For most people, a good belly laugh is a wonderful thing. For Rachel Rothwell, this can literally cause her to fall to the floor. She suffers from cataplexy, a condition whereby strong emotions, such as joy or anger, paralyze the muscles, leading to complete physical collapse. For the past nine years, a drug called clomipramine has relieved its symptoms. So effective was the medication that she almost forgot she had the disease.
In April, however, the drug disappeared from the shelves of Calne's pharmacies in southern England, where she lives. Initially she was able to place supplies in nearby cities, but within a month was not found. Rothwell's doctor prescribed a different drug, but it took months to calculate the correct dose for her. Meanwhile, his symptoms returned.
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Clomipramine is on Britain's official list of medicines to be stored by pharmaceutical companies in preparation for Brexit, the country's imminent departure from the European Union. For some reason, not everyone is confident that Brexit will work without problems. Thus, some Britons with chronic diseases are accumulating drugs on which they depend. However, the scarcity of clomipramine has little to do with Brexit. The drug has been scarce worldwide as a result of manufacturing problems at Teva and Mylan, until recently the only two companies supplying Britain.
Rothwell's experience became painfully common. Over the past three years, the number of shortage drugs in the United States has halved to over 280. In a 2018 survey of more than 700 hospital pharmacy managers, 70% said that on at least 50 occasions last year , they were unable to provide doctors and nurses with the medicines needed to treat their patients due to major scarcity. Last year, the American Medical Association urged the federal government to treat shortages of medical supplies as a matter of national security, which would allow the government to offer incentives to domestic producers.
America is not alone. In France, drug shortages increased 20-fold between 2008 and 2018, according to the country's regulator. Local pharmacists in Europe spend five to six hours a week trying to track medicines for their customers in other dispensaries because they have run out of themselves or trying to identify suitable alternatives. Reports from doctors and other health professionals in 21 EU countries in 2018 suggested that the shortage is becoming more acute.
Data from poor countries are more limited, but deficits in the United States or Europe often signal a worldwide shortage, says Jayasree Iyer of the Access to Medicines Foundation, a Dutch charity. When supplies are tight, pharmaceutical companies whip their products first to rich countries as they drive higher prices there.
Basic medicines, such as injectable antibiotics and saline (used to prepare injections), run out more often. But a wide range of medications, including common anesthetics and medicines for epilepsy, heart disease, cancer, and schizophrenia, are short of delay. The affected products are mainly generic drugs, which represent 90% of prescriptions in the United States and 70% in Europe.
The consequences can be dire (see table). Cancer treatments and operations may be postponed or canceled. When a last resort antibiotic is not available, a treatable infection can be deadly. Alternative drugs, if any, usually involve different doses. This can lead to mistakes such as doctors administering the wrong number of ampoules. One in five pharmacists in the United States and one third in Europe say they know about medication errors related to drug shortages.
Medicines usually disappear from pharmacies as a result of manufacturing problems at the factory that produces the drug or its active ingredient. About 40% of generic drugs sold in the United States have only one manufacturer each. This means that a problem on a single production line can cause a worldwide shortage.
The low price of generic drugs (a single bottle or blister can cost only $ 1) explains the lack of competition among their manufacturers. The problem is particularly serious for older medications such as penicillin or morphine. On the day a drug patent expires, a dozen generic pharmaceutical companies are ready to do so. Price competition is so intense that in a decade there is almost no profit to be made, often leaving only a single manufacturer. They keep prices low to discourage new competitors from entering the market.
The pressure to lower generic drug prices has led to an increasingly fragmented and globalized production process. It is not uncommon for a single drug to involve a ten-step process (which includes grinding, mixing and filtering chemicals several times to arrive at the final formulation). The cheapest way to do this may involve factories in three or four countries. But as production chains become more diffuse, they also become more fragile and less transparent. Researchers can't always figure out which company makes a particular drug or where the factories are located, says Erin Fox of the University of Utah, which tracks the shortage. This information is considered proprietary to the company that has the sales license. An early supply chain failure that predicts a deficit may not become apparent until the last minute.
Active chemicals for many medicines also have only a few manufacturers. These are increasingly based in India or China, where recalls of low quality products are common. The recent discovery of contamination in a Chinese factory that makes valsartan, the active compound of a widely used blood pressure drug, has led to the withdrawal of dozens of drugs in at least 22 countries, mainly in Europe. It turned out that this particular factory produced half of the world's supply of valsartan. A continuing global shortage of piperacillin-tazobactam, a last resort antibiotic, was triggered by a 2016 explosion at another factory in China – which left a single source for one of the active ingredients.
Reduced profit margins mean that manufacturers are unwilling to pay for factory upgrades. As a result, mechanical failures are more likely. Part of the US drug shortage over the last decade has been attributed to facilities in operation, with limited improvements, since the 1960s. When regulations require expensive upgrades, some manufacturers simply turn them off.
Such interruptions, even temporary ones, are problematic. Other factories cannot immediately take the time off. The typical delay between an order placed and the pill being placed is one year, says Markus Krumme of Novartis, a Swiss pharmaceutical company. Injectable drugs are particularly demanding because all equipment involved must be meticulously sterilized. Reusing existing factories to manufacture these medicines can take years. Similarly, manufacturing some antibiotics and cancer drugs requires dedicated equipment – and even buildings – that cannot be used to make other medicines. The shortage of some critical drugs in the United States has been so acute that its drug regulator has resorted to desperate measures that allow the delivery of a liquid drug containing glass particles – with instructions for doctors to use a filter to remove them before use. .
In Europe, the nature of contracts between major drug buyers and manufacturers exacerbates the difficulties caused by failures. Drug purchase and sale contracts are usually at the national or provincial level. Proposals for these contracts are usually made every year. With contracts that last for such short periods, manufacturers see no reason to invest in new production plants, says Adrian van den Hoven of Medicines for Europe, a lobby group for the generic drug industry.
If long supply chains carry one kind of risk, grouping factories in one place brings another. Puerto Rico, an American territory in the Caribbean, houses one of these clusters. When two hurricanes hit the archipelago in 2017, half of the world's top ten drug makers were affected. Storm damage to Puerto Rico's factories has limited the supply of 11 of the world's 20 most popular drugs. No one knows how many other vulnerable groups there are now.
Panic over scarcity has peaked, says Iyer – so governments are struggling to find solutions. Some countries are considering paying more for older, more critical drugs to secure their supply. America's drug regulator has begun to accelerate approval of new production lines for scarce drugs. This should make it easier for new manufacturers to enter the market. France has just published a plan to manage shortages, calling for incentives to bring active pharmaceutical ingredient production back to Europe by 2022. Other governments are working out special trade agreements with neighboring countries to speed up drug imports when there is a shortage.
Desperate, some have suggested that the drug supply should no longer be an exclusive preserve of the big pharmaceutical companies. Exasperated by the constant shortage in the world's largest pharmaceutical market, American hospitals are entering the business of the pharmaceutical industry. In 2018, a partnership of hospital groups, which together cover one third of US hospital beds, created the Civica Rx. Its mission is to ensure availability of essential drugs through five-to-ten-year contracts with manufacturers that include provisions for six months of buffer stocks.
The organization's first contract with Xelia, a Danish drug company, is for vancomycin and daptomycin, antibiotics for high-resistance infections. Xelia will also manufacture the active ingredient of vancomycin in factories in Europe; Until recently, everything came from China. In the future, the Civica Rx expects …