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Managing Oncology Drug Shortages
February 2014 : Oncology - Vol. 11 No. 2 - Page #1

Drug shortages have become a regular occurrence in US hospitals, and oncology medications have been among the most affected. According to a recent Hematology/Oncology Pharmacy Association (HOPA) survey, 98% of oncology pharmacists reported experiencing an oncology drug shortage in 2011.1 Perhaps even more concerning is the fact that delays in chemotherapy administration or changes in treatment regimens due to drug shortages were experienced by 93% of survey participants.1 Oncology drug shortages are particularly worrying from a patient safety perspective, because in some cases a suitable alternative treatment does not exist or limited clinical data may be available to support its use.2 In addition, using alternative products may increase the risk for error, lead to potential adverse events, and result in worse clinical outcomes compared with the first-line treatment.2

Managing oncology drug shortages is a continuing challenge for pharmacists, and requires substantial resources and a significant time commitment. The unavailability of oncology medications has increased the complexity of treating cancers, impacted treatment cost, and has resulted in adverse outcomes for patients, including disease progression.1 Therefore, developing effective strategies to manage and mitigate the impact of oncology drug shortages is critically important. 

Shortages Impacting Patients with Cancer
According to the HOPA survey, the most difficult oncology drugs to obtain include liposomal doxorubicin, fluorouracil, leucovorin, paclitaxel, and cytarabine.1 The repercussions of oncology drug shortages on the treatment of patients with cancer are wide-ranging and can be severe. These shortages may result in patients not receiving the most effective treatment, reduced tolerability of alternative agents, interruptions in potentially lifesaving clinical research trials, unanticipated patient safety concerns, and increased costs for the hospital and patient (see Online-Only TABLE 1). 

Click here to view a larger version of this Table

When oncology drug shortages occur, numerous patient safety issues may arise. Alternative agents must be used with caution; because staff is typically not as familiar with using these drugs, alternative medications may be more prone to medication error.  Frequent product changes may cause challenges in updating various technologies and automation systems quickly and accurately, which also may lead to medication errors. Furthermore, there often are good reasons for not using alternative agents as first-line treatment; for instance, reduced tolerability profiles could lead to more unpleasant side effects than the first-line treatment. 

More worrisome is the use of therapeutic alternatives that have not been proven equivalent, as this may result in lower cure rates and disease progression. Identifying alternative medications for oncology drug shortages is particularly challenging, because little clinical evidence may exist supporting the efficacy of some of these medications. For some disease states, there is only one known effective treatment; if this drug is on shortage, identifying an appropriate regimen is difficult. For example, cytarabine-containing regimens are the most efficacious in treating acute myelogenous leukemia; currently no published data support other medications as equivalent therapy.1

Data published in 2012 suggest that drug substitutions required due to shortages resulted in higher relapse rates among children with lymphoma who could have been cured.3,4 When mechlorethamine (nitrogen mustard) was on shortage, many patients being treated for Hodgkin’s lymphoma received cyclophosphamide instead. Although this regimen had been widely used in the past and was believed to be equivalent in efficacy to the mechlorethamine regimen, no clinical trial had been performed comparing the two regimens. Recent data reported that the cyclophosphamide regimen was significantly less effective than the mechlorethamine regimen. This information highlights the need for alternative regimens to be examined carefully prior to adoption. What may initially appear to be a suitable alternative could result in an inferior outcome.3

Increased costs resulting from oncology drug shortages can be felt across the entire health system, and affect patients’ costs as well. Maintaining an adequate supply of medications on shortage, as well as identifying useful alternative agents, requires increased efforts and a substantial time commitment. While 85% of survey participants reported incurring increased costs as a result of oncology drug shortages, and 34% reported that the shortages required ≥1000 hours annually to manage, only 4% of participants reported that their hospital hired additional staff to assist in managing the process.1

When a generic drug is on shortage and must be substituted for a more expensive brand name medication, this can cause reimbursement challenges. The brand medication may not be deemed an accepted drug, thus requiring prior authorization and possibly a higher copay. Moreover, it is important to note that when utilizing an oral drug that is not a direct substitution for an IV medication, reimbursement will be paid through a different type of insurance. Most IV cancer therapies are covered under the medical benefit, while most oral therapies are covered under prescription drug plans. Remember that not all patients may have a prescription drug plan, and if they do, this plan may charge a higher copay than the medical plan. 

During a drug shortage, oncology clinical trials may be suspended until the shorted medication is available. Likewise, delays in patient enrollment, study cancellation, protocol changes, or stockpiling may occur. In the HOPA survey, 44% of respondents reported that oncology drug shortages negatively affected the conduct of clinical trials at their hospital.1 Thus, oncology drug shortages can cause delays in obtaining the data required to bring new cancer treatments to the market.1

Collaborative Management of Shortages
Because the causes of shortages are complex and multifaceted, effective mitigation requires a collaborative effort among drug manufacturers, health care professionals, patient advocacy organizations, and government agencies. HOPA makes several recommendations to minimize the effects of oncology drug shortages5:

  • Ensure timely notification and complete transparency on all issues regarding drug shortages
  • Increase communication among health care professionals, patient advocacy organizations, manufacturers, and the FDA to support drug distribution and maintain adequate supplies
  • Enable the FDA to better assist with distribution options for drugs in short supply
  • Incentivize manufacturing redundancies
  • Consider economic incentives to manufacturers to increase capacity for sterile injectable medications 
  • Require confidential notification to the FDA when a single active pharmaceutical ingredient or manufacturing source for a particular drug exists
  • Develop efficient and equitable access programs
  • Maintain adequate reimbursement for the use of brand name treatments or alternative treatments when the existing treatment is in short supply
  • Develop guidelines for evidence-based alternatives for medications that are used in the treatment of cancer that are widely available to practitioners 

The FDA Safety and Innovation Act,6 signed into law in July 2012, includes several drug shortage provisions. It requires drug manufacturers to notify FDA at least six months, or as soon as possible, prior to any discontinuance or interruption in life-sustaining drug or drug intended to treat debilitating disease. While this is indeed a useful provision, there may be situations where the manufacturer does not know that there will be a shortage at their facility. For example, if a critical piece of machinery in the manufacturing facility breaks and a replacement part is not easily available, manufacturing capacity will suffer.

Additional provisions of the FDA Safety and Innovations Act include the requirement that the FDA disseminate shortages information to health care providers. The FDA also will expedite review and inspections when necessary to assuage possible shortages, adjust the quotas for controlled substances when necessary, permit hospitals to repackage a medication to increase supply, and report on the success of these measures in mitigating drug shortages.1,6 Nonetheless, economic incentives to assist generic drug manufacturers and changes in reimbursement that permit adequate reimbursement for the use of  brand name drugs or alternatives (when the existing generic drug is in short supply) may be required.5,7 

Since July 2012, there has been a six-fold increase in shortage notifications to the FDA, which has helped FDA prevent 195 drug shortages in 2011 and 282 shortages in 2012. In addition, the total number of new shortages decreased from 251 in 2011 to 117 in 2012.8 Although it is impossible to predict every shortage, prudent planning and active management of oncology shortages can mitigate their repercussions. As the medication experts, pharmacy should be aware of which oncology drugs are in short supply, when the shortage is anticipated to resolve, and should educate the health care team on the necessary steps to avoid possible medication errors when oncology drug shortages occur. 

Working collaboratively with other hospitals in your area may be an effective strategy to manage oncology drug shortages. At the University of Connecticut Health Center (UCHC), we work with four or five additional hospitals in the Hartford, Connecticut area to secure oncology medication if we have exhausted all other options and a substitution is deemed inappropriate or unsafe. In return, we share medication with these hospitals when they experience a similar shortage. While sharing medication will not always secure product, it is one option to consider when an oncology drug shortage develops.

Policies and procedures (P&Ps) for managing oncology drug shortages should be in place and should specify who is responsible for identifying shortages; who is charged with disseminating shortages information throughout the facility; the method of notification (eg, email, intranet); and the appropriate actions once a shortage occurs, including alternative therapies that may be used.9,10 Should an alternative medication need to be substituted for a shorted drug, ensure that proper safety processes are in place and that all automation systems and other technologies are updated to reflect the change. Each step in these processes should be included in P&Ps. 

When shortages are identified at UCHC, the oncology pharmacy clinical coordinator educates health care providers on what drug is in short supply, the anticipated length of the shortage, and the steps to take in response to the shortage. In addition, if the shortage delays or otherwise compromises patient treatment, the health care team must communicate openly with the patient and/or family members and explain the patient’s ongoing treatment options. It is especially important to maintain open lines of communication when patients previously were receiving a drug that is now on shortage, particularly if the available alternatives may not be as effective.9,10 At UCHC, the physician, and sometimes the oncology pharmacist, will have this discussion with a patient. Most importantly, the entire health care team must ensure a strong and consistent message is delivered to the patient. Some tips for approaching patients with this information include:

  • Reassure patients that continued care can be provided
  • Explain that the pharmacy will continually work to obtain the medication through another source as quickly as possible
  • Openly discuss the benefits and risks of potential alternative therapies

Most importantly, patients must be fully informed, active participants in the decision-making process.10,11 

UCHC also has convened an ethics committee, which is charged with developing strategies for allocating drugs on shortage in the event that there is an insufficient supply of medication and multiple patients require that drug. The ethics committee comprises physicians, pharmacy, nursing, risk management, upper management, and a patient or patient advocate. Fortunately, thus far we have been able to leverage other treatment options and have not yet had to utilize the ethics committee in this capacity. If the ethics committee were faced with this situation, they would review all patients who were receiving the drug and determine those patients for whom the drug is essential and cannot be interrupted for the best effect, using published data for the regimens.  

Future Directions
Although the causes of shortages are multidimensional, it is clear that narrow profit margins for generic medications—the drug class most sensitive to shortages—have reduced the incentive to produce them.3 While incentivizing manufacturing redundancies for drugs vulnerable to shortages is one of HOPA’s recommendations, specific solutions have yet to be provided. Another strategy is to increase the manufacturing capacity of current manufacturers, although specific suggestions for how to accomplish this are equally absent.

In large hospitals, patient access to drugs may be more robust given the increased purchasing power that results from high volume purchasing, or the hospital may have more than one type of purchasing account (eg, wholesaler and independent distributor). Hospitals with smaller drug budgets may have less access, although they may be able to increase purchasing power by participating in group purchasing organizations. Creating an ethics committee to develop hospital-specific policies that ensure all patients are treated equally is important to demonstrate transparency. Equally important is ensuring that payers will adequately reimburse for alternative medications (brand name or alternative agents) used during drug shortages.

As oncology shortages continue into 2014 and beyond, alternative regimens will require clinical study to determine their safety and efficacy in treating various cancers. At a time when health care resources are limited for research, it may be difficult to incentivize researchers to study alternative regimens specifically for times of drug shortages. However, following outcomes of patients who are treated with alternative regimens and sharing that information with the greater health care community is likely to be helpful. Likewise, development of evidence-based guidelines for using alternative regimens during drug shortages is needed.

Over the past few years, drug shortages have become a daily concern for health care providers. Undoubtedly, US health systems have greatly improved management and mitigation of these shortages as they have become more frequent and severe. Nevertheless, whenever a patient’s medication must be interrupted or substituted, the potential for error and the risk of a worse clinical outcome exists. When the medication on shortage involves a potentially life-saving oncology treatment, the repercussions are particularly intolerable. 

The enactment of the FDA Safety and Innovation Act is a positive step to mitigating drug shortages. It remains to be seen whether these and other policy changes will be successful in improving the state of drug shortages of oncology medications in the US.

References

  1. McBride A, Holle LM, Westendorf C, et al. National survey on the effect of oncology drug shortages on cancer care. Am J Health-Syst Pharm. 2013;70(7):609-617.
  2. New research indicating serious potential risks to cancer patients from oncology drug shortages [press release]. Glenview, IL: Hematology/Oncology Pharmacy Association; March 21, 2013.
  3. Metzger ML, Billett A, Link MP. The impact of drug shortages on children with cancer—the example of Mechlorethamine. N Engl J Med. 2012;367(26):2461-2463.
  4. Gogineni K, Shuman KL, Emanuel EJ. Survey of oncologists about shortages of cancer drugs. N Engl J Med. 2013;369(25):2463-2464.
  5. Drug Shortage Issue Brief. Hematology/Oncology Pharmacy Association Web site. http://www.hoparx.org/uploads/files/2012/hopa_drug_shortage_issue_brief_0912.pdf Accessed January 10, 2014.
  6. FDA Safety and Innovation Act. 112th Congress; S.3187.http://www.gpo.gov/fdsys/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf Accessed January 10, 2014.
  7. Pharmacy Professor Working to Prevent Cancer Drug Shortages. UConn Today; August 12, 2013. http://today.uconn.edu/blog/2013/08/pharmacy-professor-working-to-prevent-cancer-drug-shortages/Accessed January 10, 2014.
  8. FDA Facts: Drug Shortages in the United States. FDA Web site. http://www.fda.gov/downloads/NewsEvents/Newsroom/FactSheets/UCM373078.pdf Accessed January 13, 2014.
  9. Fox E, Birt A, James K, et al. ASHP guidelines on managing drug shortages in hospitals and health systems. Am J Health System Pharm. 2009;66(15):1399-1406.
  10. Ventola CL. The drug shortage crisis in the United States: causes, impact, and management strategies. P&T. 2011;36(11):740-757.
  11. Johnson TJ. Drug shortages: an increasing problem for patients and clinicians. S D Med. 2011;64(1):14-15.

 


Lisa Holle, PharmD, BCOP, is assistant clinical professor of pharmacy practice at the University of Connecticut School of Pharmacy, and practices at the University of Connecticut Health Center’s Carole & Ray Neag Comprehensive Cancer Center in Farmington. 

 

Jennifer B. Karpinski, a senior editor at Pharmacy Purchasing & Products magazine, assisted in writing this article.

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