US drug shortages could continue for years

Abstract

Recent shortages of critical drugs in the USA have hampered patient care and attracted much media attention. Sharmila Devi examines the problems with America's drug supply.Severe shortages of drugs such as sterile injectables that have forced physicians in the USA to practise medicine from crisis to crisis are likely to continue for several more years, say regulators and health-care providers.Around 280 drugs, almost all manufactured in the USA, remain in short supply because of factors including a dwindling number of makers of some drugs, deteriorating conditions in factories, and low prices for generics leading to a lack of investment to upgrade plants.The shortages have led to delays in surgery and cancer treatments, left patients in pain, and forced hospitals to prescribe less effective treatment, said a review by the Associated Press late last year. At least 15 deaths in 15 months were blamed on the shortages, according to data compiled by the Institute for Safe Medication Practices, a patient safety group, and the true number might be higher because many deaths and injuries caused by shortages go unreported.“We don't have any expectation the issue will be resolved soon”, Sandra Kweder, deputy director of the Food and Drug Administration's Office of New Drugs, told The Lancet. “It will be several years before companies building new plants get them up and running.”The FDA is at the forefront of an increasingly complex battle to ensure the USA retains access to critical drugs. President Barack Obama issued an executive order in October, 2011, requiring drug companies to report to the federal agency when critical supplies were threatened. Meanwhile, new legislation that would make it mandatory for companies to notify the FDA of a wider range of supply problems and give it extra powers languishes in Congress.Last month, the FDA stepped in to resolve shortages of two cancer drugs that threatened thousands of patients—methotrexate, used to combat lymphoblastic leukaemia, and doxorubicin, sold under the trade name Doxil, used to treat ovarian cancer, Kaposi's sarcoma related to HIV/AIDS, and multiple myeloma.The naturally emotive story of children and adult cancer patients facing increased suffering because of a shortage of these drugs led to much media coverage in the USA. “It's easier to interview a cancer patient than someone whose operation took longer because of the lack of pain relief”, Erin Fox, manager of the University of Utah Drug Information Service that tracks shortages, told The Lancet.“It looks like US manufacturing is crumbling but I hope that's not the case. The hardest part is fixing factories and we keep seeing the same companies having problems over and over again”, she said. “We end up with band-aid fixes and we don't really know what it will take to refurbish them while there is a real impact on hospitals and patients.”Kweder confirmed that problems maintaining quality at factories was the most common factor behind drug shortages. A smaller number of companies had reported difficulty in sourcing active pharmaceutical ingredients, and had decided to produce one drug at the expense of another, or made the decision to cease production of a particular drug, she said.The highly specialised manufacturer of sterile injectables meant more things could go wrong with them and they did, she said, but problems with other pharmaceutical drugs and supplies have also been reported.In the past year, the Drug Information Service alerted its pharmacist members to problems including particulate matter in indomethacin, used to treat congenital heart defects in infants; particulates in dexamethasone sodium phosphate injections, used in the treatment of cancer; and particles found in Argatroban, a type of blood thinner.According to the Drug Information Service's data, the number of new national drug shortages rose to 267 in 2011 from 70 in 2006. “Companies have been trying to address quality issues for years in many cases and they often reach a point where they feel they have no choice but to close down to make repairs”, said Kweder.Obama's executive order expanded the scope of mandatory reporting to the FDA to include manufacturers that were the sole source of a drug in the USA and were experiencing substantial disruptions. The FDA has also increased the number of staff in its Drug Shortage Programme.In 2011, the FDA helped to prevent shortages of 195 drugs, including 86 drugs produced by one company, the federal agency said in its recent guidance report. Drug companies, like any other commercial enterprise, had been unwilling to publicise any information that might give their competitors an edge. “Companies said they didn't want to air their dirty laundry to the FDA and their competitors”, said Kweder.“All these companies operate in their own little production worlds and talk to us but not to each other. There's no requirement for the FDA to do any of this, nothing in the statutes or public health service act but we're in a unique position to have information and context to solve the problems.”The FDA strove to work with companies, such as fast-tracking regulation for new facilities or sources of active ingredients, and to uphold the strictest confidentiality although companies had their “own ways to find out”, who was struggling, she said. Last month, the agency also issued lengthy guidelines for drug companies to follow when the manufacture of critical medicines was under threat.In the case of Doxil, the FDA allowed the shipment of Lipodox, a similar drug made in India by Sun Pharma Global whose laboratories had already been inspected by the FDA. The drug company Hospira was allowed to import methotrexate from its plant in Australia while the FDA speed up the approval of APP Pharmaceuticals to manufacture the drug.But imports of such drugs were not a long-term solution because other countries sought to ensure enough supply for their domestic markets and the USA needed to do the same, said Fox of the Drug Information Service.“FDA, our pharmacists, physicians, and manufacturers have cobbled together patches but we cannot continue to practise medicine from crisis to crisis”, Michael Link, president of the American Society of Clinical Oncology, said after the FDA acted to avert the shortages of Doxil and methotrexate in February.More recently, he told The Lancet that despite active lobbying by his society and other health-care professional groupings, Congress had yet to pass legislation designed to address drug shortages. “We are doing our best to keep the issue alive and are lighting fires and working to get supplies and encourage further investment in durable solutions”, he said.He believed the economics of generic drugs, whose prices were kept low in part because of wholesale buying by federal programmes such as Medicare, were one of causes of drug shortages. “In the UK, generics are priced higher and there aren't the same kind of shortages”, he said. “Here, generics are priced so low that it's difficult to make money on them. It's hard for companies to see an incentive to spend millions to fix the problem. But we don't really know what's going on behind the scenes at companies.“We need to get to the bottom of the problem and find out if it is economics. We believe it must be part of it. We'd like Congress to carry out a full investigation as to why we're having such problems now and why is it so extensive as well as to legislate remedies.”Arnold Berry, vice-president for scientific affairs at the American Society of Anesthesiologists, said he supported providing incentives for drug makers. “Drug manufacturers participate in a free-market economy and there should be consideration of incentives for companies to produce the generic drugs which have a low profit margin”, he told The Lancet. “Throughout my career, there have always been periodic shortages of drugs but the number of current shortages is unprecedented.”Legislation would also help to address the issue of the grey market in which hospitals buy from secondary suppliers at big mark-ups. Just over half of the 549 US hospitals responding to a survey last summer by the Institute for Safe Medication Practices said they had purchased one or more prescription drugs from companies other than their normal wholesalers. Most also said they had been forced to do so more recently and 7% reported side-effects or other problems with those drugs.Barack Obama signs an executive order outlining actions to reduce drug shortagesView Large Image Copyright © 2012 Charles Dharapak/AP/Press Association Images“Some distributors take advantage of looming shortages by hoarding and selling at substantial mark-ups, usurious mark-ups, putting patients' lives at risk”, said Link.Berry pointed to a survey undertaken by his society last year of 1373 anaesthesiologists that found 90% of respondents were then experiencing at least one drug shortage. These shortages resulted in a less optimum outcome for a patient (for example post-op nausea and vomiting) 49% of the time.“We need to continue to work collaboratively with the FDA and relevant stakeholders to think outside of the box for solutions to supply critical medications in shortage”, said Berry. “With more advanced notification of shortages, physicians can make informed decisions for alternative plans on how to treat patients and manage existing supplies of the drug that is in limited supply.” Recent shortages of critical drugs in the USA have hampered patient care and attracted much media attention. Sharmila Devi examines the problems with America's drug supply. Severe shortages of drugs such as sterile injectables that have forced physicians in the USA to practise medicine from crisis to crisis are likely to continue for several more years, say regulators and health-care providers. Around 280 drugs, almost all manufactured in the USA, remain in short supply because of factors including a dwindling number of makers of some drugs, deteriorating conditions in factories, and low prices for generics leading to a lack of investment to upgrade plants. The shortages have led to delays in surgery and cancer treatments, left patients in pain, and forced hospitals to prescribe less effective treatment, said a review by the Associated Press late last year. At least 15 deaths in 15 months were blamed on the shortages, according to data compiled by the Institute for Safe Medication Practices, a patient safety group, and the true number might be higher because many deaths and injuries caused by shortages go unreported. “We don't have any expectation the issue will be resolved soon”, Sandra Kweder, deputy director of the Food and Drug Administration's Office of New Drugs, told The Lancet. “It will be several years before companies building new plants get them up and running.” The FDA is at the forefront of an increasingly complex battle to ensure the USA retains access to critical drugs. President Barack Obama issued an executive order in October, 2011, requiring drug companies to report to the federal agency when critical supplies were threatened. Meanwhile, new legislation that would make it mandatory for companies to notify the FDA of a wider range of supply problems and give it extra powers languishes in Congress. Last month, the FDA stepped in to resolve shortages of two cancer drugs that threatened thousands of patients—methotrexate, used to combat lymphoblastic leukaemia, and doxorubicin, sold under the trade name Doxil, used to treat ovarian cancer, Kaposi's sarcoma related to HIV/AIDS, and multiple myeloma. The naturally emotive story of children and adult cancer patients facing increased suffering because of a shortage of these drugs led to much media coverage in the USA. “It's easier to interview a cancer patient than someone whose operation took longer because of the lack of pain relief”, Erin Fox, manager of the University of Utah Drug Information Service that tracks shortages, told The Lancet. “It looks like US manufacturing is crumbling but I hope that's not the case. The hardest part is fixing factories and we keep seeing the same companies having problems over and over again”, she said. “We end up with band-aid fixes and we don't really know what it will take to refurbish them while there is a real impact on hospitals and patients.” Kweder confirmed that problems maintaining quality at factories was the most common factor behind drug shortages. A smaller number of companies had reported difficulty in sourcing active pharmaceutical ingredients, and had decided to produce one drug at the expense of another, or made the decision to cease production of a particular drug, she said. The highly specialised manufacturer of sterile injectables meant more things could go wrong with them and they did, she said, but problems with other pharmaceutical drugs and supplies have also been reported. In the past year, the Drug Information Service alerted its pharmacist members to problems including particulate matter in indomethacin, used to treat congenital heart defects in infants; particulates in dexamethasone sodium phosphate injections, used in the treatment of cancer; and particles found in Argatroban, a type of blood thinner. According to the Drug Information Service's data, the number of new national drug shortages rose to 267 in 2011 from 70 in 2006. “Companies have been trying to address quality issues for years in many cases and they often reach a point where they feel they have no choice but to close down to make repairs”, said Kweder. Obama's executive order expanded the scope of mandatory reporting to the FDA to include manufacturers that were the sole source of a drug in the USA and were experiencing substantial disruptions. The FDA has also increased the number of staff in its Drug Shortage Programme. In 2011, the FDA helped to prevent shortages of 195 drugs, including 86 drugs produced by one company, the federal agency said in its recent guidance report. Drug companies, like any other commercial enterprise, had been unwilling to publicise any information that might give their competitors an edge. “Companies said they didn't want to air their dirty laundry to the FDA and their competitors”, said Kweder. “All these companies operate in their own little production worlds and talk to us but not to each other. There's no requirement for the FDA to do any of this, nothing in the statutes or public health service act but we're in a unique position to have information and context to solve the problems.” The FDA strove to work with companies, such as fast-tracking regulation for new facilities or sources of active ingredients, and to uphold the strictest confidentiality although companies had their “own ways to find out”, who was struggling, she said. Last month, the agency also issued lengthy guidelines for drug companies to follow when the manufacture of critical medicines was under threat. In the case of Doxil, the FDA allowed the shipment of Lipodox, a similar drug made in India by Sun Pharma Global whose laboratories had already been inspected by the FDA. The drug company Hospira was allowed to import methotrexate from its plant in Australia while the FDA speed up the approval of APP Pharmaceuticals to manufacture the drug. But imports of such drugs were not a long-term solution because other countries sought to ensure enough supply for their domestic markets and the USA needed to do the same, said Fox of the Drug Information Service. “FDA, our pharmacists, physicians, and manufacturers have cobbled together patches but we cannot continue to practise medicine from crisis to crisis”, Michael Link, president of the American Society of Clinical Oncology, said after the FDA acted to avert the shortages of Doxil and methotrexate in February. More recently, he told The Lancet that despite active lobbying by his society and other health-care professional groupings, Congress had yet to pass legislation designed to address drug shortages. “We are doing our best to keep the issue alive and are lighting fires and working to get supplies and encourage further investment in durable solutions”, he said. He believed the economics of generic drugs, whose prices were kept low in part because of wholesale buying by federal programmes such as Medicare, were one of causes of drug shortages. “In the UK, generics are priced higher and there aren't the same kind of shortages”, he said. “Here, generics are priced so low that it's difficult to make money on them. It's hard for companies to see an incentive to spend millions to fix the problem. But we don't really know what's going on behind the scenes at companies. “We need to get to the bottom of the problem and find out if it is economics. We believe it must be part of it. We'd like Congress to carry out a full investigation as to why we're having such problems now and why is it so extensive as well as to legislate remedies.” Arnold Berry, vice-president for scientific affairs at the American Society of Anesthesiologists, said he supported providing incentives for drug makers. “Drug manufacturers participate in a free-market economy and there should be consideration of incentives for companies to produce the generic drugs which have a low profit margin”, he told The Lancet. “Throughout my career, there have always been periodic shortages of drugs but the number of current shortages is unprecedented.” Legislation would also help to address the issue of the grey market in which hospitals buy from secondary suppliers at big mark-ups. Just over half of the 549 US hospitals responding to a survey last summer by the Institute for Safe Medication Practices said they had purchased one or more prescription drugs from companies other than their normal wholesalers. Most also said they had been forced to do so more recently and 7% reported side-effects or other problems with those drugs. “Some distributors take advantage of looming shortages by hoarding and selling at substantial mark-ups, usurious mark-ups, putting patients' lives at risk”, said Link. Berry pointed to a survey undertaken by his society last year of 1373 anaesthesiologists that found 90% of respondents were then experiencing at least one drug shortage. These shortages resulted in a less optimum outcome for a patient (for example post-op nausea and vomiting) 49% of the time. “We need to continue to work collaboratively with the FDA and relevant stakeholders to think outside of the box for solutions to supply critical medications in shortage”, said Berry. “With more advanced notification of shortages, physicians can make informed decisions for alternative plans on how to treat patients and manage existing supplies of the drug that is in limited supply.”