Bad medicine

Patrick Lukulay faced a daunting task this month when he stepped off a plane in Accra, Ghana. Local clinics were reporting that oxytocin, a drug used to stop hemorrhaging after childbirth, was no longer working.

Doctors had to double the dose to have the desired effect. Sometimes they had to try different brands before they found one that worked. Lukulay, vice president of global health impact programs at U.S. Pharmacopoeia (USP), had traveled to Ghana to train staff at African regulatory agencies to crack down on poor-quality drugs. According to the World Health Organization, 30% of member states have little to no regulatory oversight of pharmaceuticals.

To illustrate how bad the problem can be, a study this year by USP and the Ghana Food and Drugs Authority found 90% of oxytocin sold “failed quality specifications,” Lukulay says, calling the results “damning.”

USP, a not-for-profit organization that sets quality standards for medicines, launched its program for training overseas regulators because its purity standards are being routinely violated abroad. Substandard products from poorly regulated producers are beginning to affect the quality of the U.S. drug supply. Unlike counterfeit, or falsified, drugs, which are an intentional effort by criminals to slip fake products into the global drug supply chain, substandard drugs are made by legitimate companies that bungle the manufacturing process.

It's a threat that is likely to grow in the years ahead. American manufacturers are increasingly looking abroad for their active pharmaceutical ingredients and even finished medicines. The heparin disaster in 2008, when 81 people died in the U.S. after tainted Chinese chemicals entered the supply chain, awakened supply-chain officials to the poor oversight of foreign-made goods. Globally, substandard medicines in poorly regulated markets are causing countless injuries and deaths and are thought to be a leading cause of growing resistance to treatments for malaria, bacterial infections and tuberculosis.

“I think substandard medicines have been a neglected aspect of the poor-quality medicine problem,” says Dr. Paul Newton, an infectious disease specialist with the Wellcome Trust-Mahosot Hospital-Oxford Tropical Medicine Research Collaboration in Laos.

The manufacturers of substandard drugs are usually in low-income countries that rely on generic versions of drugs for common conditions and usually lack regulatory rigor over their own drug supplies. Roger Bate, an economist at the American Enterprise Institute, a right-of-center think tank, and his colleagues have sent local shoppers into pharmacies to buy medicines in countries such as Uganda. After testing the products, they've found substandard rates as high as 48%.

“From the research I've done, there's no doubt that income is an inverse determinant to how many substandard drugs one is likely to encounter,” Bate says.

Although poorer countries bear the burden of substandard drugs, the products can find their way to the U.S. Late in 2011, the Indian drugmaker Ranbaxy earned exclusive rights to sell the first generic version of Lipitor (atorvastatin) in the U.S., “probably the biggest prize any generics company could ask for,” says Amir Attaran, an associate professor at the University of Ottawa.

But within a year, all hopes of dominating the market for generic atorvastatin crashed when a machinery failure allowed broken glass to wind up in bottles, forcing Ranbaxy to pull the drug from the market. “They screwed it up,” Attaran says. Other companies rushed in to fill the void, and Ranbaxy quickly lost its atorvastatin franchise.

Just last week, Ranbaxy agreed to plead guilty in U.S. federal court and pay $500 million to resolve allegations of shoddy factory inspections and poor quality control. The company agreed to plead guilty to seven felony counts of introducing “adulterated” drugs into interstate commerce and making false statements to the U.S. Food and Drug Administration. All of the drugs were produced at company plants in India.

While there are scant data on the prevalence of substandard medicines, many argue that the problem is growing. In poorer countries, it's more a matter of incompetence on the part of drug companies or distributors. “The pharmaceutical industry globally has blossomed over the past 10, 15 years, and quality control has not kept up,” Newton says. For example, Bate says he's found 284 anti-malarial drugs being sold in Nigeria alone. “That's not a diverse competitive market, that's insanity,” he says.

In developed countries such as the U.S., the problem stems more from an increasing reliance on overseas suppliers, coupled with a labyrinthine supply chain. Drugs used to be made primarily in the U.S. and from active pharmaceutical ingredients procured in the U.S.

But now, “80% of what goes down an American's throat comes from abroad,” Attaran says. Globalization of drug manufacturing is a “good thing,” he says, but it has also opened up opportunities for quality to become compromised, either by a lack of know-how or pressure to reduce costs by cutting corners.

The heparin tragedy five years ago is the poster child for what can happen. The widespread poisonings occurred after Baxter purchased ingredients contaminated with a cheap product that imitated some of the drug's properties. A subsequent investigation by the FDA listed numerous chemical suppliers in China connected with providing the poisoned heparin or products used in making it. According to the FDA's website, the presence of the contaminant suggests that somewhere along the supply chain it was “added intentionally to heparin for financial reasons because it is a very cheap material prepared by a simple synthetic process.”

The incident sent shockwaves through the ranks of U.S. supply-chain officials, who have to scramble whenever there is a major recall, especially of widely used drugs. “Sometimes there are no alternatives available,” says Deborah Templeton, vice president of supply chain services at Geisinger Health System, Danville, Pa.

Drug shortages are also an indirect effect of substandard medicines. “Among the causes of drug shortages are manufacturing issues, quality issues,” says Kasey Thompson, vice president of policy, planning and communications at the American Society of Health-System Pharmacists.

Thompson says the globalization of drug manufacturing, and the inability of regulators to oversee every step of the process, is “by far the biggest challenge facing us today, and it's only going to grow.”

The most direct way to prevent substandard medicines from entering the supply chain in the first place is to strengthen regulatory oversight abroad. That's Lukulay's goal as he launches the Center for Pharmaceutical Advancement and Training in Ghana this month. The program, funded by USP, will educate regulatory agency staff in African countries. “Human resource capacity is the major issue in these countries, (especially) high staff turnover. Regulatory agencies are (staffed) with newcomers that do not have experience,” he says.

USP also runs a USAID-funded program in 35 countries to help bolster quality control. The program has helped to establish drug monitoring sites where it trains staff to conduct regular testing and identify suspicious products for further scrutiny.

“USAID and USP funding cannot reach every corner of the world that needs our help,” Lukulay says. Moreover, some countries don't put out the welcome mat for foreigners looking to train local regulators that will take action against legitimate, local drugmakers that pay taxes and employ people. “We understand this pressure exists,” he says. “I must say it's probably one of the reasons why these facilities (continue to) operate.”

Tougher regulatory oversight can bring another challenge—how to help manufacturers that serve those markets meet the higher quality standards. Companies that sell low-cost generic drugs often lack technical expertise and capital needed to bring their facilities up to a higher level of quality.

“There are a lot of costs to adhere to international standards,” says Gillian Buckley, the study director of a recent report by the Institute of Medicine on substandard and falsified drugs. Purchasing equipment in overseas markets requires hard currency that can be difficult to come by. The IOM committee recommended that development finance organizations such as the World Bank or the U.S. Overseas Private Investment Corp. invest in improving small- and medium-size drugmakers in developing countries.

Lukulay, who was one of the authors of the IOM report, recognizes it will be a gradual process and recommends encouraging foreign regulatory authorities and companies to develop five-year plans to reach the higher standards. “I think if you give companies sufficient time to recognize you are serious, that would be the best practical solution,” he says. “To just say, 'any company below standards, we're going to shut them down,' it's going to be political suicide.”

In the U.S., the FDA has recognized that substandard medicines are a growing threat. In response, the agency wants to be more proactive at preventing poor-quality drugs from being produced, rather than trying to block them at entry into the country.

It has stepped up its oversight of facilities that feed into the American drug supply chain. Foreign inspections by FDA personnel climbed from 305 in 2007 to 563 in 2013.

The FDA has also stepped up its efforts to stem the supply of substandard drugs that is plaguing developing countries in hopes it will also improve the drug supply chain in the U.S. Last month, the agency unveiled a new, handheld technology—developed under the auspices of the President's Malaria Initiative, launched in 2005—that will be tested in Africa to detect counterfeit and ineffective anti-malarials.

FDA Commissioner Dr. Margaret Hamburg said during a news conference that the “FDA hopes the testing will demonstrate the effectiveness of this tool and encourage its wide-scale use to significantly improve the integrity of products that end up on the dinner table or at the bedside of patients in the United States and around the world.”

Despite the FDA's efforts, the Government Accountability Office has expressed concerns that the agency is simply underpowered to keep a close eye on every step of the supply chain. Those foreign inspections reflect only a small fraction of the facilities that are subject to scrutiny. “FDA faces limits on its ability to require foreign establishments to allow it to inspect their facilities,” the GAO noted in a 2011 report, Drug Safety: FDA Faces Challenges Overseeing the Foreign Drug Manufacturing Supply Chain. “Logistical issues preclude the FDA from conducting unannounced inspections, as it does for domestic establishments,” according to the report.

The AEI's Bate says FDA inspections are important, but that they are not the solution. “It's going to come down to companies themselves,” he says. The drug industry also inspects the plants they use to make the active ingredients in pharmaceuticals, but Bate says it's impossible to be perfectly thorough.

Imagine the challenge: multiple suppliers of raw ingredients feed into production of the active and inactive ingredients. To fully keep an eye on the entire supply chain would have to include these suppliers, the facilities where the drug is formulated, and the plant where it is packaged. Checking on them once does not mean they will be in the same condition the next time round, Lukulay says.

“You can't run every test on every chemical because you'd run out of money,” Bate says. He proposes an auditing system that pools resources from companies to form a stronger overall inspection presence abroad. None is planned, according to a spokesman for the Pharmaceutical Research and Manufacturers of America, the drug industry's major trade group.

Meanwhile, the generic drug industry contends that substandard medicines are not a problem for the U.S. market. “There just isn't a substandard issue here” in the U.S., says David Gaugh, senior vice president for sciences and regulatory affairs at the Generic Pharmaceutical Association.

Gaugh points to the rigorous testing criteria required to import drugs for sale in the U.S. But as Lukulay notes in the case of heparin, “just because there are good manufacturing practice audits conducted, there is no fool-proof way to say you can't end up with a bad API supplier.”

Templeton at Geisinger says her group relies on the quality-control measures by manufacturers and “assumes that we're getting good quality products.” But she says it's also incumbent upon doctors and other users to take action when something doesn't appear right.

As much as globalization might introduce risk, Bate says it can't be stopped, nor should it be. “If we stop buying from these countries we'd have many more (drug) shortages than we do and prices would go up a lot,” he says.

Attaran is hopeful that the problem might work itself out over time by companies' refusing to put up with poor-quality products. Ranbaxy quickly evaluated its problems and put in corrective measures to prevent a recurrence. While the company has since renewed selling atorvastatin, “this was a blemish in our overall corporate complexion,” says Chuck Caprariello, a spokesman for the company. Ranbaxy never recovered its previous share of the market.

Baxter never resumed selling heparin and sold the division that made the drug. “Companies will make the calculation,” Attaran says. “Is it worth the damage to one's brand, is it worth the PR nightmare, the settlements to injured persons, to save a little money by sourcing from unreliable locations?”

Kerry Grens is a freelance writer in suburban Chicago. Reach her at [email protected].