the pharmaceutical industry to market drugs that save countless lives and relieve the suffering and dabilitation of millions of people. Those benefits would not materialize'f the companies were not able to find enough subjects for their clini- Cal trials: “You need patients to create new products that help us here and help people around the word. You cannot do it without test sub- fects." If citizens in the developed world will not step forward to vol Unteer for clinical trials, the drug companies have argued, then they have to search for volunteers elsewhere, even if this means going to the poorer regions of the world to look for them.