Generic drugs 鈥� cheaper copies of once-patented, brand-name medicines 鈥� are quite literally life-savers in the US, where prescription drug prices are than other nations of comparable wealth. According to the , generic and biosimilar drugs saved the US health system a whopping $338bn in 2020.
A generic drug is, ostensibly, interchangeable with the original product. As long as a generic drugmaker can prove its product has the same active ingredient and strength, and uses the same dosage form and route of administration, the company does not have to go through the same trial process the original manufacturer did to prove that the drug has the desired therapeutic effect 鈥� that much is assumed from its chemical composition.
The problem is that not all generic drugs are made equal. Some can be more or less potent than the medicine they鈥檙e mimicking (as digital pharmacy Valisure found after of a common blood pressure drug), release doses into the bloodstream incorrectly, or contain impurities 鈥� sometimes to dangerous effect.
Take heparin, a commonly used generic anticoagulant. In 2008, the blood thinning drug was subject to a worldwide recall after scientists concluded that a contaminant, known as oversulfated chondroitin sulfate, was responsible for around 350 adverse events and 150 deaths in the US. The adulterated heparin was traced back to Chinese chemical manufacturer Scientific Protein Laboratories鈥揅hangzhou, where an conducted after the scandal revealed a number of manufacturing quality issues.
Regulatory oversight and reliance on non-US manufacturers
Having very little manufacturing capacity of its own, the US relies heavily on drugmakers in countries like India and China for its supply of crucial generic drugs and active pharmaceutical ingredients (APIs). In fact, Chinese and Indian manufacturers supply an of all active pharmaceutical ingredients used in the US, while of drugmakers supplying generics to the US are located overseas.
Not only do overseas facilities offer lower labour costs and looser environmental regulations, but less monitoring and regulatory oversight. In 2010, had never been inspected by the FDA 鈥� and in 2015, were still yet to receive a visit from regulators.
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By GlobalDataWhile inspectors can, and do, turn up at US factories unannounced, it鈥檚 far trickier to perform surprise inspections at facilities located on the other side of the world, particularly amid a global pandemic 鈥� making it easier for rules to be flouted and improper practices to be covered up.
Michael White is chair of the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy, and has written extensively about the drug quality issues associated with generics manufactured outside of the US.
鈥淥verseas, they usually have several weeks鈥� worth of lead time, where they know that on these dates, the inspectors are going to be coming,鈥� White explains. 鈥淚t remains to be seen whether or not the inspections that are occurring overseas are of the same quality of the ones inside the US 鈥� because if you know what those issues are, you have time to get all your paperwork in order and make sure your facility is sparkling clean.鈥�
A prime example of foreign manufacturing oversight is Ranbaxy, the Indian drug manufacturer that had plants after it was revealed the company had fabricated drug test reports and knowingly distributed substandard generic medicines. The malfeasance only came to light after two of the facility鈥檚 employees blew the whistle in 2004 鈥� six years after the company had first begun making drugs for the US market.
The FDA鈥檚 monitoring of overseas manufacturers improved in the wake of the Ranbaxy scandal 鈥� foreign inspections have increased from to 鈥� but the challenges of properly regulating non-US generic drugmakers, and ensuring the medicines they make are of consistently high quality, remain.
White says that while the number of inspections done overseas is now close to those conducted domestically, that doesn鈥檛 necessarily mean better regulation is taking place.
鈥淎 lot of that parity is because they’re dropping the number of inspections for manufacturers inside the United States, to be able to have enough inspectors to be able to do the inspection elsewhere,鈥� White explains.
A spokesperson for the FDA told Pharmaceutical Technology: 鈥淭he FDA鈥檚 global inspection and facility evaluation efforts focus on higher-risk facilities to prevent, uncover and correct data integrity issues and manufacturing problems.
鈥淲e also monitor reports from industry, patients and healthcare providers to identify and to resolve quality problems and concerns.鈥�
US health regulators have been implementing small-batch tests of imported drugs more regularly in recent years. White says this is 鈥渁 good start鈥�, but that the number of tests carried out must increase to serve as a 鈥渟topgap鈥� until more in-person foreign inspections can take place.
Competition and cutting corners
The appeal of generics, for patients and health insurance companies alike, is their affordability; the most successful generic drug on the market will usually be the cheapest. The goal for any generics manufacturer, therefore, is to undercut the competition by offering the drug for the lowest price possible.
This race to the bottom between competitors means drugmakers producing cheap generics will be looking to spare costs elsewhere 鈥� and sometimes, that means cutting corners when it comes to manufacturing operations and quality control.
鈥淭he financial pressures in the generic market are such that it’s very hard for people to be able to raise prices, even if they needed to raise prices for quality,鈥� White says. 鈥淸Drug companies鈥橾 financial solvency is contingent upon meeting certain price points. Their competitor ends up coming out at a lower price point, and then they鈥檙e under pressure to be able to go down and meet it.
鈥淢anufacturing quality is something that’s hidden from the consumers, it’s hidden from the pharmacies that are purchasing the products,鈥� he explains. 鈥淲hen you have the financial pressure on one side, with lower levels of accountability on the other, just based on how the regulatory oversight is occurring, you end up creating a recipe for issues.鈥�
Patient trust and traceability
When drugs are manufactured overseas, transparency about their origin and the conditions under which they were produced can be compromised. Supply chain traceability is even more opaque for the patients consuming the medicines, who are kept relatively out of the loop when it comes to safety and quality issues of some generic manufacturing plants.
鈥淲hen a manufacturing facility ends up having issues with an inspection, it’s not really communicated well outside of the FDA 鈥� to purchasers, to clinicians or to patients 鈥� what the implications of that manufacturing facility鈥檚 issues are,鈥� White says.
鈥淪o it’s difficult for a patient to come in and be able to ask the pharmacist at the counter, 鈥榯his didn’t come out of one of those manufacturing facilities that had quality issues, did it?鈥� It’s really, really hard for anybody to be able to ask those questions.鈥�
Most patients likely won鈥檛 become aware that the drug they鈥檙e taking is substandard or dangerous until something catastrophic happens, and the FDA is forced to announce a recall 鈥� but poorly made generics don鈥檛 have to be poisonous to have serious implications for patients. A person whose blood pressure medicine doesn鈥檛 work properly risks a heart attack or stroke; low-quality insulin will see a patient鈥檚 diabetes go unchecked; an improperly treated infection could turn fatal.
For White, an official list of drugmakers that have been found to have breached regulatory requirements, published by the FDA, would go a long way towards encouraging good manufacturing practice and ensuring public trust in generic medicines.
鈥淚 do think that public shaming is something that can help to put pressure on manufacturers; there’s a lot of different levers that people can be pulling to have greater transparency and a greater level of oversight for drugs,鈥� he says.
鈥淭o some extent, though, I think the FDA was very worried that if they pulled too many of those levers simultaneously, they could end up in a scenario where they didn’t have an adequate number of drugs for everyone to have them.
鈥淭hey’re trying to move into greater enforcement for some of those quality standards, but in a way that gives the manufacturers time to be able to build up to that.鈥�
Drug supply shortage risks
Low-quality drugs aren鈥檛 the only threat the US鈥檚 fragile supply chain poses to public health. Heavy reliance on foreign manufacturers means the country鈥檚 access to crucial and widely used drugs is precarious, and shortages could result in crisis. In fact, at the time of writing, are currently in short supply in the US.
Drug shortages can occur for many reasons, including widespread recalls 鈥� such as that of generic blood pressure drug valsartan 鈥� manufacturing and quality problems, or geopolitical issues. White says that due to its limited domestic manufacturing capabilities, the US is particularly vulnerable to shortages of vital medicines like antibiotics.
鈥淭he US now has virtually no capacity to make the active ingredients in many antibiotics; you need special fermentation plants,鈥� he says. 鈥淪o what if something horrible happens between the United States and China, or other regions, where virtually all of this capacity exists?
鈥淲e could have zero antibiotics and [shortages of] many, many different categories [of drugs] here in the United States 鈥� that’s the horrible vulnerability.鈥�
Fixing a broken system
It鈥檚 clear that something must be done to secure the US鈥檚 supply of high-quality generic drugs 鈥� but as an FDA spokesperson told Pharmaceutical Technology, simply transferring all manufacturing facilities back home is not an option.
鈥淚t is not realistic to envision a future where all of American patients鈥� drugs are produced domestically,鈥� the spokesperson said. 鈥淥ther strategies include targeted investments in global resiliency throughout the drug supply chain, establishing emergency stocks of critical drug substances and drug products, as well as capacity expansion in allied countries to aid in the response to future crises.鈥�
Further measures to ensure a secure, safe generics supply, White says, should include a rating system for drugmakers based on manufacturing or product quality; better international collaboration between drug regulators; and employing continuous manufacturing methods in the US to increase domestic production of critical medicines.
The introduction of affordable generic medicines and the globalisation of drug production has saved countless lives and dollars in the US, but flaws in this fragile system have also allowed bad actors to profit and cause harm.
Ensuring safe, effective drugs should be of the utmost priority to the US government and its health officials 鈥� because the very least patients should be able to expect is that their medicine is exactly what it says it is.
