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 walow a drug company to market a newly discovered drug within the United States, however, I 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 "phoses. In Phase 1, the new drug is tested on 20 to 100 people in order to evaluate its safety and is 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 10 3,000 people to confim is effectiveness and salety compared with other drugs, study diferent dosages, and identity additional side effects." U.S. taw 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 comented 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 beforo signing the form Until 1980 al clinical trials had to be conducted within the United Staten on people living in the country, and were usually conducted in medical schools and Hospitals. That year, however, the FDA begin to slow drug compares to test their new drugs on people in other countries. A key reason for this change in FDA policy was the fact that everage Americans are reluctant to enter clinical rowing that they olton Carry high risks. New drugs are tested on human because no one knows the side effects which might range from any berignotects such as a temporary rash or headache to more serious is such as permanent paralysis, organ lalure, or death Before the FDA began accept- ing foreign cinical trials, American drug companies had found it increasingly difficult and more time-consuming to find the large numbers of U.S. volunteers they needed to complete their Phase 1, 2 and 3 trials. Tme was important to the companies since each year a company spent looking for volunteers to test its drug was a year of lost sales Time pressures and the difficulty of finding volunteers led the companies to look for alternalives, and their lobbying efforts eventually convinced the FDA 10 allow them to look for test subjects in other countries. In the following decades, the number of cinical trials con- ducted outside the United States exploded. By 2015 American drug companies were testing a largo 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 ther cinical tests was much easier when the drug companies began conducting ther clinical trials in poor countries. Poor people in tess developed nations have Itle access to medical personnel, and so they are attracted by the opportunity to be sumined by health care profes sonals even tho examination is part of a drug experiment. Mary people in less developed nations, in fact, beleve they are being treated for a disease when they take part in a clinical trial. Regula 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 willing to enter a cinical trial but also substan- taly lowered the costs of their clinical trials. Clinical trial particl- pants are compensated, and the compensation required to convince most Americans to accept the inconveniences and risks of drug testing are higher than the compensation required to con vnce a one of a poor nation to accept the same. Moreover, for poor people in developing nations to compensation the drug companies provide is chen more than they make in a month a In 2010, the Department of Health and Human Services The practice of paying local doctors to provide test subjects reported that "between 40 percent and 65 percent of clinical trials is widespread. A psychiatrist in Budapest stated: "Drug compa- investigating FDA-regulated products are conducted outside of nies make us offers they know turn our heads." Athough at the the United States."12 time he was earning S178 a month in salary, he said, the drug According to cntics, one of the main reasons it is easier to companies would offer him as much as $1,000 and $2,000 for find clinical trial participants in poor nations is because they can each test subject he recruited. 19 be poorly educated, sometimes even illerate. Consequently, they A site that several American and European drug compa- may not understand the consent forms they are asked to sign and nies have chosen for many of their clinical trials is Maharaja are not aware of, or do not understand, the nature of a clinical trial Yeshwantrao Hospital, which is located in Indore, India. Its and its risks. GlaxoSmithKline, for example, developed a vaccine patients are often inducted into clinical trials. However, accord- for hepatitis E and began testing it during the early part of this ing to the BBC. patients do not always know that they have century. World Health Organization estimates that each year, been enrolled in a clinical trial. Chandrakala Bai's daughter-in- about 20 milion people are infected with hepatitis E, and about law, for example, brought her to the hospital when she com- 56,600 people de of the liver disease the virus causes. The virus plained of chest pains. A doctor at the hospital told thern that is transmitted mainly through contaminated drinking water, and she would be treated with a new heart drug. Both Chandrakala most infections and deaths occur in poor nations where people and her daughter-in-law are low-caste Hindus who are literate have Imited access to clean drinking water, and so could not read whatever paperwork they were given. GlaxoSmithKline decided to test the vaccine in Lalitpur, The drug Chandrakala was given, was, in fact, Tonapolyline, an Nepal, where hepatitis Eis endemic and where much of the pop- experimental drug then being tested by Blogen, an American walion lives in extreme poverty." GlaucoSmithKline did not expect drug company headquartered in Cambridge, Massachusetts. to market the drug in poor countries such as Nepal, since their Shortly after taking the drug. Chandrakala suffered heart abnor. Citizens would not be able to afford the vaccine. Instead, the malities and less than a month later, her heart stopped besling company had thought it might market the drug lo people in the and she died. Altogether, the hospital had enroled about 3,300 developed world who planned to travel to a region where the dis- patients in 73 clinical trials over the previous seven years, 80 ease is common or to the U.S. military whose soldiers often were had died or suffered some serious adverse event. According deployed to such countries. Critics suggested that this to Dr. Anand Rai, who once worked at the hospital, "They chose approach could be seen as a form of explotation snce in clinical poor, literate people who do not understand the meaning of research, exploitation involves asking others to bear risk while clinical drug trials. 20 benefits accrue to persons not exposed to those risks Iso in Poland, Wojciech, a 24-year-old homoloss man, was that the rich and advantaged gain at the expense of those who standing outside a church-run shelter in Warsaw when he was are neither." approached by three men who asked him and other homeless Before GlaxoSmithKline could begin its tests, however, a people if any of them wanted to test a new fu vaccine for 50 PLN local Nepalese NGO, Lumanti, protested against the tests, argu- in cash (about $20 at the time) ? Wojciech agreed and a few ing that the majority of the population of Lalpur, Nepal, was it. days later went to a clinic to begin the cinical trial. There, he was erate, highly vulnerable, and likely unable to understand what the asked to sign a lengthy lam; tests involved. Faced with this opposition, GlaxoSmithKline I did not really understand it, was around 50 pages long and turned to the government, who agreed to provide 2.000 soldiers from the Royal Nepalese Army as test subjects. However, the the language was dificult to understand. I asked the trial officials some questons about it but they said explaining everything soldiers were also largely poor and nate. Moreover, critics would take too much time 12 argued, as soldiers the participation would hely not be volun tary since they would feel they were being ordered to participate He nevertheless sgned the form, got the vaccine, and was by their officers. Nevertheless, GlaroSmithKline went ahead paid When asked why he did it, he said. "All care about is mak. adidit lanmony what tary since they would feel they were being ordered to participate He nevertheless signed the form, got the vaccine, and was by their officers. Nevertheless, GlaxoSmithKline went ahead paid. When asked why he did it, he said: "All care about is mak- and carried out its clinical trial on the Nepalese soldiers. ing easy money. I did what I had to do and got paid,"23 In 2008, GlaxoSmithKline carried out another clinical trial in Mrs. Lu, the wife of a poor peasant farmer living in a village the Argentinean province of Santiago del Estero, one of Argenti- south of Beijing, China, was diagnosed with lung cancer. Three na's poorest regions. This clinical trial was for Synflorix, a vaccine years later, when she began getting headaches and vomiting, developed to prevent pneumonia and ear infections. The trial she borrowed money from her son and Journeyed to Bejing to was designed to test whether the vaccine was sale to use on see a doctor who told her the cancer had moved to her brain babies. Many of the parents of the babies used in the clinical trial When she told the doctor her family was too poor to pay for any were illiterate, however, and did not understand that they were treatment, the doctor offered to enrol her in a trial of a drug that, allowing their babies to be used in a medical experiment. The par he said, would help shrink her tumor. She later said: ents were persuaded to enter their babies in the clinical trial by I didn't really understand anything but he said I could have the local doctors, who received about $350 from GlaxoSmithKine for treatment for free which was a good thing. I do not really under each baby a doctor enrolled in the trial. At least 14 babies died stand what a clinical trial means, but we are poor farmers and during the trial. The two principle investigators running the clinical the most important thing for us is saving money... We didn't trial as well as GlaxoSmithKline were fined. However, the company ask the doctors anything. I didn't think about any risks, just insisted that the mortality rate of the infants participating in the trial wanted the free benefits and to save some money. They didn't was comparable to the morality rate of the local population ask me to sign anything 120 Chapter 2 Although Mrs. Lu took tho drug. It did not help her condil the companies were not able to fnd enough subjects for therein tion. Later her husband said, " we were a rich family we would cal trials. You need patients to create new products that help us here not have to take part in these clinical trials. 33 and lp people around the world. You cannot do it without test sub jects.orgers in the developed world will not step forward to vol- The Problem of Finding Ways to Test Drugs intoor lor clinical trials, the drug companies have argued, then they In 1996 a meningilis epidemic broke out in the city of Kano, in fave to search for volunteers elsewhere, even if this means going to northern Nigeria, scores of people were soon dying. Doctors the poorer regions of the world to look for them Without Borders, an organization of doctors dedicated to caring for the sick for free anywhere in the world, quickly arrived and set WRITING PROMPT up a treatment font on one side of a hospital compound. They were soon administering an antibiotic that is a standard treat Your Thoughts on Testing Drugs in the Developing World mont for curing meningitis, a disease that is caused by certain 1. Several critics of the drug companies have claimed that the bacteria. On the other side of the world, researchers at Pfizer companies' practice of festing drugs on poor people in devel- Inc., a major American drug company, heard about the mening- oping countries violatos principles of justice. Why would they say this? Which principles of justice would be involved? Although Mrs look lhe drug, it did not help her condi- il the companies were not able to find enough subjects for their cini tion. Later her husband said, "I we were a rich farnily we would cal trials. You need patients to create new products that help us here not have to take part in these cinical trials. 23 and help people around the world. You cannot do it without lost sub- jects. 2? f ctizens in the developed world will not step forward to val- The Problem of Finding Ways to Test Drugs unteer lor cinical trials, the drug companies have argued, then they In 1996 a meningitis epidemic broke out in the city of Kano, in have to search for volunteers elsewhere, even if this means going to northern Nigeria; scores of people were soon dying. Doctors the poorer regions of the world to bok for them. 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 Your Thoughts on Testing Drugs in the Developing World WRITING PROMPT were soon administering an antibiotic that is a standard treat- ment for curing meningitis, a disease that is caused by certain 1. Several critics of the drug companies have claimed that the bacteria. On the other side of the world, researchers at Pfizer companies' practice of testing drugs on poor people in devel- Inc., a major American drug company, heard about the meningi- oping countries violatos principles of justice. Why would they say this? Which principles of justice would be involved? tia epidemic. Pfizer at the Imo was trying to got the FDA in 2. Some crities of the drug companies have around that the doc. approve Trovan, a new antibiotic the company had recently tors that have agreed to participate in the drug trails have vio- developed. The drug had never been tested on children, and isted the requirements of the ethic of care. Explain why these Pfizer's researchers saw the Nigerian op dernic as an opportu- critics are right or why they are wrong. nity to lost an oral form of their drug on children with meningitis The company therefore quickly organized a learn that flow into The response entored here will appear in the performance dashboard and can be viewed by your instructor 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: Submit mental drug. When puronts brought their sick children into the hospital, they were generally sleered toward the Pfizer team Case Notes Most of the families were literate, and so could not understand 11. Step 3: Cinical Research US Food and Drug Administration, the consent forms they were given. Instead, local nurses talked accessed October 12, 2016. http://www.da gow For Patients to the families, saying that they were administering a new medi- Approvals Drugs/ucm405622.htmatical_Research_Phase_ cino for treating their child's disease, and they had a right to say Studes 12. Chris Galvin, Changes to FOAS Ally lo Monitor and inspect no. They failed to tell them that there was an alternativo available Forngn Cinical Trials, report 08-01-08 00510 Washington for their children: walking over to the Doctors Without Borders DC Office of Inspector Generat US Department of Health & tent and taking the standard known and well-tested treatment Human Services, 2010), http://og hus.gowoelreports/0001- for meningus. Several of the children treated with Trovan died, 08-00510 pot although it is not clear whether the death rate was lower than tho 13. World Health Organization, "Hepates E Fact Sheet No. 280.* death rate of those treated by Doctors Without Borders. The Juy 2015. accessed August 20, 2015, http://www.who.in Pfizer team to Nigeria two weeks after it had arrived, without modacentractsheets/280/. providing the follow up exams that are called for by U.S medical 14. Marty Loga, "Nepal Guinea Pigs in Hepata E Vaccino Tres Quidelines. However, one of the physicians from Doctors Without Inter Press Service News Agency, February 6, 2005, http:// Borders later saw several of the children who had been treated www.psnews.net/2006/02epal guinea pigs-in-hepatitis vaccine-trials with the Pfizer drug and who had returned for folow-up exams. 15. Phip C. Stevenson. "Nepal Cat's the Shots in Hepatitis E Virus He said. "Al those patients and ther families came back sayng Vaccine TraLance 355 (June 2000) 1623. http://www. that they had never been informed that they wanted in excer Suomi 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 literale, 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 lof Nigeria two weeks after it had arrived, without 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- mentation with an unproved medicine. 26 Eventualy Pizer's Trovan was approved for adults, but the FDA refused to approve it for children in Europe regulators spo ofically 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 Ivers 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 Who may have criticised the drug industry's growing tendency to conduct their drug trin poor countries, industry representatives defend the practice Bert Spher a spokesman for the Promis cal Research and Manufacturers of America pointed to the enormous bereits drug tras produce by ring the pharmaceutical Industry to market drugs that save countless lives and roleve the suffering and debitation of millions of people. Thoso bereits would not materiale Case Notes 11. Step 3. Cinical Research, "U.S. Food and Drug Administration accessed October 12, 2016, http://www.ida gov/ForPatients/ Approval Drugs/ucm405622. HmCinical Research_Phase_ Studies 12. Chris Galvin, Chalenges to FDA's Ability to Monitor and inspect Formign Clinical Trials, report OE-01-08 00510 Washington, DC Office of Inspector General, US Department of Health & Human Services, 2010), http://oighhs.gowoe/reports/08-01- 08-00510.pdt 13. World Health Organization, "Hepatitis E Fact Sheet No. 280." July 2015. accessed August 20, 2015, http://www.who.in mediacentre/tactsheets/fs2800. 14. Marty Logan"Nepal: Guinea Pigs in Hepatitis E Vaccino Trials." Inter Pruss Service News Agency, February 6, 2006, http:// www.psnews.ne/2006/02epa guinea pigs-in-hepatitis-o- Vaccine-trials 15. Philip C. Stevenson, "Nopal Calls the Shots in Hepatitis E Virus Vaccine Trial, Lancer 355 June 2000; 1623. http://www. researchgate.net/publicafor/12497389 Nepal_cats_the_ shots_in_hepatitis_E.Virus_vaccino trial 16. A Caplan, "Cinical Trials of Drugs and Vaccines Among the Desperatey Poor in Poor Nations Ethical Challenges and Ethical Solutions. "Cinical Pharmacology & Therapeutics BB. no. 5 November 2010): 583-84 17 J. Andrews, "Research in the Ranks Winerable Subjects, Corrable Colaboration, and the Hepatitis E Vaccino Traal in Nepal Perspectives in Bology and Medicine 49, no. 1 Winter 2006) 35-51 18. Donald L. Barlott and Jarnes 3. Sle, "Deady Medicine Vanity Fair, January 2011 19. Mary Pat Flaherty, Deborah Nelson, and Joe Stephans. The Body Hunters Overwhelming the Watchdogs. Washington Post December 18, 2000 20. Sua Lloyd-Roberts, "Have India's Poor Become Human Guinea Pigs?" BBC News, November 2012. http://www.bbc.com nowsmagazine-20130654. Your Thoughts on Testing Drugs in the Developing World 1. Several critics of the drug companies have claimed that the companies' practice of testing drugs on poor people in devel- oping countries violates principles of justice. Why would they say this? Which principles of justice would be involved? 2. Some critics of the drug companies have argued that the doc- tors that have agreed to participate in the drug trails have vio- lated the requirements of the ethic of care. Explain why these critics are right or why they are wrong, The response entered here will appear in the performance dashboard and can be viewed by your instructor. e Read Case Study 2.2: Testing Drugs in the Developing World