How Some Generic Drugs Could Do More Harm Than Good
For the 16 years that Dr. Brian Westerberg, a Canadian surgeon, worked volunteer missions at the Mulago National Referral Hospital in Kampala, Uganda, scarcity was the norm. The patients usually exceeded the 1,500 allotted beds. Running water was once cut off when the debt-ridden hospital was unable to pay its bills. On some of his early trips, Westerberg even brought over drugs from Canada in order to treat patients. But as low-cost generics made in India and China became widely available through Uganda’s government and international aid agencies in the early 2000s, it seemed at first like the supply issue had been solved.
Then on February 7, 2013, Westerberg examined a feverish 13-year-old boy who had fluid oozing from an ear infection. He suspected bacterial meningitis, though he couldn’t confirm his diagnosis because the CT scanner had broken down. The boy was given intravenous ceftriaxone, a broad-spectrum antibiotic that Westerberg believed would cure him. But after four days of treatment, the ear had only gotten worse. As Westerberg prepared to operate, the boy had a seizure. With the CT scanner working again, Westerberg ordered an urgent scan, which revealed small abscesses in the boy’s skull, likely caused by the infection.
When a hospital neurosurgeon looked at the images and confidently declared that surgery was unnecessary and the swelling and abscesses would abate with effective antibiotic treatment, Westerberg was confused. They had already treated the boy with intravenous ceftriaxone, which hadn’t worked. His confusion deepened when his colleague suggested that they switch the boy to a more expensive version of the drug. Why swap one ceftriaxone for another?
Most people assume that a drug is a drug — that Lipitor, for example, or a generic version, is the same anywhere in the world, so long as it’s made by a reputable drug company that has been inspected and approved by regulators. That, at least, is the logic that has driven the global generic-drug revolution: that drug companies in countries like India and China can make low-cost, high-quality drugs for markets around the world. These companies have been hailed as public-health heroes and global equalizers, by making the same cures available to the wealthy and impoverished.
But many of the generic drug companies that Americans and Africans alike depend on, which I spent a decade investigating, hold a dark secret: they routinely adjust their manufacturing standards depending on the country buying their drugs, a practice that could endanger not just those who take the lower-quality medicine but the population at large.
These companies send their highest-quality drugs to markets with the most vigilant regulators, such as the U.S. and the European Union. They send their worst drugs — made with lower-quality ingredients and less scrupulous testing — to countries with the weakest review.
The U.S. drug supply is not immune to quality crises — over the last ten months, dozens of versions of the generic blood pressure drugs valsartan, losartan and irbesartan have been subject to sweeping recalls. The active ingredients in some, manufactured in China, contained a probable carcinogen once used in the production of liquid rocket fuel. But the patients who suffer most are those in so-called “R.O.W. markets” — the generic-drug industry’s shorthand for “Rest of World.” In swaths of Africa, Southeast Asia and other areas with developing markets, some generic drug companies have made a cold calculation: they can sell their cheapest drugs where they will be least likely to get caught.
In Africa, for instance, pharmaceuticals used to come from more developed countries, through donations and small purchases. So when Indian drug reps offering cheap generics started arriving, the initial feeling was positive. But Africa soon became an avenue “to send anything at all,” said Kwabena Ofori-Kwakye, associate professor in the pharmaceutics department at the Kwame Nkrumah University of Science and Technology in Kumasi, Ghana. The poor quality has affected every type of medication, and the adverse impact on health has been “astronomical,” he told me.
Multiple doctors I spoke to throughout the continent said they have adjusted their medical treatment in response, sometimes tripling recommended doses to produce a therapeutic effect. Dr. Gordon Donnir, former head of the psychiatry department at the Komfo Anokye teaching hospital in Kumasi, treats middle-class Ghanaians in his private practice and says that almost all the drugs his patients take are substandard, leading him to increase his patients’ doses significantly. While his European colleagues typically prescribe 2.5 milligrams of haloperidol (a generic form of Haldol) several times a day to treat psychosis, he’ll prescribe 10 milligrams, also several times a day, because he knows the 2.5 milligrams “won’t do anything.” Donnir once gave ten times the typical dose of generic Diazepam, an anti-anxiety drug, to a 15-year-old boy, an amount that should have knocked him out. The patient was “still smiling,” Donnir said.
Many hospitals also keep a stash of what they call “fancy” drugs — either brand-name drugs or higher-quality generics — to treat patients who should have recovered after a round of treatment but didn’t. Confronted with the ailing boy at the Mulago hospital, Westerberg’s colleagues swapped in the more expensive version of ceftriaxone and added more drugs to the treatment plan. But it was too late. In the second week of his treatment, the boy was declared brain dead.
Westerberg’s Ugandan colleagues were not surprised. Their patients frequently died when treated with drugs that should have saved them. And there were not enough “fancy” drugs to go around, making every day an exercise in pharmaceutical triage. It was also hard to keep track of which generics were safe and which were not to be trusted, said one doctor in Western Uganda: “It’s anesthesia today, ceftriaxone tomorrow, amoxicillin the next day.”
Westerberg, shaken by his newfound knowledge, flew back to Canada and teamed up with a Canadian respiratory therapist, Jason Nickerson, who’d had similar experiences with bad medicine in Ghana. They decided to test the chemical properties of the generic ceftriaxone that had been implicated in the Ugandan boy’s death. Another of Westerberg’s colleagues brought him a vial from the Mulago hospital pharmacy. The drug had been made by a manufacturer in northern China, which also exported to the U.S. and other developed markets. But when they tested the ceftriaxone at Nickerson’s lab, it contained less than half the active drug ingredient stated on the label. At such low concentration, the drug was basically useless, Nickerson said. He and Westerberg published a case report in the CDC’s Morbidity and Mortality Weekly Report. Although they couldn’t say with certainty that the boy had died due to substandard ceftriaxone, their report offered compelling evidence that he had.
Some companies claim that, while their drugs are all high-quality, there may be some variance in how they are produced because regulations differ from market to market. But Patrick H. Lukulay, former vice president of global health impact programs for USP (formerly U.S. Pharmacopeia), one of the world’s top pharmaceutical standard-setting organizations, calls that argument “totally garbage.” For any given drug, he says, “There’s only one standard, and that standard was set by the originator,” meaning the brand-name company that developed the product.
It’s not just those in developing markets who should be alarmed. Often, substandard drugs do not contain enough active ingredient to effectively cure sick patients. But they do contain enough to kill off the weakest microbes while leaving the strongest intact. These surviving microbes go on to reproduce, creating a new generation of pathogens capable of resisting even fully potent, properly made medicine. In 2011, during an outbreak of drug-resistant malaria on the Thailand-Cambodia border, USP’s chief of party in Indonesia Christopher Raymond strongly suspected substandard drugs as a culprit. Treating patients with drugs that contain a little bit of active ingredient, as he put it, is like “putting out fire with gasoline.”
USP is so concerned about this issue that in 2017 it launched a center called the Quality Institute, which funds research into the link between drug quality and resistance. In late 2018, Boston University biomedical engineering professor Muhammad Zaman studied a commonly used antibiotic called rifampicin that, if not manufactured properly, yields a chemical substance called rifampicin quinone when it degrades. When Zaman subjected bacteria to this substance, it developed mutations that helped it resist rifampicin and other similar drugs. Zaman concluded from his work that substandard drugs are an “independent pillar” in the global menace of drug resistance.
The low cost of generic drugs makes them essential to global public health. But if those bargain drugs are of low quality, they do more harm than good. For years, politicians, regulators and aid workers have focused on ensuring access to these drugs. Going forward, they must place equal value on quality, through an exacting program of unannounced inspections, routine testing of drugs already on the market and strict legal enforcement against companies manufacturing subpar medicine. One model is the airline industry, which through international laws and treaties, has established clear global standards for aviation safety.
Without something similar for safe and effective drugs, the twin forces of subpar medicine and growing drug resistance will be so destructive that developed countries won’t be able to ignore them. As Elizabeth Pisani, an epidemiologist who has studied drug quality in Indonesia, put it, “The fact is, pathogens know no borders.”
Adapted from an excerpt of Bottle of Lies: The Inside Story of the Generic Drug Boom by Katherine Eban with permission from Ecco, an imprint of HarperCollins Publishers. Copyright © 2019 by Katherine Eban. All rights reserved.