Last July, according to a report by HealthAffairs.org. the Chair of the House Energy and Commerce Committee, Cathy McMorris Rodgers (R-WA) and two colleagues on the Health and Oversight Subcommittee sent a forceful letter to Food and Drug Administration (FDA) Commissioner Robert Califf regarding FDA’s inadequate inspections of drug manufacturing plants in India and China: “The FDA’s recent decision to address shortages of critical drugs by allowing the temporary import of otherwise unapproved drugs from India and China makes having effective foreign inspection programs in those countries critical … we are worried that the United States is overly reliant on sourcing from foreign manufacturers with a demonstrated pattern of repeatedly violating FDA safety regulations.”
Bloomberg News reports that the Department of Defense recently announced that it will begin independently testing the quality and safety of imported generic drugs. Defense officials are in talks with Valisure, an independent lab, to test the quality and safety of generic drugs it purchases for millions of military members and their families, according to several people familiar with the matter who asked not to be named as the details aren’t public..
Generic drugs account for 90 percent of prescriptions dispensed in the United States. They also represent a sizeable share of the drugs used by hospitals to treat patients in ICUs, oncology units, transplant centers and emergency departments.
Because generic drugs sold in the U.S. must be FDA-approved, health care providers and patients assume that they are safe and effective. There is growing evidence that this confidence may be misplaced. In fact, quality issues are the precipitating factor in more than 60 percent of generic drug shortages.
The Hatch-Waxman Act of 1984 created a streamlined pathway for generic drugs. All a manufacturer must do is demonstrate that the generic version it proposes to sell is “bioequivalent” – meaning it delivers roughly the same amount of active pharmaceutical ingredient (API) into a person’s bloodstream, at roughly the same rate and duration, as the brand-name drug on which it is based. To demonstrate bioequivalence, a manufacturer typically hires a contract research organization (CRO) to perform the necessary testing with 24 to 36 healthy volunteers.
Once a drug is approved for sale in the U.S., FDA relies on periodic inspections of pharmaceutical plants and record reviews to ensure that a company complies with “Good Manufacturing Practices,” (GMP). FDA does not routinely test the medicines themselves. Instead, it asserts that manufacturers are responsible for the quality and safety of their products. In the early years of Hatch-Waxman, this honor system worked reasonably well. It does not today. Recent FDA actions and published research indicate that generic medicines are not always bioequivalent or safe. For example:
– – In 2009, researchers published a study in Neurology titled “The risks and costs of multiple-generic substitution of topiramate,” a drug that treats epilepsy. They found that switching generics was associated with significantly higher rates of hospitalizations, head injury or fracture and longer hospital stays.
– – In 2012, an FDA-sponsored a study of Budeprion XL, an extended-release antidepressant, revealed that a manufacturer’s generic did not perform as well as the brand-name drug. Years after hundreds of consumers first raised concerns, the product was withdrawn from the market.
– – Although generic manufacturers may contain different “inactive” ingredients, such as fillers and binders, than the brand-name drug, few of these ingredients have been tested to determine if they can affect bioequivalence. In 2015, FDA reported that in some instances, they do.
– – In 2017, Circulation published a study titled “Impact of the Commercialization of Three Generic Angiotensin II Receptor Blockers on Adverse Events in Quebec, Canada.” The researchers found that shortly after the generic versions came on the market, reports of adverse events significantly increased.
– – In 2018, after being alerted by independent industry testing, FDA determined that some generic ARB medicines, including versions of valsartan, losartan, and irbesartan, contained nitrosamines – a probable carcinogen.
– – In 2020, an independent laboratory found “unacceptable levels” of NDMA, a known carcinogen, in samples of metformin, a diabetes medication taken by 20 million The finding was reported to FDA and led to broad recalls.
– – In 2021, a study of generic versions of tacrolimus, an immunosuppressant, found that some dissolve too rapidly. This might affect therapeutic duration and increase the risk of organ rejection.
– – Also in 2021, FDA raised integrity concerns with the bioequivalence studies of approximately 100 drugs conducted by two Indian CROs. The agency rejected the studies and required manufacturers to repeat them. Unlike its European counterpart, which suspended marketing of the products, the FDA allowed the drugs to continue to be sold with a special code to alert pharmacists that they should not be considered “automatically substitutable” for their brand-name counterparts.
Because FDA approval is considered the benchmark for drug quality, the US companies that supply most generic drugs to America’s pharmacies, clinics, and hospitals search the globe for the least expensive generic versions of brand-name drugs. The “race to the bottom” this engendered drove most generic drug production offshore. As a result, America is highly reliant on other countries for its generic drugs and the ingredients and raw materials required to make them.