In January 2012, biomedical engineer Muhammad Zaman received a disturbing call from a friend. There was trouble in Lahore, the Pakistani city where, coincidentally, Zaman’s father had spent most of his life. People were dying from a mysterious illness, and all of the victims had one thing in common: they had been treated at the Punjab Institute of Cardiology. More than 200 people would die before the government of Punjab province stepped up and seized several drugs that had been used to treat the patients, then sent them to be tested in the United Kingdom. It was a long way to go for an answer, but local drug testing in Lahore was known to be unreliable. The British labs reported that a hypertensive drug, one that was manufactured in Karachi, had been contaminated with an antimalarial, whose active ingredient in raw form looked very similar to the active ingredient in the hypertensive drug. The combination of chemicals allowed the antimalarial to enter the bone marrow in lethal amounts. The killer, in pharmacological language, was “substandard drugs.”
Zaman, a Boston University College of Engineering (ENG) professor of biomedical engineering and a Howard Hughes Medical Institute Professor, was not surprised. As a child in Pakistan, he and his mother would make their way across town to buy medicine at a particular pharmacy, one whose drugs were thought less likely to be adulterated than those from pharmacies closer to his home. “It was just part of the system,” he says. “It’s like you go to a good bakery or a good restaurant. It was much later in life that I realized that that’s not how it’s supposed to be.”
For Zaman, the Lahore deaths were one more reminder of a serious health risk that plagues many developing countries: fake or substandard drugs. It’s a global problem that has been flourishing for three decades and that authorities say gets worse each year. Two BU professors, Zaman and Veronika Wirtz, a School of Public Health (SPH) associate professor of global health, are working on their own ways to solve it.
“Substandard” is the term most often used to describe medicines so poorly manufactured that they contain ingredients that are either toxic or have little or no effective ingredient. Sometimes the deficiency is deliberate, as in the case of falsified, or counterfeit, drugs, although the term “counterfeit” is also used to describe effective drugs made by unlicensed manufacturers. Most often it results from the kind of sloppy or unsanitary manufacturing that is common in developing nations, where quality control is not a priority and enforcement of safe manufacturing practices is feeble or nonexistent. In Pakistan, for example, a country of nearly 200 million people, the number of federal inspectors is around two dozen.
Researchers say that determining the financial impact of substandard or falsified medicines is challenging. In terms of impact on health, a recent study estimates the number of lives lost in children in 39 African countries because of poor-quality malaria medicines to be in the hundreds of thousands.
One study conducted by the World Health Organization (WHO) and written in part by Paul Newton, an Oxford University professor of tropical medicine and an SPH visiting professor, found that substandard antimalarials killed more than 120,000 children under the age of five in sub-Saharan Africa in 2013. Another WHO study, conducted in 2008, found that 64 percent of antimalarial drugs tested in Nigeria were substandard. When the same study looked at antimalarials in Cameroon, Ethiopia, Ghana, Kenya, Nigeria, and Tanzania, it found that 28 percent of 267 samples were substandard.
And the problem is not limited to the developing world. In 2012, more than 60 people died after a steroid used to treat back pain was contaminated with a fungus at the New England Compounding Center in Framingham, Mass.
Zaman says there are no truly accurate estimates of the number of deaths caused by substandard drugs because many people don’t always die immediately. It could take weeks or months for a drug to kill someone. Even if the drug is not toxic, but merely ineffective, it could eventually result in the death of patients who are counting on it to save them.
By 2012, he had heard so many stories of death and injury from substandard drugs that he decided to do something about it. He has been developing a portable device that can test the purity of medicine in the field quickly and easily.
In the last five years, Zaman has traveled throughout Africa and Asia, learning about the tools that were available to test drugs. Many didn’t work. Some hadn’t been used in years, often because no one knew how to use them. What was needed, he realized, was a cheap, portable, easy-to-use device that could quickly determine if a drug was real, fake, or something in between.
Working with researchers Darash Desai (ENG’12,’16), Nga Ho (ENG’16,’16), Andrew Acevedo (ENG’19), Zohar Weinstein (MED’20), Katie Clifford (SPH’12, Questrom’18), and Andrea Fernandes (SPH’10, Questrom’15), and research scientist Atena Shemirani, Zaman has built a toolbox-sized unit that uses a microfluidic sensor to detect molecules that bind to different drugs. Medicines are dissolved in a small amount of water, a second solution is added, and within 15 minutes, a chemical reaction fluoresces in a way that indicates the amount of active ingredient in a particular medicine.
Called PharmaChk, the device was sufficiently impressive to win an initial grant from the US Pharmacopeial Convention under the Promoting the Quality of Medicines program, funded by the US Agency for International Development, and a seed grant of $250,000 from Saving Lives at Birth: A Grand Challenge for Development in 2012. Zaman has also received funding from the Center for Integration of Medicine and Innovative Technology, with critical assistance from medical device entrepreneur Wolfgang Krull and the National Collegiate Inventors and Innovators Alliance, now called VentureWell. In 2014, he won a $2 million “transition-to-scale” grant from Saving Lives at Birth.
He is now testing PharmaChk in Ghana, starting with antimalarials. “They are a huge problem in Africa,” he says. “Out of the 215 million cases of malaria every year, a significant number are in Africa, and anywhere from 30 to 50 percent of the patients in Africa are getting poor-quality drugs.”
So far, he says, his team has run extensive tests in Ghana, and the device is working as well as other more expensive or more cumbersome state-of-the-art instruments used for similar purposes in developing nations. If PharmaChk performs as expected, providing accurate results quickly and easily, Zaman says, he will expand the kinds of drugs tested to include uterotonics, which are used to reduce postpartum hemorrhage. He will also extend his reach, into Indonesia, where he will test the device on antimalarials.
“The next step is to leave PharmaChk in Ghana for three months in real-world scenarios such as large public hospitals and see what happens,” he says. “We want to demonstrate that we can handle a small problem really well, then expand it.”
Zaman is quick to say that the solution to the substandard drug problem does not lie in technology alone. The answers will come from many quarters, including the regulatory agencies and policymakers that are the focus of Wirtz’s research. She identifies policy and regulatory changes that could stem the sale of substandard medicines, with a special focus on developing nations.
Between 2014 and 2016, Wirtz was the cochair of The Lancet Commission on Essential Medicines Policies, which in 2016 published a 74-page report on the global availability of necessary drugs, including an investigation of the quality and safety of drugs in developing nations. The commission found several reasons for hope: some countries are stepping up efforts to agree on quality standards, and several new technologies, including mobile phone apps, promise to help health providers and consumers detect problematic drugs. But the commission also reported some bad news: “The sophistication of falsified medicines seems to be increasing, as does their number,” adding that the perceived increase may be the result of better reporting.
“The problem of quality-assured medicine is so important, not just in terms of harm, but in terms of efficiency,” says Wirtz. “Particularly in low- and middle-income countries, where there are very little resources, it’s very important to have products that actually work. Otherwise we waste scarce resources.”
The Lancet Commission report relates the story of Adwoa, a two-year-old girl whose three-day fever sent her mother, Grace, to a local shop for antimalarial drugs. Grace was given three loose tablets and told to give her child a half-tablet at once and the rest over two days. When the medicine failed to cool Adwoa’s fevered body, her family rushed her to a hospital, where she was diagnosed with cerebral malaria, a syndrome that would almost certainly have killed her had she not been treated, and one that often causes permanent brain damage. Investigators later found that the antimalarial that Adwoa had been given lacked enough of the active ingredient necessary to be effective.
For Wirtz, Adwoa’s story is all too familiar. The Lancet Commission reports that in 2016 in Myanmar, the packaging on two different drugs used to treat hepatitis C was falsely marked with the name of a manufacturer that never actually produced either of the drugs. And when the WHO looked at the quality of misoprostol, used to jump-start labor, in 15 middle-income countries, its researchers found that only 55 percent of 215 products contained the correct quantity of the active ingredient and 7 percent did not contain any of the active ingredient. The Lancet Commission also notes that more than 100 children were killed in Panama in 2006 when toxic diethylene glycol ended up in a paracetamol—also known as the pain reliever acetaminophen—oral liquid.
The Lancet Commission found more than 1,000 reports of substandard and falsified drugs had been filed by national medicine regulatory (NMRAs—country-specific FDA-like agencies) and other procurement agencies with the WHO’s Rapid Alert System since the organization started to encourage such reporting in 2011. But even when authorities like the NMRAs are alerted to bad drugs, the commission determined, many of them lack the resources needed for meaningful action.
The NMRA, says Wirtz, “is not necessarily the most beloved child of the minister of health.” Most agencies have little staff and very little money. “The result is they’ll say, ‘Oh, do we really need another quality check? We just did one two years ago. Let’s wait another two years.’”
Even when the origin of a medicine is known, she says, there can still be questions about its risk. That’s because different countries have different ideas about what makes a good manufacturing practice (GMP) standard, and many of those national definitions are not in sync with the definition established internationally. One study mentioned by the commission found that 44 generic drugmakers in low- and middle-income countries were in compliance with their national GMP standards, but less than a third of those met the global standards set by the WHO or the Pharmaceutical Inspection Co-operation Scheme, an extension of the Pharmaceutical Inspection Convention founded by the European Free Trade Association.
Wirtz believes that the battle against substandard drugs must be fought on several fronts, from the bureaucratic to the technological. She and commission members would like to see the significant expansion of the successful WHO Prequalification of Medicines Programme (PQP), which prequalifies drugs sold by international vendors. PQP, started in 1987 with childhood vaccines, now prequalifies vaccines that immunize 64 percent of infants worldwide. It has earned the allegiance of the nonprofit Global Fund, which fights against AIDS, tuberculosis, and malaria and now buys only drugs that have been prequalified.
“The program works,” says Wirtz, whose research is funded by the Bill & Melinda Gates Foundation. “It publishes all of the results on its website, so you can go and see which products have been quality-tested.”
Still, she says, the WHO program is put to work in far too few countries. In January 2016, only six countries in Africa and six in Asia had medicine quality-control laboratories prequalified by the WHO. Wirtz would like to see more countries get on board or do something similar to what was done in Kenya, where the Mission for Essential Drugs and Supplies, a collective of faith-based health organizations, operates its own quality-control laboratory. From 1997 to 2015, the well-published results of the collective’s testing have helped reduce the failure rate of drugs from about 35 percent to 5 percent.
Other answers to the problem will likely be found in technology, says Wirtz. She cites Zaman’s PharmaChk as a promising example, and there are others, such as the Minilab, which uses chromatography to identify false or substandard products. She says more than 700 Minilabs, which can be used in the field by people with almost no training, are now in use in 70 countries.
“A wide array of technologies have been proposed,” the commission’s report states, “from unique serial numbers to radio frequency identification tags, miniature edible tablet tags, and short message service verification.”
Wirtz’s Lancet study also mentions mobile phone technologies that enable consumers to scratch a panel on a packet and scan a special single-use code verifying a product’s authenticity. As is often the case with technology, the commission warns, the solutions offered may well be undermined by more technology. In fact, attempts to game one such phone-based system have already been seen in Nigeria. “We are going to need multiple tools,” Wirtz says. “We need the right tools for the right context. We are coming closer, but it’s still a field that is relatively young.”