April 22, 2018
Woman working at the factory

Foreignceuticals: Our Drugs Go Global

by Berkeley Wellness  

You are used to seeing “made in China” (or India, Romania, or wherever) stickers on items you buy. One of the few places you probably haven't seen such labels is on your medicine bottles; yet even the most casual reader of the news must know that U.S. pharmaceutical companies are buying increasing amounts of drugs and ingredients for drugs from other countries—billions of dollars' worth.

Your blood pressure medicine or over-the-counter pain reliever, for example, may come from a factory abroad, but you have no way of knowing. The same is true of your multivitamin. Many dietary supplements are imported, though the labels don’t say so. Nearly all of the vitamin C used in supplements (and fortified foods), for example, is made in China—it might as well be called vitamin China. Herbs are harvested all over the world, and the bottles typically don’t say where they come from. What’s more, there’s no guarantee that the bottles contain what’s stated on the labels, since dietary supplements are very lightly regulated in this country.

The big advantage of these imports is lower prices. But that may not remain true if the new U.S. administration has its way. President Donald Trump has stated that companies, including drug companies, should do their manufacturing in the U.S. Should imports fall off, it could cause drug prices to rise, especially when you consider that some 88 percent of all prescriptions are now filled as generics—the vast majority of which are imported. Both the active and inactive ingredients used in the manufacture of these drugs and the completed drugs are imported from all over the world—mostly India and China, but also Mexico, Thailand, Turkey, Brazil, Slovakia and other Eastern European countries, and elsewhere.

Made in ???

Unlike so many other goods we import in the U.S., from sweaters to cell phones, it’s not so easy to find out where your drugs have been manufactured. Though the FDA requires the bulk packages of imported drugs to include the name and country of the manufacturer, this may or may not be the same as the country where the ingredients originated. And the consumer wouldn’t likely see those packages when they fill their prescriptionanyway.

You could ask your pharmacist where the drug was manufactured, but if the drug was made in the U.S. with imported active ingredients, it’s not likely you’ll find that out. And if you decide you’d rather forgo a drug made abroad, some pharmacies don’t even carry a U.S.-manufactured alternative.

But it’s not just knowing a drug's country of origin that matters. Drugs manufactured in the U.S. are regulated according to strict standards, and manufacturing facilities undergo periodic inspections by the FDA, a federal agency. Canada and the European Union have their own standards, but this is not generally true all over the world. The FDA has a staff of inspectors who travel to a number of countries and regions in the world, including India, China, Europe, and Latin America. But it’s a job of overwhelming proportions, and the staff size is often small. The agency has only a handful of inspectors who cover China, for example.

The risks of that limited oversight have been demonstrated in more than one unsettling episode so far. For example, in 2008 an anticoagulant (heparin) sold by an American company but made in China caused dozens of deaths worldwide, including four in the U.S., plus many allergic reactions. It turned out not to contain the real drug at all, but a cheap substitute. In 2015, French regulators who inspected a Chinese factory where heparin was made found more concerns with it, including contamination and a failure to properly record the testing of samples, which is needed for safety and good quality control.

In 2016, the FDA issued a warning to Wockhardt, a drug manufacturer in India, charging that it hid and deleted unfavorable manufacturing test results, which called into question the quality of the drugs it exported. Indeed, the previous year Wockhardt was forced to recall millions of tablets and capsules, including the antibiotic azithromycin and the blood pressure medication lisinopril, because the company hid poor test results and deleted data necessary to assess safety and quality.

Wockhardt is only one of many India-based drug companies that have run afoul of the FDA. Others include Ranbaxy Laboratories, which was forced to pay $500 million in fines in 2013 because it was found to have falsified data about quality and safety testing. The company was recently purchased by Sun Pharmaceuticals, another Indian company with offices all over the world—which has also been accused by the FDA of falsifying data. Altogether, almost four dozen drug facilities in India have had products banned by the FDA from entering the U.S. And one of China’s largest manufacturers, Zhejiang Hisun, has been accused by the FDA of numerous violations, such as not showing the complete set of data from lab testing and not taking safeguards to ensure that the data couldn’t be altered by someone in the lab. This company is a partner of pharmaceutical giants Pfizer and Merck & Co and makes the key raw ingredients for an array of drugs, from chemotherapy drugs to those that lower cholesterol.

For the FDA, the importing of drugs is a balancing act between ensuring that imported drugs are safe and that there is adequate availability of needed drugs. Indeed, since 2013 the FDA has allowed more than a half dozen foreign factories with products that the agency had banned for export to the U.S. to export specific ingredients or drugs so that there wouldn’t be a shortage. These include Wockhardt and Zhejiang Hisun Pharmaceutical.

Also of concern: Just because FDA has inspectors in a foreign country doesn’t mean the plant must necessarily allow them in. For example, a China-based company that manufactures steroids, Jiangxi Yuneng Pharmaceutical, recently refused FDA inspection, resulting in that company’s being added to an import alert list.

How the FDA reviews drugs

The drug review system of the FDA was enacted into law in 1938. (The previous year an impure sulfa drug, manufactured in this country, killed 107 people, many of them children.) The agency was empowered to require proof of safety before a drug went on the market, and to enforce safe drug manufacturing practices by means of an inspection system.

According to William Hubbard, a former FDA Associate Commissioner and author of an article from a number of years ago in the Archives of Internal Medicine, this system has become “the worldwide gold standard by which drugs are developed, tested, and approved for use in the general public.”

The FDA, to be sure, is not perfect. As is normal in a democracy, the FDA has been buffeted by criticism and constant debate. Many critics say the agency is too lax, others say too hidebound and cautious. Some point to its industry ties. Some say its mandate is too big, but even its detractors admit that it is severely understaffed and underfunded, considering its enormous responsibilities. Anti-regulatory groups are quick to highlight its shortcomings.

Just as we need firefighters and police officers to do their essential jobs, we need the FDA to do its job. Still, the safety record of the FDA as a drug regulator is excellent, and U.S. drug manufacturers accept the need for high standards. Manufacturers in other countries presumably see the need for high standards, too.

The U.S. cannot regulate and inspect every facility in the world. On the other hand, Americans expect their drugs to be safe, and can look only to the federal government to make them safe. Recently, Congress approved the Generic Drug User Fee Act, providing the FDA with additional funding and authority to inspect generic drug manufacturing facilities, prevent drugs from being imported if there are improprieties, and review generic drug applications.

What you can do now

In fact, there isn’t a lot of practical, do-it-yourself advice at the moment. But it helps to be aware of a few things:

  • The globalization of the pharmaceutical industry is not likely to reverse itself. Nations like Vietnam and Malaysia, for example, want to become drug exporters.
  • The FDA needs more people. “Regulation” may be an un­­popular idea in some quarters, but high manufacturing standards, rigorously enforced, are a necessity for our medicines. The better the regulation and oversight, the healthier and safer we’ll all be. This should not be a partisan issue.
  • If you take prescription medications regularly, it won’t hurt to inspect your refills. Talk with your pharmacist, for instance, if a pill you usually cut in half splits too easily (or won’t split);if a drug you usually dissolve won’t dissolve; if a drug that has always worked is not working or causes some unexpected side effect; or if a drug seems different in any other way. There may be a perfectly good explanation, but a handful of reports have found that pills returned to the companies for testing are fake. You can also report quality problems or other prescription-drug issues to the FDA at this link.
  • “Imported” is not necessarily a dirty word. Some HIV drugs used in developing nations, for example, come from India—making them affordable. Lower prices can be lifesavers, in poor countries as well as rich ones. We just need quality control.

Also see How Good Are Generic Drugs?