01/04/2012 - They assumed the medicine would make them better.
Instead, at least 105 Americans died after taking a new sulfa drug that had been tainted with an industrial solvent. There was public outrage, and Congress responded swiftly, passing a law to protect people from dangerous, contaminated or counterfeit products.
That episode was nearly three-quarters of a century ago, and ever since Americans have trusted that the medicine they buy at the local pharmacy is safe. For the most part, it has been.
But the world has changed considerably since President Franklin D. Roosevelt signed the Food, Drug, and Cosmetic Act in 1938, the year after that deadly sulfa scare. In those days, almost all the medications Americans relied on, as well as the ingredients that went into them, were produced in the United States. Today, 80 percent of the ingredients used in medications sold in this country and 40 percent of finished drugs are manufactured overseas, with little U.S. government oversight.
Time and again in recent years, common medications, altered by accident or design, have killed or harmed people in this country and elsewhere. In late 2007 and early 2008, dozens of people in the United States suffered adverse reactions, including several who died, after taking adulterated heparin, a common blood thinner. In 2006, at least 78 patients died in Panama when the government unwittingly distributed cough syrup that contained diethylene glycol, the same solvent that killed so many Americans 69 years earlier and that has killed children in Haiti and Nigeria in recent decades.
There are too many unscrupulous actors eager to make a buck—or, more likely, millions of them—from counterfeit or adulterated drugs, too many middlemen with the wherewithal to tamper with medications, too many opportunities for the drugs to be stolen or diverted, too few safeguards to protect them from criminal acts or negligence and too little money to get the job done, said U.S. officials charged with protecting the public from unsafe drugs.
“I think it’s important to recognize that while drug crises aren’t documented that frequently, there are real threats in the supply chain,” said Deborah Autor, the U.S. Food and Drug Administration (FDA) official who oversees global drug production. “With respect to another crisis like heparin, it’s really not a question of if it will happen. It’s a question of when it will happen.”
The FDA has outlined proposals that would give the agency increased authority and more money, especially for overseas inspections, to better protect the public.
“It really would be much better for the American public if we have in place a sufficient statutory scheme and safety net to prevent drug-contamination-quality problems and counterfeiting to the fullest extent possible,” Autor said. “That new legislation is essential to equip the FDA to move from being a regulator of domestic products to being one overseeing a worldwide enterprise.”
The Pew Health Group has been working toward that goal since the heparin deaths.
“Heparin was a wake-up call for a lot of parties, including the pharmaceutical industry and the FDA itself … and for us,” said Allan Coukell, the health group’s director of medical programs.
In late 2007, the FDA and the U.S. Centers for Disease Control and Prevention began fielding complaints that patients undergoing dialysis were suffering from allergic-type reactions and hypotension. The culprit turned out to be heparin, and investigators determined that the drug’s active ingredient, which is derived from pig tissue, had been contaminated with a cheaper, synthetic material during the manufacturing process in China.
Gordon Johnston, senior adviser for regulatory sciences for the Generic Pharmaceutical Association, called the heparin deaths the turning point for drug companies and others up and down the supply chain. The event forced the industry “to understand that there are those out there who have economic motivations to adulterate materials used in drugs.”
The heparin episode made clear that the system designed to safeguard drug production in the United States did not work on a global scale, Coukell said.
The 1938 law spurred by those earlier deaths enumerated a host of requirements for companies that produced drugs and their ingredients in the United States. But it could not foresee that one day much of that production would occur overseas. Currently, Americans consume medications manufactured in about 150 countries, led by China and India, according to the FDA.
The difference in oversight is stark: If you operate a plant that manufactures drugs or their ingredients in the United States, you can expect an FDA inspector to visit every two or three years. If you run a similar plant overseas, you can expect an FDA inspector to visit maybe every nine years, the stated average. Some plants may never be inspected, Coukell said.
“In reality, what you get is pre-approval inspections”—the FDA gives the nod to a plant to begin production—“then they don’t get back there,” he said. “They’re done before the company’s actually making drugs.”
Once they receive pre-approval to manufacture a drug overseas, it is up to pharmaceutical companies to ensure the medications they sell are safe. But, again, the global marketplace makes that difficult, according to Coukell and industry representatives. From production to transportation to distribution, there are numerous points during which a drug might become jeopardized. In some countries, estimates of counterfeit drugs infiltrating the supply chain are as high as 30 percent, according to the World Health Organization’s International Medical Products Anti-Counterfeiting Taskforce. Although there are no precise estimates for counterfeit or adulterated drugs in the United States—and the figure certainly is nowhere near 30 percent—vulnerabilities exist.
“A lot of companies are outsourcing their manufacturing, and some don’t have good insight as to who their suppliers are or the conditions under which drugs are being manufactured,” Coukell said.
Further, he said, suppliers can outsource production without the knowledge of the pharmaceutical companies that affix their names to the medications. In some cases, the FDA has documented the existence of “show-shadow factories,” in which the makers of potentially unsafe drugs or ingredients set up two factories—a fake, clean one to show inspectors and one where the work actually takes place, Coukell said.
“We need the manufacturers themselves to be held accountable for overseeing their own supply chain,” he said. “Many companies already do that. But we have to make sure the weakest actors and those who want to cut corners meet standards.”
Fresh from a victory on food safety in which Pew helped bring together industry representatives and food safety advocates, the Pew Health Group has conducted extensive research, produced a 2011 report titled After Heparin: Protecting Consumers from the Risks of Substandard and Counterfeit Drugs, convened a roundtable and, again, served as an “honest broker” among stakeholders as it works toward the goal of better protecting the American public’s drug supply. In January 2011, President Barack Obama signed the FDA Food Safety Modernization Act, which represents the first significant change to food-safety provisions of the Food, Drug and Cosmetic Act since Roosevelt’s day. Pew, the FDA and a number of pharmaceutical companies and trade associations are pushing for a similar update to laws regulating medications.
“There are dangerous, hidden, unnecessary risks in the products we rely on every day,” said Shelley A. Hearne, managing director of the Pew Health Group. “We look for those smart, commonsense improvements that make for a better, more efficient, safer marketplace.”
The new food safety law “gave some basic, long-overdue fixes to an antiquated food safety system overseen by the FDA,” Hearne noted. It gave the FDA the authority to recall contaminated products and to increase inspection. It put into place risk-based standards for inspecting fruits and vegetables. It took into consideration that food is not produced in the same way or in the same places as it was seven decades ago.
Similarly, Hearne said, Congress should update the law on pharmaceuticals. “We do not have the same type of tools and sophistication within the FDA to ensure the safety and efficacy of our drugs,” she said. “It’s shockingly similar to those commonsense fixes we just got in place for fruits and vegetables.
“Most Americans sleep better assuming that their government is keeping an eye out to ensure that contaminated, counterfeit, adulterated products aren’t coming into the marketplace. We fixed it on foods; now we need to fix it on pharmaceuticals. We count on it to improve and save our lives.”
On two days in March 2011, Pew convened a Washington, DC, conference that brought together people involved in the manufacture, distribution, sales, analysis, research and oversight of pharmaceuticals in the United States. Participants included the president of the nation’s largest generic drug company, the director of a China-based pharmaceutical auditing company, representatives of pharmaceutical companies, pharmacists, and chain and independent drugstores. Also participating in the meeting were representatives of physicians and consumers, AARP, the FDA and trade associations representing just about everyone along the supply chain.
“Like most people, I didn’t spend a lot of time worrying about the safety of pharmaceutical products. Tainted pharmaceutical drugs were simply a news story that I read about in the papers. But now we know how globalized the drug supply chain has become,” said Sen. Michael Bennet, a Colorado Democrat and member of the Health, Education, Labor, and Pensions Committee, who delivered the conference’s keynote.
“Making sure pharmaceutical drugs meet the highest standards for safety and quality is important to me, not only as a U.S. senator but as a parent.”
Bennet has introduced legislation that would strengthen the FDA’s oversight of pharmaceuticals by giving it the power to recall medications—a practice that currently is voluntary—improve its tracking systems and require drug companies to have quality-management plans.
“We can take key steps, including more accountability of drug company ingredients, requiring the FDA to fix its inadequate monitoring systems, and increasing penalties for those who game the system,” he said.
Advocates for improved oversight hope Congress will act in 2012, when it is expected to reauthorize the Prescription Drug User Fee Act and pass the Generic Drug User Fee Act, which will help finance FDA inspections.
- After the conference, Pew’s final report made a number of policy recommendations, including these:
- Significantly increase the FDA’s oversight of foreign drug manufacturing and use comprehensive risk assessment to prioritize inspections.
- Augment the FDA’s oversight through the use of other inspections, including those conducted by trusted foreign regulatory agencies or third-party inspectors.
- Improving baseline requirements for manufacturer-quality systems, including oversight of contractors and suppliers.
- Strengthening border screening and give the FDA the authority to destroy or refuse entry to products at the border.
- Allow the FDA to require drug recalls and providing it with subpoena power.
- Stiffen criminal and civil penalties for violations.
- Create a “track and trace” system, featuring unique serial numbers for every bottle or box of medicine, to allow wholesalers and pharmacies to verify authenticity.
Pew is following through on the report and conference outcomes, educating members of Congress and their staffs about the need to update the law and working to build a bipartisan coalition of support.
“This is not a partisan issue,” Hearne said. Instead, the challenge is bringing about change in an era of austerity. “We’ve got a constricting federal budget, we have a federal agency that is already overburdened and understaffed, we have a wide range of interests and concerns out there,” she said. “While these are commonsense fixes, we’ve got to make sure that they stay in a high-priority queue.”
A number of industry advocates are joining with the FDA and Pew to push for change. That is unusual in Washington, where it is far more commonplace for regulators and the regulated to be on opposite sides of issues related to mandates, compliance and fees. But in this case, with some coordination from Pew, many groups are collaborating to protect the public—and themselves. After all, if the medications that Americans need are unsafe, there will be plenty of blame to go around.
“The pharmaceutical companies are responsible for the safety of their supply chain. We as an industry are stepping up to that challenge in the face of the threats coming at us,” said Martin Van Trieste, founder and board member of Rx-360, a nonprofit consortium of pharmaceutical companies and their suppliers. “However,” he said, “we can use help from policy makers and regulators around the world.”
The 70 companies represented by Rx-360 would be willing to pay higher fees to finance FDA inspections because it would “level the playing field” by penalizing those who today are “profiting from cutting corners,” said Van Trieste, who also is senior vice president for quality at Amgen. “It will economically help the compliant manufacturers.”
Additionally, he said, tougher regulations, increased transparency along the entire supply line and harsher penalties would make it more difficult for counterfeiters to get their products into pharmacies. Under current law, he said, there is little disincentive—and considerable financial motivation—for those who deal in phony or adulterated medications.
“If you get caught counterfeiting a Gucci purse or a DVD, you will go to jail longer than if you counterfeit a pharmaceutical that kills people,” he said. “If a criminal takes $1,000 and then turns that into a counterfeit consumer good like a Gucci purse or a Rolex, he can make about $10,000. If he takes that same $1,000 and turns it into an illicit drug like crack cocaine or heroin, he can make $100,000. If he takes $1,000 and turns it into a pharmaceutical, he can turn it into a million dollars.”After Heparin
cited one industry insider who estimated that the makers of the adulterated heparin made $1 million to $3 million in profits.
What’s more, counterfeit and adulterated drugs are becoming more sophisticated than in the past, and harder to detect. Standard tests on the tainted heparin did not indicate the presence of oversulfated chondroitin sulfate, a synthetic that is similar to the actual drug but substantially cheaper to produce. In Panama, it took investigators more than a month to identify that children’s cough syrup contained diethylene glycol, the solvent used in antifreeze, rather than glycerin. And because the material went through brokers in China and Spain—and was relabeled by each one—officials had trouble pinpointing the source.
For most of seven decades, the Food, Drug, and Cosmetic Act permitted Americans to feel secure that the contents of their medicine cabinets were safe. Globalization has removed some of that assurance.
“The assumption is that, of course, the government is doing that,” Hearne said. “There are certain, basic things you just want to trust. So let’s make sure those systems are in place.”
Jodi Enda, former White House correspondent for Knight-Ridder Newspapers, is a Washington-based writer. She last wrote for Trust about Pew’s Public Safety Performance Project.