The future of drug safety: What the IOM report may mean to the emergency department

Abstract

The Institute of Medicine’s recent report on drug safety may lead to more evidence-based pharmacology in the emergency department (ED), a modernized federal Food and Drug Administration and better pediatric medication studies.The report, published in September and titled “The Future of Drug Safety,” reviews the viability of present drug safety regulations and recommends expanding Food and Drug Administration (FDA) manpower and funding.Although the report does not directly address EDs and the doctors who work there, its recommendations have the potential to improve health care, including emergency medicine.The good news for emergency physicians is that the new report, among its more than a dozen recommendations, makes 2 suggestions that move medicine toward an evidence-based goal: the committee calls for more post-marketing monitoring of drugs, and recommends hundreds of millions of dollars in additional funding to support drug safety and efficacy studies over a product’s lifecycle.Ongoing drug evaluations needed“The bottom line message is that the Food and Drug Administration, like the science and practice of medicine, needs to evolve and to modernize its approach to the evaluation of drugs, not just prior to their approval, but after their approval,” said Dr. David Blumenthal, a primary care physician who was a member of the IOM committee that wrote the FDA report.“That’s because, for all drugs, whether they have a short or very long life-span, we’re constantly learning about their usefulness and safety models.”The IOM study was sponsored by the US FDA, the National Institutes of Health, Agency for Healthcare Research and Quality, Centers for Medicare and Medicaid Services, and the Department of Veterans Affairs.Like the members of the IOM committee, emergency physicians recognize that the FDA task of balancing fast access to drugs with patient safety is no simple one. However, that fact does not make better any number of the questionable decisions made by the FDA concerning drugs used in the ED.The droperidol exampleThe FDA approved droperidol for clinical use as an antiemetic drug and as an adjuvant during general anesthesia more than 3 decades ago. The drug found its way into many EDs as an inexpensive, safe means of sedating patients.Then, in 2001, the FDA mandated the manufacturer of a generic formulation of the drug, Akorn Pharmaceuticals, add a “Black Box” warning to its packaging because of adverse cardiac effects. As part of its rationale the FDA cited more than 100 unique reports of cardiovascular events.But emergency physicians and anesthesiologists soon discovered that about 75% of these cases occurred outside the United States, and nearly all came after doses at least 10 times those generally used in the ED. At the time an exasperated Dr. Paul White, a professor of anesthesiology at the University of Texas-Southwestern in Dallas, wrote the following in an Anesthesia & Analgesia editorial:“Given the increasing pressure on physicians to make cost-effective choices in medicine, it is difficult to understand why the FDA would place these impractical restrictions on the use of the most cost-effective parenteral antiemetic on the market.”1As a result of the “Black Box” warning, many hospital pharmacies have removed droperidol from their formularies, White said, replacing an inexpensive drug (US $1.28 for droperidol 2.5 mg) with a much more expensive 5-HT3 antagonist (Zofran 4 mg is $20.87; Anzemet 12.5 mg is $15.25; and Kytril 1 mg is $36.75).“More importantly, the 5-HT3 antagonists may actually possess a higher risk of cardiac arrhythmias than droperidol!” White wrote.It wasn’t simply the cost issue that mattered to EDs, but the need for practicality as well.“The ‘Black Box’ decision really hurt us,” said Dr. Joshua Kugler, Chairman of the South Nassau Communities Hospital’s Emergency Services Department, in New York. “We were handcuffed. This is a classic example of how the practice of medicine can be hamstrung by the FDA.”The committee recommended more post-marketing analysis to head off problems like those with droperidol. The idea of continuing surveillance and study of a drug throughout its life cycle is not a new one, but the IOM panel bluntly states that the FDA has implemented it “at best, in a limited and fragmented manner.” Such an approach requires periodic access to new data on a drug, as well as the active reassessment of its performance and safety.New powers for the FDATo accomplish this goal the committee recommends several steps, perhaps the most significant of which is giving the FDA the authority to require that pharmaceutical companies perform post-marketing studies. Currently the FDA’s only tool to compel such studies is to pull a drug from the market.The IOM committee also sought to create a multi-year trial period in which, after a drug’s approval, consumers were made explicitly aware of the uncertainty about its risks and benefits. Such information would come through both labeling on packages as well prominent disclosure in any direct-to-consumer marketing. The committee preferred no direct advertising to consumers at all during this time, but recognized that legal difficulties might attend any efforts to impose this.Blumenthal noted that reaction to the report has generally been positive, but said he could understand if the pharmaceutical industry was less than pleased. However, he noted that there were some potential incentives, citing the FDA Modernization Act of 1997, which gave benefits to drug companies that performed post-marketing studies.No child left behindThis law provided a 6-month extension of license exclusivity for pharmaceutical companies that included children in their clinical trials. It was an important step, regulators say, to address the serious dosage questions doctors face when prescribing medicines for children that have only been tested in adults.That law was extended in 2002 by the Best Pharmaceuticals for Children Act, in which the National Institute of Child Health and Development formalized a process to identify off-label drugs used in children that require study, such as lorazepam, design trials, select sites and eventually to consider whether to modify the FDA label. The following year the FDA was given a “stick,” the Pediatric Research Equity Act, which allowed it to require such studies in children.Before the laws, there was essentially no infrastructure for pediatric drug research.“There are many people who feel it may be somewhat redundant because we have such a long track record of post-approval use with some of these drugs,” said Dr. Jill Baren, an associate professor of emergency medicine and pediatrics at University of Pennsylvania School of Medicine, and a practicing physician at Children’s Hospital of Philadelphia and the Hospital of the University of Pennsylvania. “My opinion is that I feel strongly that patients are much safer in a clinical trial than being given a therapy, willy nilly, that hasn’t been tested in a rigorous scientific setting.”Off-label usage, of course, isn’t restricted to children in the ED. It happens with adults all the time, too. Typically these are medications that have been used for years. Examples range from antibiotics used for certain infections that the FDA has not approved them for dosing, said Dr. Jeff Kalina, an associate medical director of emergency medicine at The Methodist Hospital in Houston. The label for Plavix, a drug frequently used for heart attacks, recommends a 300 mg dose. But there’s some good data that suggests a 600 mg dose is safe, and still more effective.Input from the “average joe”As part of its effort to expand post-marketing studies, Kalina said, the FDA would do well to solicit input from the “average Joe” practitioners who are regularly using the drugs, rather than the pharmaceutical companies and academic researchers who perform the majority of clinical trials.“I think there are many medications that having the input from the practitioners, input from the front line, would probably improve the process,” he said.The IOM report’s call for more post-marketing studies was generally welcomed by emergency medicine practitioners who view it as a means of finding more certainty in the emergency department.“The reason why you would want to do this is to improve the outcome of patients,” said Dr. Steven Krug, a professor of pediatrics at Northwestern University’s Feinberg School of Medicine, and head of Pediatric Emergency Medicine at Children’s Memorial Hospital, in Chicago. “The medicine we practice today is driven in part by evidence, and in part by consensus. I think we would all be better doctors, and our patients would do better, if a greater percentage of our practice were driven by evidence.”All of this requires more resources at the FDA. Along with new regulatory authority, and the potential for incentives for pharmaceutical companies, industry might be expected to bear some of the costs for gathering more information about the nation’s drugs.Yet the IOM committee warns of the potential for conflicts of interest of using drug company funds and suggests that the FDA already has an “over-dependence” on money raised from the Prescription Drug User Fee Act.As a result, the committee recommended that the FDA request and Congress approve a substantial budget increase. According to Blumenthal, a committee member, that means hundreds of millions of dollars to supplement the $1.9 billion budget of the FDA in fiscal year 2006. Because of conflict of interest concerns, the committee said the money should come from the general fund rather than user fees.The report also suggests, in light of the Vioxx controversy and other drug safety matters that have bubbled into public consciousness, that now is a prime time for the agency to seek substantial increases in funding to improve its work.An underfunded FDAThe additional funds would not only help pay the costs of post-marketing studies and analyses, the committee says, but also add staffing to handle the markedly increased workload.Acknowledging that, just like many other ED physicians, he treats patients with medications that lack well-defined dosing requirements, Krug said, the government needs to do its part to improve medical care.“I do believe it is fair to say the FDA is under-funded and under-resourced,” Krug said. “Obviously, if we value some of these proposed recommendations and the associated benefits that might come from the report, in order for the FDA to achieve what we’d like it to, it is going to need to be a lot bigger.“I think there’s a lot that people can do at a grassroots level to improve care, but ultimately there’s a role for the government and for funding to support these changes.” The Institute of Medicine’s recent report on drug safety may lead to more evidence-based pharmacology in the emergency department (ED), a modernized federal Food and Drug Administration and better pediatric medication studies. The report, published in September and titled “The Future of Drug Safety,” reviews the viability of present drug safety regulations and recommends expanding Food and Drug Administration (FDA) manpower and funding. Although the report does not directly address EDs and the doctors who work there, its recommendations have the potential to improve health care, including emergency medicine. The good news for emergency physicians is that the new report, among its more than a dozen recommendations, makes 2 suggestions that move medicine toward an evidence-based goal: the committee calls for more post-marketing monitoring of drugs, and recommends hundreds of millions of dollars in additional funding to support drug safety and efficacy studies over a product’s lifecycle. Ongoing drug evaluations needed“The bottom line message is that the Food and Drug Administration, like the science and practice of medicine, needs to evolve and to modernize its approach to the evaluation of drugs, not just prior to their approval, but after their approval,” said Dr. David Blumenthal, a primary care physician who was a member of the IOM committee that wrote the FDA report.“That’s because, for all drugs, whether they have a short or very long life-span, we’re constantly learning about their usefulness and safety models.”The IOM study was sponsored by the US FDA, the National Institutes of Health, Agency for Healthcare Research and Quality, Centers for Medicare and Medicaid Services, and the Department of Veterans Affairs.Like the members of the IOM committee, emergency physicians recognize that the FDA task of balancing fast access to drugs with patient safety is no simple one. However, that fact does not make better any number of the questionable decisions made by the FDA concerning drugs used in the ED. “The bottom line message is that the Food and Drug Administration, like the science and practice of medicine, needs to evolve and to modernize its approach to the evaluation of drugs, not just prior to their approval, but after their approval,” said Dr. David Blumenthal, a primary care physician who was a member of the IOM committee that wrote the FDA report. “That’s because, for all drugs, whether they have a short or very long life-span, we’re constantly learning about their usefulness and safety models.” The IOM study was sponsored by the US FDA, the National Institutes of Health, Agency for Healthcare Research and Quality, Centers for Medicare and Medicaid Services, and the Department of Veterans Affairs. Like the members of the IOM committee, emergency physicians recognize that the FDA task of balancing fast access to drugs with patient safety is no simple one. However, that fact does not make better any number of the questionable decisions made by the FDA concerning drugs used in the ED. The droperidol exampleThe FDA approved droperidol for clinical use as an antiemetic drug and as an adjuvant during general anesthesia more than 3 decades ago. The drug found its way into many EDs as an inexpensive, safe means of sedating patients.Then, in 2001, the FDA mandated the manufacturer of a generic formulation of the drug, Akorn Pharmaceuticals, add a “Black Box” warning to its packaging because of adverse cardiac effects. As part of its rationale the FDA cited more than 100 unique reports of cardiovascular events.But emergency physicians and anesthesiologists soon discovered that about 75% of these cases occurred outside the United States, and nearly all came after doses at least 10 times those generally used in the ED. At the time an exasperated Dr. Paul White, a professor of anesthesiology at the University of Texas-Southwestern in Dallas, wrote the following in an Anesthesia & Analgesia editorial:“Given the increasing pressure on physicians to make cost-effective choices in medicine, it is difficult to understand why the FDA would place these impractical restrictions on the use of the most cost-effective parenteral antiemetic on the market.”1As a result of the “Black Box” warning, many hospital pharmacies have removed droperidol from their formularies, White said, replacing an inexpensive drug (US $1.28 for droperidol 2.5 mg) with a much more expensive 5-HT3 antagonist (Zofran 4 mg is $20.87; Anzemet 12.5 mg is $15.25; and Kytril 1 mg is $36.75).“More importantly, the 5-HT3 antagonists may actually possess a higher risk of cardiac arrhythmias than droperidol!” White wrote.It wasn’t simply the cost issue that mattered to EDs, but the need for practicality as well.“The ‘Black Box’ decision really hurt us,” said Dr. Joshua Kugler, Chairman of the South Nassau Communities Hospital’s Emergency Services Department, in New York. “We were handcuffed. This is a classic example of how the practice of medicine can be hamstrung by the FDA.”The committee recommended more post-marketing analysis to head off problems like those with droperidol. The idea of continuing surveillance and study of a drug throughout its life cycle is not a new one, but the IOM panel bluntly states that the FDA has implemented it “at best, in a limited and fragmented manner.” Such an approach requires periodic access to new data on a drug, as well as the active reassessment of its performance and safety. The FDA approved droperidol for clinical use as an antiemetic drug and as an adjuvant during general anesthesia more than 3 decades ago. The drug found its way into many EDs as an inexpensive, safe means of sedating patients. Then, in 2001, the FDA mandated the manufacturer of a generic formulation of the drug, Akorn Pharmaceuticals, add a “Black Box” warning to its packaging because of adverse cardiac effects. As part of its rationale the FDA cited more than 100 unique reports of cardiovascular events. But emergency physicians and anesthesiologists soon discovered that about 75% of these cases occurred outside the United States, and nearly all came after doses at least 10 times those generally used in the ED. At the time an exasperated Dr. Paul White, a professor of anesthesiology at the University of Texas-Southwestern in Dallas, wrote the following in an Anesthesia & Analgesia editorial: “Given the increasing pressure on physicians to make cost-effective choices in medicine, it is difficult to understand why the FDA would place these impractical restrictions on the use of the most cost-effective parenteral antiemetic on the market.”1 As a result of the “Black Box” warning, many hospital pharmacies have removed droperidol from their formularies, White said, replacing an inexpensive drug (US $1.28 for droperidol 2.5 mg) with a much more expensive 5-HT3 antagonist (Zofran 4 mg is $20.87; Anzemet 12.5 mg is $15.25; and Kytril 1 mg is $36.75). “More importantly, the 5-HT3 antagonists may actually possess a higher risk of cardiac arrhythmias than droperidol!” White wrote. It wasn’t simply the cost issue that mattered to EDs, but the need for practicality as well. “The ‘Black Box’ decision really hurt us,” said Dr. Joshua Kugler, Chairman of the South Nassau Communities Hospital’s Emergency Services Department, in New York. “We were handcuffed. This is a classic example of how the practice of medicine can be hamstrung by the FDA.” The committee recommended more post-marketing analysis to head off problems like those with droperidol. The idea of continuing surveillance and study of a drug throughout its life cycle is not a new one, but the IOM panel bluntly states that the FDA has implemented it “at best, in a limited and fragmented manner.” Such an approach requires periodic access to new data on a drug, as well as the active reassessment of its performance and safety. New powers for the FDATo accomplish this goal the committee recommends several steps, perhaps the most significant of which is giving the FDA the authority to require that pharmaceutical companies perform post-marketing studies. Currently the FDA’s only tool to compel such studies is to pull a drug from the market.The IOM committee also sought to create a multi-year trial period in which, after a drug’s approval, consumers were made explicitly aware of the uncertainty about its risks and benefits. Such information would come through both labeling on packages as well prominent disclosure in any direct-to-consumer marketing. The committee preferred no direct advertising to consumers at all during this time, but recognized that legal difficulties might attend any efforts to impose this.Blumenthal noted that reaction to the report has generally been positive, but said he could understand if the pharmaceutical industry was less than pleased. However, he noted that there were some potential incentives, citing the FDA Modernization Act of 1997, which gave benefits to drug companies that performed post-marketing studies. To accomplish this goal the committee recommends several steps, perhaps the most significant of which is giving the FDA the authority to require that pharmaceutical companies perform post-marketing studies. Currently the FDA’s only tool to compel such studies is to pull a drug from the market. The IOM committee also sought to create a multi-year trial period in which, after a drug’s approval, consumers were made explicitly aware of the uncertainty about its risks and benefits. Such information would come through both labeling on packages as well prominent disclosure in any direct-to-consumer marketing. The committee preferred no direct advertising to consumers at all during this time, but recognized that legal difficulties might attend any efforts to impose this. Blumenthal noted that reaction to the report has generally been positive, but said he could understand if the pharmaceutical industry was less than pleased. However, he noted that there were some potential incentives, citing the FDA Modernization Act of 1997, which gave benefits to drug companies that performed post-marketing studies. No child left behindThis law provided a 6-month extension of license exclusivity for pharmaceutical companies that included children in their clinical trials. It was an important step, regulators say, to address the serious dosage questions doctors face when prescribing medicines for children that have only been tested in adults.That law was extended in 2002 by the Best Pharmaceuticals for Children Act, in which the National Institute of Child Health and Development formalized a process to identify off-label drugs used in children that require study, such as lorazepam, design trials, select sites and eventually to consider whether to modify the FDA label. The following year the FDA was given a “stick,” the Pediatric Research Equity Act, which allowed it to require such studies in children.Before the laws, there was essentially no infrastructure for pediatric drug research.“There are many people who feel it may be somewhat redundant because we have such a long track record of post-approval use with some of these drugs,” said Dr. Jill Baren, an associate professor of emergency medicine and pediatrics at University of Pennsylvania School of Medicine, and a practicing physician at Children’s Hospital of Philadelphia and the Hospital of the University of Pennsylvania. “My opinion is that I feel strongly that patients are much safer in a clinical trial than being given a therapy, willy nilly, that hasn’t been tested in a rigorous scientific setting.”Off-label usage, of course, isn’t restricted to children in the ED. It happens with adults all the time, too. Typically these are medications that have been used for years. Examples range from antibiotics used for certain infections that the FDA has not approved them for dosing, said Dr. Jeff Kalina, an associate medical director of emergency medicine at The Methodist Hospital in Houston. The label for Plavix, a drug frequently used for heart attacks, recommends a 300 mg dose. But there’s some good data that suggests a 600 mg dose is safe, and still more effective. This law provided a 6-month extension of license exclusivity for pharmaceutical companies that included children in their clinical trials. It was an important step, regulators say, to address the serious dosage questions doctors face when prescribing medicines for children that have only been tested in adults. That law was extended in 2002 by the Best Pharmaceuticals for Children Act, in which the National Institute of Child Health and Development formalized a process to identify off-label drugs used in children that require study, such as lorazepam, design trials, select sites and eventually to consider whether to modify the FDA label. The following year the FDA was given a “stick,” the Pediatric Research Equity Act, which allowed it to require such studies in children. Before the laws, there was essentially no infrastructure for pediatric drug research. “There are many people who feel it may be somewhat redundant because we have such a long track record of post-approval use with some of these drugs,” said Dr. Jill Baren, an associate professor of emergency medicine and pediatrics at University of Pennsylvania School of Medicine, and a practicing physician at Children’s Hospital of Philadelphia and the Hospital of the University of Pennsylvania. “My opinion is that I feel strongly that patients are much safer in a clinical trial than being given a therapy, willy nilly, that hasn’t been tested in a rigorous scientific setting.” Off-label usage, of course, isn’t restricted to children in the ED. It happens with adults all the time, too. Typically these are medications that have been used for years. Examples range from antibiotics used for certain infections that the FDA has not approved them for dosing, said Dr. Jeff Kalina, an associate medical director of emergency medicine at The Methodist Hospital in Houston. The label for Plavix, a drug frequently used for heart attacks, recommends a 300 mg dose. But there’s some good data that suggests a 600 mg dose is safe, and still more effective. Input from the “average joe”As part of its effort to expand post-marketing studies, Kalina said, the FDA would do well to solicit input from the “average Joe” practitioners who are regularly using the drugs, rather than the pharmaceutical companies and academic researchers who perform the majority of clinical trials.“I think there are many medications that having the input from the practitioners, input from the front line, would probably improve the process,” he said.The IOM report’s call for more post-marketing studies was generally welcomed by emergency medicine practitioners who view it as a means of finding more certainty in the emergency department.“The reason why you would want to do this is to improve the outcome of patients,” said Dr. Steven Krug, a professor of pediatrics at Northwestern University’s Feinberg School of Medicine, and head of Pediatric Emergency Medicine at Children’s Memorial Hospital, in Chicago. “The medicine we practice today is driven in part by evidence, and in part by consensus. I think we would all be better doctors, and our patients would do better, if a greater percentage of our practice were driven by evidence.”All of this requires more resources at the FDA. Along with new regulatory authority, and the potential for incentives for pharmaceutical companies, industry might be expected to bear some of the costs for gathering more information about the nation’s drugs.Yet the IOM committee warns of the potential for conflicts of interest of using drug company funds and suggests that the FDA already has an “over-dependence” on money raised from the Prescription Drug User Fee Act.As a result, the committee recommended that the FDA request and Congress approve a substantial budget increase. According to Blumenthal, a committee member, that means hundreds of millions of dollars to supplement the $1.9 billion budget of the FDA in fiscal year 2006. Because of conflict of interest concerns, the committee said the money should come from the general fund rather than user fees.The report also suggests, in light of the Vioxx controversy and other drug safety matters that have bubbled into public consciousness, that now is a prime time for the agency to seek substantial increases in funding to improve its work. As part of its effort to expand post-marketing studies, Kalina said, the FDA would do well to solicit input from the “average Joe” practitioners who are regularly using the drugs, rather than the pharmaceutical companies and academic researchers who perform the majority of clinical trials. “I think there are many medications that having the input from the practitioners, input from the front line, would probably improve the process,” he said. The IOM report’s call for more post-marketing studies was generally welcomed by emergency medicine practitioners who view it as a means of finding more certainty in the emergency department. “The reason why you would want to do this is to improve the outcome of patients,” said Dr. Steven Krug, a professor of pediatrics at Northwestern University’s Feinberg School of Medicine, and head of Pediatric Emergency Medicine at Children’s Memorial Hospital, in Chicago. “The medicine we practice today is driven in part by evidence, and in part by consensus. I think we would all be better doctors, and our patients would do better, if a greater percentage of our practice were driven by evidence.” All of this requires more resources at the FDA. Along with new regulatory authority, and the potential for incentives for pharmaceutical companies, industry might be expected to bear some of the costs for gathering more information about the nation’s drugs. Yet the IOM committee warns of the potential for conflicts of interest of using drug company funds and suggests that the FDA already has an “over-dependence” on money raised from the Prescription Drug User Fee Act. As a result, the committee recommended that the FDA request and Congress approve a substantial budget increase. According to Blumenthal, a committee member, that means hundreds of millions of dollars to supplement the $1.9 billion budget of the FDA in fiscal year 2006. Because of conflict of interest concerns, the committee said the money should come from the general fund rather than user fees. The report also suggests, in light of the Vioxx controversy and other drug safety matters that have bubbled into public consciousness, that now is a prime time for the agency to seek substantial increases in funding to improve its work. An underfunded FDAThe additional funds would not only help pay the costs of post-marketing studies and analyses, the committee says, but also add staffing to handle the markedly increased workload.Acknowledging that, just like many other ED physicians, he treats patients with medications that lack well-defined dosing requirements, Krug said, the government needs to do its part to improve medical care.“I do believe it is fair to say the FDA is under-funded and under-resourced,” Krug said. “Obviously, if we value some of these proposed recommendations and the associated benefits that might come from the report, in order for the FDA to achieve what we’d like it to, it is going to need to be a lot bigger.“I think there’s a lot that people can do at a grassroots level to improve care, but ultimately there’s a role for the government and for funding to support these changes.” The additional funds would not only help pay the costs of post-marketing studies and analyses, the committee says, but also add staffing to handle the markedly increased workload. Acknowledging that, just like many other ED physicians, he treats patients with medications that lack well-defined dosing requirements, Krug said, the government needs to do its part to improve medical care. “I do believe it is fair to say the FDA is under-funded and under-resourced,” Krug said. “Obviously, if we value some of these proposed recommendations and the associated benefits that might come from the report, in order for the FDA to achieve what we’d like it to, it is going to need to be a lot bigger. “I think there’s a lot that people can do at a grassroots level to improve care, but ultimately there’s a role for the government and for funding to support these changes.”