Generic Drugs Not as Safe as FDA Wants You to Believe

Generics have been a financial success story for the American patient. Overall, ~90% of prescribed medications in the United States are generics but only account for 26% of drug spending, saving ~$1.7 trillion dollars over the past decade.¹ The Food and Drug Administration (FDA) set a new record in 2018, approving 781 new generics.²

When patients are switched from a brand to generic drug or between 2 generics, they sometimes complain of adverse events or state their drug is not working as well. I always attributed this to patient anxiety or happenstance. However, the lack of quality verification of overseas generic manufacturing plants may also be an explanation in some of these cases.

The FDA has strict regulations that, if followed, ensures that generics are of high quality and deliver blood concentrations consistent with brand name products.³ These products can be finished drug products or active pharmaceutical ingredients (APIs; ie, bulk powders) sold to other manufacturers to create finished drug products. Manufacturers must extensively test their products, destroy batches of products that do not adhere to high standards, and have these test results available for inspection. The FDA reviews documents in an abbreviated new drug application to make sure the manufacturer can make a new high-quality finished drug product before giving permission to manufacture it. After that, the FDA does site visits to ensure good manufacturing procedures, adequate testing, and appropriate responses when the tests show quality issues. FDA also does limited spot testing of finished drug products for quality.³

In February 2019, FDA stated unequivocally that generics are safe and effective and outlined the steps that the FDA takes to ensure quality.⁴

Approximately 80% of APIs and 40% of the finished pharmaceutical products are no longer manufactured in the United States.⁵ This poses a major challenge for the FDA because they lack the capacity to adequately oversee foreign manufacturers and struggle with international logistics.

According to the US Government Accountability Office, in 2010, there were 1148 manufacturing plant inspections domestically and 440 internationally, with 64% of foreign plants never being inspected.⁶ Even though the number of foreign inspections increased to 842 in 2015, 33% of foreign plants were still never inspected by the FDA.⁶ Domestically, inspections are frequently unannounced, whereas in foreign countries, this almost never occurs.⁷ As FDA guidance for inspectors specifies: “Preannounced inspections are necessary when conducting international inspections. This is due primarily to the potential waste of resources if the establishment is not operating or not producing the product in question, political sensitivities, availability of English speaking personnel, local holidays, etc. A request containing the proposed inspection dates is made to the foreign manufacturer either by direct contact or through an U.S. agent. Upon their agreement the inspection is conducted.”⁸ Prescheduling gives manufacturers time to clean their facilities, get their paperwork in order, and ensure that workers are on their best behavior.

What has been the result? Companies are not adhering to good manufacturing practices and falsifying, adjusting, or hiding data from the FDA. As inspections have recently increased, a glimpse into these chronic quality issues have come to light.⁴ Warning letters from the FDA have increased 5-fold from 2015 to 2018, going from 19 to 94 actions a year over that time. The FDA contends that this is not indicative of a growing problem in drug quality, and this is likely true. However, because so many issues are being found when these suboptimal preannounced inspections are conducted, it is likely that these manufacturers were supplying substandard medications to US citizens for years.⁴

In 2013, Ranbaxy pleaded guilty to failing to report that its drugs did not meet specifications and making intentionally false statements to the FDA, paying a $500 million penalty.⁹ Ranbaxy manufactured drugs that they knew tested out-of-specification, had unknown impurities, and would not maintain their expected shelf life. They sometimes recorded stability test results they never conducted.¹⁰ However, the FDA did not uncover these issues: a whistle blower tipped them off.⁹ Why was the FDA not more diligent? The World Health Organization alerted Ranbaxy Laboratories that their antiretroviral drug data looked fraudulent in 2004, causing the company to withdraw its antiretroviral drug applications.¹¹

By 2015, 46 Indian manufacturing facilities were barred from shipping drugs to the US for one or more of the following: (1) alteration/manipulation of product and air quality data; (2) failure to review consumer complaints and hiding incident reports off site; (3) back dating quality testing; (4) altering/forging clinical trial data; (5) alteration of training records for quality assurance personnel or functions; (6) using data recording methods where data were preliminarily written down but could be overwritten, with the original data lost; (7) presence of unauthorized quality assurance stamps; and (8) performing multiple retesting of deviant samples and only recording the one that passed.¹² Since that time, other manufacturers in India were found to have (1) shredded documents late at night before an FDA inspection, (2) allowed unsanitary manufacturing conditions, or (3) allowed “uncontrolled use of ‘trial’ injections during chromatographic testing” to achieve passing tests for drug batches or other reporting irregularities.^13-16

Chinese-made drugs accounted for 8% of FDA generic approvals in 2018, up from 1% in 2015.¹⁷ A major current drug issue in the United States is the contamination of finished angiotensin II receptor blocker products (valsartan, losartan, irbesartan) with unacceptably high concentrations of potential carcinogens N-nitrosodimethylamine (NDMA) or N-nitrosodiethylamine.¹⁸ One of the major producers of valsartan and losartan API was Zhejiang Huahai Pharmaceuticals, a company with a history of quality issues.^17,19 When inspected in 2017, the FDA found that they omitted from official test results that drug batches failed to meet US quality standards and instead recorded passing grades. In 2016, Chinese regulators asked the company to withdraw any applications to sell new drugs containing false or incomplete data. The company pulled applications in 3 drug classes.^17,19 Ranitidine generics were recently found to have NDMA impurities as well.²⁰

Issues with APIs in China first came to light in 2008 when patients receiving heparin in the United States suddenly started experiencing severe anaphylactoid reactions, with more than 100 cases resulting in death.²¹ After a viral disease began decimating the Asian pig population, an anticoagulant contaminant (over sulphated chondroitin) was intentionally but secretly added to heparin API in Asia as a replacement. The point in the supply chain where this occurred is not entirely clear. However, one manufacturer of the heparin API, Changzhou SPL Company, was inspected by FDA and received a warning letter after it was found to have used raw material (pig intestines) from uncertified farms; the tanks used in production or storing had unidentified material adhering to it, and testing for impurities was found to be insufficient.²²

European generic manufacturers are not immune either. In 2016, FDA caught Italian drugmaker Facta Farmaceutici reporting only passing quality tests even though original reports indicated out-of-specification results for things like particulates in sterile drugs.²³ On top of that, the FDA said that the inspector saw employees shredding records.²³

This issue is not just limited to drugs being sold in the United States and could actually be worse internationally. The previous Drug Controller General of India, Dr G. N. Singh, was interviewed and asked about the ability of Indian manufacturers to meet FDA quality standards in 2014. He replied frankly, “If I have to follow US standards in inspecting facilities supplying to the Indian market, we will have to shut almost all of those.”²⁴

Generic medications are a critical component of a financially sustainable health care system. There are honest generic manufacturers, but without independent verification, clinicians can rightfully be skeptical. Through a history of almost nonexistent quality verification of foreign drug manufacturers, the FDA allowed companies to produce poorly manufactured products and to ship them into the United States while guaranteeing physicians, pharmacists, and the US consumer that these products were interchangeable with other generic products and their brand name counterpart. Companies caught defrauding and endangering the US consumer are not permanently banned from shipping drugs into the United States; they are just required to raise their standards and, in some cases, to pay a fine. At the same time, US manufacturers were subject to much more frequent inspections that were unannounced and could not produce their products as cheaply, shuttering domestic plants and laying off US citizens. We run the risk of slaying the golden goose if we cannot secure our generic drug supply, and although the FDA has been making progress, their response is inadequate, and it has much left to do.