Editorials
Falling Short: Causes and Implications of Drug Shortages in the United States SINCE 2001 the number of new or ongoing drug shortages has increased, creating a crisis in the United States. According to the University of Utah Drug Information Service which tracks these data, there were 305 drug shortages in the first quarter of 2014 compared to only 152 in 2010.1 This crisis has now caught the attention of urologists confronting dwindling supplies of bacillus Calmette-Guerin (BCG) as we try to cure or prevent progression of bladder cancer. What makes the lack of BCG of particular concern is that alternatives such as mitomycin C are less effective or scarce. Reviewing the list of drug shortages at the ASHP (American Society of Health System Pharmacists) web site (http://www.ashp.org/drugshortages/ current/), other drugs commonly prescribed by urologists or urology medical oncologists are in short supply or unavailable. Were you aware that alprostadil, BactrimÔ, bleomycin, human chorionic gonadotropin, IV ciprofloxacin, doxazosin, IV gentamicin, indigo carmine, methylene blue, phenylephrine, IM testosterone cypionate, tamsulosin and vancomycin are in short supply?1 Today at the University of Virginia we cannot administer indigo carmine during surgery to identify ureters, inject testosterone in hypogonadal men or instill mitomycin C after bladder tumor resection as advised by AUA (American Urological Association) guidelines. In our clinic we have 2 vials remaining of TICEÒ BCG to instill into patients at high risk for bladder cancer. Urologists need to be aware of the magnitude of the problem. Until a pharmacy fails to deliver a drug or sends a warning to physicians, we are often unaware of a looming crisis. Weekly drug shortage emails are routine from our pharmacy. How do agencies define a drug shortage? The FDA (Food and Drug Administration) considers a drug shortage “when products used to prevent or treat serious or life threatening diseases or medical conditions for which no alternative product or drug exists.”2 Drugs for surgical prophylaxis, benign prostatic hyperplasia, erectile dysfunction and androgen deficiency are obviously not life threating, and short periods of interruption in treatment are
0022-5347/14/1925-1315/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
rarely serious. I prefer the ASHP broader definition, “a supply issue that effects how a pharmacy prepares or dispenses a drug or product that influences patient care such that a prescriber must use an alternative agent.”2 In 2013, 44% of shortages were for injectable generics (17% were antibiotics and 7% represented chemotherapeutic agents).3 I mention these 2 classes of drugs because of the potential for life threatening events or death. While estimates of deaths due to drug shortages in emergency departments and intensive care units may be in the hundreds, those due to delays or alternative agents for malignancies are more difficult to estimate because no drug has a 100% cure rate and oncologic outcomes are uncertain. A 2013 national survey that focused on the impact of oncology drug shortages revealed that 93% of 243 respondents of 1,672 surveyed dealt with a chemotherapy shortage, which created increased costs, challenges in reimbursement and additional man hours of work for the provider.4 Of the respondents 16% had a near miss ordering an unfamiliar alternate drug and 6% of patients experienced a documented dosage error. In 44% of institutions the conduct of clinical trials was disrupted. What is particularly disturbing and American in the GAO (Government Accounting Office) February 2014 report to Congress was their statement that while the proximate cause was a disruption in supply or reduced manufacturing capacity, “all cases can be traced to the economics of the generic sterile injectable drug market.”2 The U.S. represents 7% of the global population but uses more than 75% of the world’s prescription drugs. You would think we could ensure production and distribution of our life saving drugs better. Based on an analysis of the FDA data, the GAO determined that the most common cause of drug shortages was quality problems (40%), followed by manufacturing delays and capacity issues (30%), and product discontinuation (12%).2 Plant closures, site changes and renovation rarely cause shortages (3%) nor did lack of precursor material (9%). The rate of shortage due to increased demand was 6%.2
http://dx.doi.org/10.1016/j.juro.2014.09.003 Vol. 192, 1315-1317, November 2014 Printed in U.S.A.
www.jurology.com
j
1315
1316
CAUSES AND IMPLICATIONS OF DRUG SHORTAGES IN THE UNITED STATES
A change in guidelines/national practice patterns or shortage of 1 drug can increase demand or trigger a chain reaction as a lesser used agent is rapidly adopted and then becomes scarce. Some authors have even suggested that adoption of Medicare’s Part B reimbursement policy exerted downward pressure on group purchasing organizations, paradoxically leading to reduced manufacture of generics as higher priced nongenerics are prescribed because these newer agents are now covered to some extent.2 The FDA oversees the safety and efficacy of drugs marketed in the U.S. As opposed to New Drug Applications, generics get an Abbreviated New Drug Application in which bioequivalence among other data is required. If a location, precursor or manufacturing process is changed, the FDA requires an application supplement and approval. The FDA performs site visits to ascertain whether the facility conforms to Current Good Manufacturing Practice. It has been suspected that generic manufacturers are more frequently inspected, leading to citations and possible cessation of production more often than nongeneric drugs.2 The Drug Shortage Staff is the unit within the FDA charged with preventing, reducing and resolving shortages. Since 2011 the FDA has encouraged the pharmaceutical industry to report potential shortages earlier but the FDA cannot mandate a company to make a drug. One can envision potential effects on stock prices for publically traded companies if even a hint of a decrease in revenue or possible adverse publicity were announced, thereby reducing the impetus for an early warning to the medical community. The degree to which these shortages are indirectly related to tension among companies with nongeneric versus generic drugs is unclear. In 2013 the FDA published a strategic plan for preventing and mitigating drug shortages5 but its capacity to enact changes in this regard is limited. Some of these strategies have been adopted, such as earlier notification or allowing temporary use of foreign or unapproved drugs, while other recommendations await legislation. Sometimes, as is the case for TICE BCG, it appears that MERCK proactively voluntarily stops or slows production as it investigates a manufacturing issue. While often posting the earliest date the disruption may be resolved (October 2014 for BCG), there remains no guarantee an agent will be available. Most annual drug shortages are on-going rather than new drug shortfalls, suggesting chronic issues, cost concerns or major changes in production. Providers respond to the escalating shortages in a variety of ways. Procedures may be delayed, drugs rationed and patients triaged. For the BCG crisis,
the AUA in concert with the Society of Urologic Oncology sent out an advisory that recommended use of alternative agents for low risk patients and reserving BCG for those individuals in whom a course of this intravesical agent has never failed.6 Patients should undergo re-staging transurethral bladder biopsy to ensure that treatable disease exists before be given BCG. If the situation worsens other options our faculty have discussed include abandoning maintenance therapy and avoiding use in those less likely to respond, such as the extreme elderly or immunocompromised patient. The FDA does not recommend lowering the dose, diluting or using non-U.S. sources, although it has the power to allow these coping mechanisms if equivalency and safety data are presented. The impact of these shortages on our patients is dire. It has been documented that shortages can lead to more medication errors, deaths, morbidity, violation of clinical protocols and strained professional relationships. As urologists continue to cope with ever increasing shortages, several generic strategies can be adopted. Counsel families and patients about alternative measures when a shortage occurs or is expected to delay or compromise care so they can participate in their care. When using an alternative unfamiliar agent, oversee staff to ensure proper dosing. Use extra sterility precautions because some alternative preparations may lack substrates to deter bacterial growth. Develop an action plan with staff and colleagues to optimize and ration remaining supplies at your institution or office. Properly document reasons and rationale for a therapeutic plan in the medical record. Note any protocol violation if part of a clinical trial. Routinely scan the following websites for current information (http://www.ashp.org/drugshortages/ current/; http://www.fda.gov/Drugs/DrugSafety/ DrugShortages/default.htm). Encourage patients and colleagues to contact national professional associations, such as the AUA and Society of Urologic Oncology, patient organizations or even the media to draw attention to the issue. As the FDA advances more strategies and Congress attempts new legislation, physicians must find ways to solve the problem at the bedside with compassion and candor. William D. Steers, MD Editor
CAUSES AND IMPLICATIONS OF DRUG SHORTAGES IN THE UNITED STATES
1317
REFERENCES 1. U.S. Food and Drug Administration: Drug Shortages. Available at http://www.fda.gov/Drugs/DrugSafety/ DrugShortages/default.htm. Accessed September 4, 2014. 2. Drug Shortages: Public Health Threat Continues Despite Efforts to Help Ensure Product Availability. Washington, DC: United States Government Accountability Office. February 2014; GAO 14-194, pp 1e93.
3. Ventola CL: The drug shortage crisis in the United States. P T 2011; 36: 740. 4. McBride A, Holle LM, Westendorf C et al: National survey on the effect of oncology drug shortages on cancer care. Am J Health Sys Pharm 2013; 70: 609. 5. U.S. Food and Drug Administration: Strategic Plan for Preventing and Mitigating Drug Shortages.
Available at http://www.fda.gov/downloads/ Drugs/DrugSafety/DrugShortages/UCM372566. pdf. Accessed September 4, 2014. 6. American Urological Association: Important information about BCG. Health Policy Brief, July 17, 2012. Available at http://www.auanet. org/advnews/hpbrief/view.cfm?i¼1160&a¼2764. Accessed September 4, 2014.
Falling Short: Causes and Implications of Drug Shortages in the United States SINCE 2001 the number of new or ongoing drug shortages has increased, creating a crisis in the United States. According to the University of Utah Drug Information Service which tracks these data, there were 305 drug shortages in the first quarter of 2014 compared to only 152 in 2010.1 This crisis has now caught the attention of urologists confronting dwindling supplies of bacillus Calmette-Guerin (BCG) as we try to cure or prevent progression of bladder cancer. What makes the lack of BCG of particular concern is that alternatives such as mitomycin C are less effective or scarce. Reviewing the list of drug shortages at the ASHP (American Society of Health System Pharmacists) web site (http://www.ashp.org/drugshortages/ current/), other drugs commonly prescribed by urologists or urology medical oncologists are in short supply or unavailable. Were you aware that alprostadil, BactrimÔ, bleomycin, human chorionic gonadotropin, IV ciprofloxacin, doxazosin, IV gentamicin, indigo carmine, methylene blue, phenylephrine, IM testosterone cypionate, tamsulosin and vancomycin are in short supply?1 Today at the University of Virginia we cannot administer indigo carmine during surgery to identify ureters, inject testosterone in hypogonadal men or instill mitomycin C after bladder tumor resection as advised by AUA (American Urological Association) guidelines. In our clinic we have 2 vials remaining of TICEÒ BCG to instill into patients at high risk for bladder cancer. Urologists need to be aware of the magnitude of the problem. Until a pharmacy fails to deliver a drug or sends a warning to physicians, we are often unaware of a looming crisis. Weekly drug shortage emails are routine from our pharmacy. How do agencies define a drug shortage? The FDA (Food and Drug Administration) considers a drug shortage “when products used to prevent or treat serious or life threatening diseases or medical conditions for which no alternative product or drug exists.”2 Drugs for surgical prophylaxis, benign prostatic hyperplasia, erectile dysfunction and androgen deficiency are obviously not life threating, and short periods of interruption in treatment are
0022-5347/14/1925-1315/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
rarely serious. I prefer the ASHP broader definition, “a supply issue that effects how a pharmacy prepares or dispenses a drug or product that influences patient care such that a prescriber must use an alternative agent.”2 In 2013, 44% of shortages were for injectable generics (17% were antibiotics and 7% represented chemotherapeutic agents).3 I mention these 2 classes of drugs because of the potential for life threatening events or death. While estimates of deaths due to drug shortages in emergency departments and intensive care units may be in the hundreds, those due to delays or alternative agents for malignancies are more difficult to estimate because no drug has a 100% cure rate and oncologic outcomes are uncertain. A 2013 national survey that focused on the impact of oncology drug shortages revealed that 93% of 243 respondents of 1,672 surveyed dealt with a chemotherapy shortage, which created increased costs, challenges in reimbursement and additional man hours of work for the provider.4 Of the respondents 16% had a near miss ordering an unfamiliar alternate drug and 6% of patients experienced a documented dosage error. In 44% of institutions the conduct of clinical trials was disrupted. What is particularly disturbing and American in the GAO (Government Accounting Office) February 2014 report to Congress was their statement that while the proximate cause was a disruption in supply or reduced manufacturing capacity, “all cases can be traced to the economics of the generic sterile injectable drug market.”2 The U.S. represents 7% of the global population but uses more than 75% of the world’s prescription drugs. You would think we could ensure production and distribution of our life saving drugs better. Based on an analysis of the FDA data, the GAO determined that the most common cause of drug shortages was quality problems (40%), followed by manufacturing delays and capacity issues (30%), and product discontinuation (12%).2 Plant closures, site changes and renovation rarely cause shortages (3%) nor did lack of precursor material (9%). The rate of shortage due to increased demand was 6%.2
http://dx.doi.org/10.1016/j.juro.2014.09.003 Vol. 192, 1315-1317, November 2014 Printed in U.S.A.
www.jurology.com
j
1315
1316
CAUSES AND IMPLICATIONS OF DRUG SHORTAGES IN THE UNITED STATES
A change in guidelines/national practice patterns or shortage of 1 drug can increase demand or trigger a chain reaction as a lesser used agent is rapidly adopted and then becomes scarce. Some authors have even suggested that adoption of Medicare’s Part B reimbursement policy exerted downward pressure on group purchasing organizations, paradoxically leading to reduced manufacture of generics as higher priced nongenerics are prescribed because these newer agents are now covered to some extent.2 The FDA oversees the safety and efficacy of drugs marketed in the U.S. As opposed to New Drug Applications, generics get an Abbreviated New Drug Application in which bioequivalence among other data is required. If a location, precursor or manufacturing process is changed, the FDA requires an application supplement and approval. The FDA performs site visits to ascertain whether the facility conforms to Current Good Manufacturing Practice. It has been suspected that generic manufacturers are more frequently inspected, leading to citations and possible cessation of production more often than nongeneric drugs.2 The Drug Shortage Staff is the unit within the FDA charged with preventing, reducing and resolving shortages. Since 2011 the FDA has encouraged the pharmaceutical industry to report potential shortages earlier but the FDA cannot mandate a company to make a drug. One can envision potential effects on stock prices for publically traded companies if even a hint of a decrease in revenue or possible adverse publicity were announced, thereby reducing the impetus for an early warning to the medical community. The degree to which these shortages are indirectly related to tension among companies with nongeneric versus generic drugs is unclear. In 2013 the FDA published a strategic plan for preventing and mitigating drug shortages5 but its capacity to enact changes in this regard is limited. Some of these strategies have been adopted, such as earlier notification or allowing temporary use of foreign or unapproved drugs, while other recommendations await legislation. Sometimes, as is the case for TICE BCG, it appears that MERCK proactively voluntarily stops or slows production as it investigates a manufacturing issue. While often posting the earliest date the disruption may be resolved (October 2014 for BCG), there remains no guarantee an agent will be available. Most annual drug shortages are on-going rather than new drug shortfalls, suggesting chronic issues, cost concerns or major changes in production. Providers respond to the escalating shortages in a variety of ways. Procedures may be delayed, drugs rationed and patients triaged. For the BCG crisis,
the AUA in concert with the Society of Urologic Oncology sent out an advisory that recommended use of alternative agents for low risk patients and reserving BCG for those individuals in whom a course of this intravesical agent has never failed.6 Patients should undergo re-staging transurethral bladder biopsy to ensure that treatable disease exists before be given BCG. If the situation worsens other options our faculty have discussed include abandoning maintenance therapy and avoiding use in those less likely to respond, such as the extreme elderly or immunocompromised patient. The FDA does not recommend lowering the dose, diluting or using non-U.S. sources, although it has the power to allow these coping mechanisms if equivalency and safety data are presented. The impact of these shortages on our patients is dire. It has been documented that shortages can lead to more medication errors, deaths, morbidity, violation of clinical protocols and strained professional relationships. As urologists continue to cope with ever increasing shortages, several generic strategies can be adopted. Counsel families and patients about alternative measures when a shortage occurs or is expected to delay or compromise care so they can participate in their care. When using an alternative unfamiliar agent, oversee staff to ensure proper dosing. Use extra sterility precautions because some alternative preparations may lack substrates to deter bacterial growth. Develop an action plan with staff and colleagues to optimize and ration remaining supplies at your institution or office. Properly document reasons and rationale for a therapeutic plan in the medical record. Note any protocol violation if part of a clinical trial. Routinely scan the following websites for current information (http://www.ashp.org/drugshortages/ current/; http://www.fda.gov/Drugs/DrugSafety/ DrugShortages/default.htm). Encourage patients and colleagues to contact national professional associations, such as the AUA and Society of Urologic Oncology, patient organizations or even the media to draw attention to the issue. As the FDA advances more strategies and Congress attempts new legislation, physicians must find ways to solve the problem at the bedside with compassion and candor. William D. Steers, MD Editor
CAUSES AND IMPLICATIONS OF DRUG SHORTAGES IN THE UNITED STATES
1317
REFERENCES 1. U.S. Food and Drug Administration: Drug Shortages. Available at http://www.fda.gov/Drugs/DrugSafety/ DrugShortages/default.htm. Accessed September 4, 2014. 2. Drug Shortages: Public Health Threat Continues Despite Efforts to Help Ensure Product Availability. Washington, DC: United States Government Accountability Office. February 2014; GAO 14-194, pp 1e93.
3. Ventola CL: The drug shortage crisis in the United States. P T 2011; 36: 740. 4. McBride A, Holle LM, Westendorf C et al: National survey on the effect of oncology drug shortages on cancer care. Am J Health Sys Pharm 2013; 70: 609. 5. U.S. Food and Drug Administration: Strategic Plan for Preventing and Mitigating Drug Shortages.
Available at http://www.fda.gov/downloads/ Drugs/DrugSafety/DrugShortages/UCM372566. pdf. Accessed September 4, 2014. 6. American Urological Association: Important information about BCG. Health Policy Brief, July 17, 2012. Available at http://www.auanet. org/advnews/hpbrief/view.cfm?i¼1160&a¼2764. Accessed September 4, 2014.
