ASHP/FDA
Aminocaproic Acid Injection
Amiodarone Hydrochloride Injection
Intravenous Fat Emulsion
Multiple Vitamins for Infusion
Tranexamic Acid Injection
http://www.ashp.org/Drugshortages/Current/?sort=2
Thursday, August 22, 2013
Wednesday, August 21, 2013
New England Journal of Med - The Impact of Drug Shortages on Children with Cancer — The Example of Mechlorethamine
Over the past several years, patients and caregivers have faced an increasing number of drug shortages, predominantly of generic injectable agents. The reasons for these shortages are complex. Narrow profit margins for generic drugs have limited the incentive to produce them. Other reasons include the limited number of manufacturers, increased worldwide demand, shortages of raw materials, production problems, aging production plants, stockpiling, and long timelines for approval.1 Patient care may suffer significantly as a result: alternative drugs must be prescribed, but the replacement may be less efficacious, more toxic, prohibitively expensive, or all of the above, and safety may be compromised if providers are unfamiliar with administering the substitute.
Shortages of anticancer agents are even more critical, because there may be no equivalents for the drugs that are in short supply, and conversion factors and dose adjustments may be unknown. Recent media coverage has highlighted shortages of cytarabine, daunorubicin, and methotrexate, which are essential for treating childhood leukemia, a highly curable cancer. Fortunately, those shortages were quickly resolved, and alternative strategies such as prioritizing patients for access to certain drugs and using equivalent agents sufficed to bridge the gap.
One shortage that hasn't made the news is that of mechlorethamine, or nitrogen mustard, one of the first anticancer agents, which was used in the 1960s in combination with vincristine, procarbazine, and prednisone in the MOPP regimen for Hodgkin's lymphoma. Although this regimen was effective, it was associated with secondary leukemia and infertility. Alternative chemotherapy combinations were developed to avoid these complications. In an effort to maintain excellent outcomes while minimizing toxicity, a 12-week chemotherapy regimen was developed at Stanford University (the Stanford V regimen) that included vinblastine, mechlorethamine, doxorubicin, vincristine, bleomycin, etoposide, and prednisone. This regimen's main features are an abbreviated course of treatment, unchanged or increased dose intensity of individual drugs, lower cumulative doses of bleomycin and doxorubicin than in other standard regimens, exposure to lower cumulative mechlorethamine than in MOPP, and omission of procarbazine. This regimen proved to be effective while allowing for preserved fertility and reduced risk of secondary leukemia as compared with MOPP, and reduced risk of cardiopulmonary dysfunction as compared with other regimens in use.
The Pediatric Hodgkin Lymphoma Consortium, which includes St. Jude Children's Research Hospital, Stanford University, Dana–Farber Cancer Institute/Boston Children's Hospital, Massachusetts General Hospital, and Maine Medical Center, has conducted clinical trials for pediatric Hodgkin's lymphoma since the 1990s. It adopted the Stanford V regimen, along with response-based, low-dose radiotherapy, in 2002 for patients with high-risk Hodgkin's lymphoma and in 2006 for patients with intermediate-risk Hodgkin's lymphoma. More than 170 patients had been treated with this regimen in our studies when a shortage of mechlorethamine emerged in 2009. A review of the literature suggested that cyclophosphamide at a dose of 650 mg per square meter of body-surface area could safely be substituted for mechlorethamine 6 mg per square meter. When mechlorethamine became unavailable, we amended our studies to use cyclophosphamide instead. Although the COPP regimen (cyclophosphamide 600 to 650 mg per square meter, vincristine, procarbazine, and prednisone) has been widely used in adult and pediatric trials and was believed to be equivalent in efficacy to MOPP, no randomized study had ever compared the two.
Many published reports describe in detail the sources of drug shortages, as well as reactions of the Food and Drug Administration, the American Society of Clinical Oncology, or Congress. Other reports speculate on possible solutions, but few comment on individual patient safety.2,3 Although concerns have been raised about reduced efficacy and possible adverse outcomes related to shortages of anticancer agents, we have seen no report documenting the adverse effects of these shortages on a specific patient population or the way in which a substitution has affected outcomes.
To assess the impact of the substitution that we were forced to adopt, we compared the probability of event-free survival among 181 patients who were treated with the original Stanford V regimen including mechlorethamine with the probability among 40 patients treated with the modified Stanford V regimen including cyclophosphamide. In this retrospective comparison, we discovered that treatment with cyclophosphamide was significantly less effective (2-year event-free survival, 75% with cyclophosphamide [SE, 12.5%] vs. 88% with mechlorethamine [SE, 2.5%; P=0.01 by the log-rank test]) (see graphEvent-Free Survival Distributions among Children with Hodgkin's Lymphoma Treated with the Original Stanford V Regimen with Mechlorethamine, as Compared with Those Treated with a Modified Stanford V Regimen with Cyclophosphamide.).
We can think of no credible explanation for this dramatic difference in event-free survival other than the drug substitution, since careful analysis of our data demonstrated that patients in the cyclophosphamide cohort did not have more unfavorable clinical features than those in the mechlorethamine cohort. In fact, patients in the cyclophosphamide cohort were less likely to have B symptoms (fever, unintentional weight loss, and night sweats) and more likely to have intermediate-risk or high-risk Hodgkin's lymphoma, with no difference in mediastinal bulk or stage distribution.
Follow-up is still short (median follow-up, 1.5 years in the cyclophosphamide group and 4.7 years in the mechlorethamine group), and no patient in the study has died, so there is no survival difference between the cohorts. However, patients who had a relapse received salvage therapy including intensive cytoreduction followed by autologous stem-cell transplantation — therapy that is associated with infertility and a greater risk of long-term toxic effects. These complications might have been avoided if such patients had been treated with mechlorethamine. Moreover, it is unknown as yet whether salvage therapy has been successful in all patients who have had a relapse.
Almost 80% of children and adolescents with cancer can be cured with current therapy. Most of the curative treatment regimens are based on chemotherapeutic agents that have been available for decades, but some of these have recently been in short supply. These shortages are likely to have devastating effects on patients with cancer and must be prevented. For many of these agents, no adequate substitute drugs are available. Our results suggest that even promising substitute regimens should be examined carefully before adoption; what might appear to be a suitable alternative regimen may result in an inferior outcome — an intolerable situation for young people with curable diseases.
http://www.nejm.org/doi/full/10.1056/NEJMp1212468
Shortages of anticancer agents are even more critical, because there may be no equivalents for the drugs that are in short supply, and conversion factors and dose adjustments may be unknown. Recent media coverage has highlighted shortages of cytarabine, daunorubicin, and methotrexate, which are essential for treating childhood leukemia, a highly curable cancer. Fortunately, those shortages were quickly resolved, and alternative strategies such as prioritizing patients for access to certain drugs and using equivalent agents sufficed to bridge the gap.
One shortage that hasn't made the news is that of mechlorethamine, or nitrogen mustard, one of the first anticancer agents, which was used in the 1960s in combination with vincristine, procarbazine, and prednisone in the MOPP regimen for Hodgkin's lymphoma. Although this regimen was effective, it was associated with secondary leukemia and infertility. Alternative chemotherapy combinations were developed to avoid these complications. In an effort to maintain excellent outcomes while minimizing toxicity, a 12-week chemotherapy regimen was developed at Stanford University (the Stanford V regimen) that included vinblastine, mechlorethamine, doxorubicin, vincristine, bleomycin, etoposide, and prednisone. This regimen's main features are an abbreviated course of treatment, unchanged or increased dose intensity of individual drugs, lower cumulative doses of bleomycin and doxorubicin than in other standard regimens, exposure to lower cumulative mechlorethamine than in MOPP, and omission of procarbazine. This regimen proved to be effective while allowing for preserved fertility and reduced risk of secondary leukemia as compared with MOPP, and reduced risk of cardiopulmonary dysfunction as compared with other regimens in use.
The Pediatric Hodgkin Lymphoma Consortium, which includes St. Jude Children's Research Hospital, Stanford University, Dana–Farber Cancer Institute/Boston Children's Hospital, Massachusetts General Hospital, and Maine Medical Center, has conducted clinical trials for pediatric Hodgkin's lymphoma since the 1990s. It adopted the Stanford V regimen, along with response-based, low-dose radiotherapy, in 2002 for patients with high-risk Hodgkin's lymphoma and in 2006 for patients with intermediate-risk Hodgkin's lymphoma. More than 170 patients had been treated with this regimen in our studies when a shortage of mechlorethamine emerged in 2009. A review of the literature suggested that cyclophosphamide at a dose of 650 mg per square meter of body-surface area could safely be substituted for mechlorethamine 6 mg per square meter. When mechlorethamine became unavailable, we amended our studies to use cyclophosphamide instead. Although the COPP regimen (cyclophosphamide 600 to 650 mg per square meter, vincristine, procarbazine, and prednisone) has been widely used in adult and pediatric trials and was believed to be equivalent in efficacy to MOPP, no randomized study had ever compared the two.
Many published reports describe in detail the sources of drug shortages, as well as reactions of the Food and Drug Administration, the American Society of Clinical Oncology, or Congress. Other reports speculate on possible solutions, but few comment on individual patient safety.2,3 Although concerns have been raised about reduced efficacy and possible adverse outcomes related to shortages of anticancer agents, we have seen no report documenting the adverse effects of these shortages on a specific patient population or the way in which a substitution has affected outcomes.
To assess the impact of the substitution that we were forced to adopt, we compared the probability of event-free survival among 181 patients who were treated with the original Stanford V regimen including mechlorethamine with the probability among 40 patients treated with the modified Stanford V regimen including cyclophosphamide. In this retrospective comparison, we discovered that treatment with cyclophosphamide was significantly less effective (2-year event-free survival, 75% with cyclophosphamide [SE, 12.5%] vs. 88% with mechlorethamine [SE, 2.5%; P=0.01 by the log-rank test]) (see graphEvent-Free Survival Distributions among Children with Hodgkin's Lymphoma Treated with the Original Stanford V Regimen with Mechlorethamine, as Compared with Those Treated with a Modified Stanford V Regimen with Cyclophosphamide.).
We can think of no credible explanation for this dramatic difference in event-free survival other than the drug substitution, since careful analysis of our data demonstrated that patients in the cyclophosphamide cohort did not have more unfavorable clinical features than those in the mechlorethamine cohort. In fact, patients in the cyclophosphamide cohort were less likely to have B symptoms (fever, unintentional weight loss, and night sweats) and more likely to have intermediate-risk or high-risk Hodgkin's lymphoma, with no difference in mediastinal bulk or stage distribution.
Follow-up is still short (median follow-up, 1.5 years in the cyclophosphamide group and 4.7 years in the mechlorethamine group), and no patient in the study has died, so there is no survival difference between the cohorts. However, patients who had a relapse received salvage therapy including intensive cytoreduction followed by autologous stem-cell transplantation — therapy that is associated with infertility and a greater risk of long-term toxic effects. These complications might have been avoided if such patients had been treated with mechlorethamine. Moreover, it is unknown as yet whether salvage therapy has been successful in all patients who have had a relapse.
Almost 80% of children and adolescents with cancer can be cured with current therapy. Most of the curative treatment regimens are based on chemotherapeutic agents that have been available for decades, but some of these have recently been in short supply. These shortages are likely to have devastating effects on patients with cancer and must be prevented. For many of these agents, no adequate substitute drugs are available. Our results suggest that even promising substitute regimens should be examined carefully before adoption; what might appear to be a suitable alternative regimen may result in an inferior outcome — an intolerable situation for young people with curable diseases.
http://www.nejm.org/doi/full/10.1056/NEJMp1212468
How Modern Healthcare Grinds to a Halt: Drug Shortages
Surprisingly, one of the biggest challenges in healthcare over the past five years has been a shortage of pharmaceuticals. From 2006 to 2011 drug shortages grew by 400%.[1] It is now a common practice for hospital pharmacies to maintain lists of which pharmaceuticals are available for physicians to prescribe.
In the U.S, the FDA has been tasked with tackling the problem of drug shortages. They provide updates through their website listing of new, current and resolved drugs shortages. In 2012, the FDA even undertook the unusual action of bypassing patent protection for the oncology medication, Doxil, by allowing the importation of a generic equivalent to resolve a critical shortage. While these efforts have improved the situation over the past two years, drug shortages remain stubbornly high, and the FDA is not able to require firms to provide the reason for drug shortages or how long the shortage will take to be resolved.
A recent report from the Tufts University Center for the Study of Drug Development provides insights into how our modern healthcare supply chain is so severely impacted by simple shortages of important drugs. The top two reasons for shortages are manufacturing problems such as not meeting FDA quality requirements and increase in demand for a particular drug as in a sudden need for a drug substitution.[2] Both of these reasons draw attention to how delicate our healthcare supply chain has become. The healthcare industry, similar to other industries, follows lean inventory policies. While an average pharmacy turns its inventory just under 12 times each year – the average drug shortage lasts 19 months.[3] Implementing improved supply chain technology and transportation can help speed the delivery of inventory to providers and patients. But only when the products are available for distribution.
Do you think the FDA should be allowed to require firms to report the reason for shortages and an estimated duration to resolution?
http://blog.ups.com/2013/08/20/how-modern-healthcare-grinds-to-a-halt-drug-shortages/
In the U.S, the FDA has been tasked with tackling the problem of drug shortages. They provide updates through their website listing of new, current and resolved drugs shortages. In 2012, the FDA even undertook the unusual action of bypassing patent protection for the oncology medication, Doxil, by allowing the importation of a generic equivalent to resolve a critical shortage. While these efforts have improved the situation over the past two years, drug shortages remain stubbornly high, and the FDA is not able to require firms to provide the reason for drug shortages or how long the shortage will take to be resolved.
A recent report from the Tufts University Center for the Study of Drug Development provides insights into how our modern healthcare supply chain is so severely impacted by simple shortages of important drugs. The top two reasons for shortages are manufacturing problems such as not meeting FDA quality requirements and increase in demand for a particular drug as in a sudden need for a drug substitution.[2] Both of these reasons draw attention to how delicate our healthcare supply chain has become. The healthcare industry, similar to other industries, follows lean inventory policies. While an average pharmacy turns its inventory just under 12 times each year – the average drug shortage lasts 19 months.[3] Implementing improved supply chain technology and transportation can help speed the delivery of inventory to providers and patients. But only when the products are available for distribution.
Do you think the FDA should be allowed to require firms to report the reason for shortages and an estimated duration to resolution?
http://blog.ups.com/2013/08/20/how-modern-healthcare-grinds-to-a-halt-drug-shortages/
Drug Shortages Persist in Months after Surveys Make Headlines at ASCO
August 20, 2013 — Cancer drug shortages continue to confound the best efforts of the Food & Drug Administration to head them off, in part because the agency has little authority to address what causes them to occur, according to a co-author of an attention-getting study about shortages.
Dr. Keerthi Gogenini, a medical oncologist with the Abramson Cancer Center at the University of Pennsylvania, helped present one of several studies that grabbed headlines at the June meeting of the American Society of Clinical Oncology. Evidence-Based Oncology, checked back with Gogenini and with the FDA on the current state of shortages for its August issue. EBO is an indexed news publication that is a supplement to The American Journal of Managed Care.
An FDA spokeswoman, Lisa Kubaska, PharmD, credited the 2012 Food and Drug Safety Innovation Act with allowing the agency to identify shortages and find temporary solutions, such as importations of drugs. But Gogenini said on the front lines, the picture is not that rosy, although she believes the FDA is doing what it can.
“There are factors that contribute to drug shortages that the agency has limited control over,” Gogenini said.
The FDA, Gogenini and multiple other experts attribute cancer drug shortages to quality control problems at large manufacturers. The trouble is, the FDA cannot force drug manufacturers to direct manufacturing resources to generics instead of branded drugs, which cost more. The 2012 legislation basically serves as an early warning system that gives the FDA time to come up with alternatives when a shortage looms.
The June surveys presented at ASCO, including the study conducted at the University of Pennsylvania, showed widespread effects of shortages. In the Penn study, 94 percent of oncologist and hematologists said patients’ treatment had been affected by shortages, and 13 percent reported that patient participation in clinical trials had been compromised.
Gogenini attributes shortages to the lack of redundancy across the manufacturing system, while others have blamed the low cost of generics, which give companies little incentive to invest in capacity for these drugs.
“There are few penalties for failing to supply critical drugs, and no incentive for companies to invest in ‘excess’ capacity,” Gogeini told EBO. “This is not something the FDA would have control over.”
http://www.thelundreport.org/resource/drug_shortages_persist_in_months_after_surveys_make_headlines_at_asco
Dr. Keerthi Gogenini, a medical oncologist with the Abramson Cancer Center at the University of Pennsylvania, helped present one of several studies that grabbed headlines at the June meeting of the American Society of Clinical Oncology. Evidence-Based Oncology, checked back with Gogenini and with the FDA on the current state of shortages for its August issue. EBO is an indexed news publication that is a supplement to The American Journal of Managed Care.
An FDA spokeswoman, Lisa Kubaska, PharmD, credited the 2012 Food and Drug Safety Innovation Act with allowing the agency to identify shortages and find temporary solutions, such as importations of drugs. But Gogenini said on the front lines, the picture is not that rosy, although she believes the FDA is doing what it can.
“There are factors that contribute to drug shortages that the agency has limited control over,” Gogenini said.
The FDA, Gogenini and multiple other experts attribute cancer drug shortages to quality control problems at large manufacturers. The trouble is, the FDA cannot force drug manufacturers to direct manufacturing resources to generics instead of branded drugs, which cost more. The 2012 legislation basically serves as an early warning system that gives the FDA time to come up with alternatives when a shortage looms.
The June surveys presented at ASCO, including the study conducted at the University of Pennsylvania, showed widespread effects of shortages. In the Penn study, 94 percent of oncologist and hematologists said patients’ treatment had been affected by shortages, and 13 percent reported that patient participation in clinical trials had been compromised.
Gogenini attributes shortages to the lack of redundancy across the manufacturing system, while others have blamed the low cost of generics, which give companies little incentive to invest in capacity for these drugs.
“There are few penalties for failing to supply critical drugs, and no incentive for companies to invest in ‘excess’ capacity,” Gogeini told EBO. “This is not something the FDA would have control over.”
http://www.thelundreport.org/resource/drug_shortages_persist_in_months_after_surveys_make_headlines_at_asco
Two compounding pharmacies closed after inspections
Compounding pharmacies in Quincy and Norwood have been shut down after a surprise state inspection found several alleged violations.
Anne Roach, media relations manager for the Massachusetts Department of Public Health, said the state agency conducted a surprise inspection of Medi-Son Solutions of Norwood on April 2.
“During the inspection, the pharmacy was observed to be non-compliant with Board regulations, including requirements pertaining to verifying prescriptions, drug inventories, expired medications and sterile compounding,” Roach said in an e-mail.
The Board of Registration in Pharmacy subsequently ordered the pharmacy, located at 898 Washington St., to halt all pharmacy operations.
Despite the cease-and-desist notice, in a follow up inspection on May 8, the pharmacy was still in operation.
A cease-and-desist notice was sent to the manager of record – Medi-Son’s sister company, CarePro in Quincy, for assisting Medi-Son in violating the cease and desist notice. CarePro is located at 343 Newport Ave.
The Board of Registration also voted on July 2 to suspend the licenses for Medi-Son, CarePro, and managers Christopher Le and Son Dinh.
“The hearings on summary suspension and cease-and-desist orders began on August 12 and remain ongoing. The licenses of the pharmacies and pharmacists will remain suspended pending the outcome of the hearings,” Roach said.
Neither manager returned messages left at the closed pharmacy. A recorded message acknowledged the closure, but didn’t specify the reason.
“Due to unforeseen circumstances, our pharmacy has been forced to close temporarily. We will do everything we can in the meantime to facilitate the transfer of your medications,” the message said.
“Nothing is more important to us than your health and well being. We’re sorry for the inconvenience and hope we can take care of you once we are able to open again. Thank you for your support.”
Roach said the inspections are part of enhanced oversight of the pharmacy industry since the New England Compounding Center in Framingham was blamed for the fatal outbreak of fungal meningitis in 2012.
Between last fall and February, 37 compounding pharmacies in Massachusetts were inspected, only four of which passed inspection.
Unannounced inspections will continue to be part of an enhanced oversight, Roach said.
“The Department of Public Health has made great strides to enhance oversight of the pharmacy industry in Massachusetts since last fall,” Roach said. “The Governor provided more than $1 million in new funding in this year’s budget to enable the Board to hire additional staff to enhance inspections of pharmacies.”
http://www.bostonglobe.com/2013/08/20/compounding-pharmacies-quincy-norwood-closed-after-surprise-state-inspection/0bZxQCjsb7vrBu8Qk8AW0I/story.html
Anne Roach, media relations manager for the Massachusetts Department of Public Health, said the state agency conducted a surprise inspection of Medi-Son Solutions of Norwood on April 2.
“During the inspection, the pharmacy was observed to be non-compliant with Board regulations, including requirements pertaining to verifying prescriptions, drug inventories, expired medications and sterile compounding,” Roach said in an e-mail.
The Board of Registration in Pharmacy subsequently ordered the pharmacy, located at 898 Washington St., to halt all pharmacy operations.
Roach did not specify whether any drugs had been recalled due to issues with compounding, in which medicines not available from drug manufacturers are prepared for individual patients, and did not respond to follow-up questions.
Despite the cease-and-desist notice, in a follow up inspection on May 8, the pharmacy was still in operation.
A cease-and-desist notice was sent to the manager of record – Medi-Son’s sister company, CarePro in Quincy, for assisting Medi-Son in violating the cease and desist notice. CarePro is located at 343 Newport Ave.
The Board of Registration also voted on July 2 to suspend the licenses for Medi-Son, CarePro, and managers Christopher Le and Son Dinh.
“The hearings on summary suspension and cease-and-desist orders began on August 12 and remain ongoing. The licenses of the pharmacies and pharmacists will remain suspended pending the outcome of the hearings,” Roach said.
Neither manager returned messages left at the closed pharmacy. A recorded message acknowledged the closure, but didn’t specify the reason.
“Due to unforeseen circumstances, our pharmacy has been forced to close temporarily. We will do everything we can in the meantime to facilitate the transfer of your medications,” the message said.
“Nothing is more important to us than your health and well being. We’re sorry for the inconvenience and hope we can take care of you once we are able to open again. Thank you for your support.”
Roach said the inspections are part of enhanced oversight of the pharmacy industry since the New England Compounding Center in Framingham was blamed for the fatal outbreak of fungal meningitis in 2012.
Between last fall and February, 37 compounding pharmacies in Massachusetts were inspected, only four of which passed inspection.
Unannounced inspections will continue to be part of an enhanced oversight, Roach said.
“The Department of Public Health has made great strides to enhance oversight of the pharmacy industry in Massachusetts since last fall,” Roach said. “The Governor provided more than $1 million in new funding in this year’s budget to enable the Board to hire additional staff to enhance inspections of pharmacies.”
http://www.bostonglobe.com/2013/08/20/compounding-pharmacies-quincy-norwood-closed-after-surprise-state-inspection/0bZxQCjsb7vrBu8Qk8AW0I/story.html
Tuesday, August 20, 2013
Pew Charitable Trust Report of Sterile Compounding
Pew
Recommendations:
We
recommend that the Secretary of Health and Human Services direct the
Commissioner of the FDA to take steps to
consistently collect reliable and timely information in FDA’s
existing databases on inspections and enforcement actions associated
with compounded drugs, and clearly
differentiate in FDA’s database, those manufacturers of FDA approved drugs
that FDA inspects for compliance with good manufacturing
practices from those entities compounding drugs that are not FDA-approved and
that FDA does not routinely inspect.See full report
http://www.pewhealth.org/uploadedFiles/PHG/Content_Level_Pages/Other_Resource/Compounding_report.pdf
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