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Manufacturing Quality Drives Drug Shortages


March 2014 - Vol. 11 No. 3 - Page #2

The current state of drug shortages in the US has evolved from a situation that brought a new shortage almost daily in 2010 and 2011, to one where the number of new drug shortages has decreased; however, because the ongoing drug shortages are not resolving, large number of products remain extremely difficult to obtain.

On October 31, 2013, the Food and Drug Administration (FDA) unveiled its new strategic plan for preventing and mitigating drug shortages.1 This plan was released exactly two years following President Obama’s Executive Order2 recommending manufacturers provide FDA with advanced notice of drug shortages and just over a year after the FDA Safety and Innovation Act (FDASIA) was signed into law with provisions requiring notification.3 In fact, the strategic plan was one of the measures outlined in FDASIA. FDA’s actions to prevent shortages have been extremely successful in decreasing the incidence of new shortages (see FIGURE 1), with the drug shortages team preventing approximately 200 shortages in 2011 and over 280 shortages in 2012. Nonetheless, the number of shortages impacting patients and clinicians remains at an all-time high of approximately 300 active drug shortages, and this high level has remained consistent over the past five quarters (see FIGURE 2). 

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Risk of Losing Generic Manufacturers
The general landscape of drug shortages has changed little over the years. Most drugs in short supply are generic injectables, with few suppliers (approximately six) producing the majority of these products. In fact, just three suppliers provide 71% of the market by volume.4 The economics of this situation cannot be ignored. Drug manufacturing is a business, and no matter how critical or life-saving these products may be, the FDA cannot compel any company to continue or expand production. 

Recently, one key manufacturer of generic injectable drugs (Ben Venue Laboratories) made the business decision to discontinue the refurbishing of their manufacturing site, noting that the financial investment required to ensure product quality was not sustainable in the long term.5 Because Ben Venue’s production had been halted since the fall of 2011, this decision did not have an immediate clinical impact. However, the long-term impact of this business decision could be significant, as a decreasing number of large manufacturers of generic injectables will weaken an already fragile supply chain. Bedford, a generic company that distributes products manufactured by a variety of sources (including Ben Venue Laboratories) is actively working to find another manufacturer for their critical products. Other manufacturers, such as Pfizer Injectables and BD Rx, are working to expand the number of generic injectables in their product portfolios. Nevertheless, additional generic manufacturers are needed to stabilize the generic injectable supply chain. 

The number of generic manufacturers is important. When one company has a supply problem, there are few suppliers to make up the difference; thus, a long-term shortage is created. The Generic Pharmaceutical Association’s Accelerated Recovery Initiative (ARI) with IMS Health and the FDA is currently halted because there are too few suppliers of the products that are in short supply.6 When only two or three companies manufacture a product, the ARI is powerless to help alleviate the shortage.6 This raises the question of when a drug shortage situation may benefit from ARI, and the answer is unclear. Data from IMS in 2011 show that 36% of generic injectables have two or fewer suppliers, and 51% of generic injectables in short supply have two or fewer suppliers.7

Manufacturing Quality is Not Transparent
The types of drugs in short supply range from antimicrobials and chemotherapy agents to central nervous system drugs and nutrition products (see FIGURE 3). Predicting which drugs may be in short supply in the future is particularly difficult, as shortages generally follow failures of specific manufacturing lines (not particular therapeutic classes), and which drugs are produced at any given factory or manufacturing line is typically not publicly available information. For example, the large increase in chemotherapy drug shortages between 2009 and 2010 can be attributed to problems on just a few production lines.6 The current critical shortage of electrolytes and nutrition products stems from the closure of a facility that supplied the majority of these products. The ability to predict quality problems at a particular facility is problematic. In their new strategic plan, the FDA outlines a strategy to continue to develop methods to identify early warning signals with regard to manufacturing quality problems. For the public, it is even more difficult to predict quality problems, as public postings of such issues may be delayed. 



The quality of manufactured products is generally taken for granted by most purchasers. If a generic product is FDA-approved and AB- or AP-rated to a branded product, then the purchaser assumes the product is of high quality (basically a pass/fail system). Yet there may be clear quality differences that are not apparent to the purchaser. It has been posited that because quality is not transparent to the end purchaser, manufacturers have little incentive to invest in quality and make quality manufacturing a top priority.8 One source for quality data are the FDA Warning Letters and Form 483 Inspection summaries that are available at http://www.fda.gov/ICECI/EnforcementActions/ucm256377.htm, although there is little direction available to clinicians or purchasers regarding how to interpret this information (eg, a grading system). However, the FDA clearly believes these data are important, and their new strategic plan for preventing and mitigating drug shortages recommends purchasers use such data to potentially incentivize manufacturers to focus on quality.1 Using quality data to inform purchasing decisions is ideal, however, because the supply chain is so concentrated, purchasers may have little choice when there are only one or two suppliers of a given product. 

Tactics for Managing Shortages
To manage drug shortages, clinicians are forced to rely on small allocations and drop shipments to piece together sufficient supplies to treat patients. Buyers must resort to purchasing a variety of products, often in different sizes or strengths than are normally used. This situation can create safety issues, but all too often, there is simply no choice. One potentially effective purchasing strategy is to utilize all possible accounts for allocations. However, this approach must be accompanied by a conscientious commitment to avoiding over-purchasing and hoarding. In many cases, products may be short dated, and purchasing more than can reasonably be used simply exacerbates the amount of product wasted. Diligent efforts to review stock on hand, usage data, as well as allocations can prevent over-purchasing. Likewise, it is imperative to continuously review the backorders in place to ensure an appropriate allocation when the product is released.

The large number of ongoing shortages at any given health system can be overwhelming. Many health systems struggle to identify the best methods of communication during drug shortages. In particular, management strategies can be difficult to implement when small supplies of product are being shipped, yet the overall supply remains unreliable. Determining when a shortage is actually resolved is difficult to pinpoint, because quite often even when the health system receives some supply, there is still no indication when additional supplies will be available. The use of notifications in the CPOE system with a specific recommendation of an alternative to prescribe provides successful results, but must be maintained and reversed when the shortage resolves. Continued education with regard to which product is preferred is essential, particularly for pharmacy staff who may see some supply of a product on the shelf and then wonder why an alternative is still in use. It may be helpful for health systems to delegate leadership around drug shortages to a group of people or a single individual; however, no single person or group can manage drug shortages alone. Teamwork is essential in managing all of the details, from purchasing logistics, to determining alternatives, to communication. 

A particular challenge for pharmacies managing recent drug shortages is addressing the use of imported products. Allowing manufacturers to import products not approved in the US to alleviate shortages is a key tool for the FDA in their efforts to prevent and mitigate drug shortages. The FDA works diligently to ensure these products  are safe, however, imported products may pose additional issues for health systems. For example, to manage the formidable shortage of products used to prepare total parenteral nutrition (TPN), imported trace elements have been made available along with Glycophos, an imported phosphate injection product. While these products are essential for patient care, the use of injectable products without available published stability and compatibility data poses a challenge for pharmacy. Accessing these imported products also can be problematic. While the FDA endeavors to find US distributors for imported products, in some cases this is not possible and pharmacies must work through complicated ordering and payment procedures to access product directly from overseas. Even simple differences, such as the lack of a bar code or an NDC code, can pose logistical challenges in today’s highly automated pharmacy environment. 

Compounded products can help bridge the gaps in some shortage situations. However, health systems must ensure their Pharmacy and Therapeutics Committee is aware that compounded products will be substituted for commercial products. Health systems also must ensure the safety of the compounded products, whether the system intends to compound the product in-house or outsource to a compounding pharmacy. In the wake of the New England Compounding Center’s product contamination tragedy that has resulted in multiple deaths, the FDA has increased its scrutiny of compounding pharmacies resulting in the recall of hundreds of compounded products from multiple compounding pharmacies.9,10 Legislation to enhance the safety of compounding pharmacies and clarify the role of FDA’s regulation of compounding was signed into law in November 2013.11

Ethics of Rationing
The ongoing drug shortage problem means that care is often rationed and clinicians must make difficult ethical decisions regarding treatment. In some cases, national guidance is available for rationing, such as recommendations provided by the American Society for Parenteral and Enteral Nutrition (ASPEN) with regard to rationing multivitamin injection.12 Unfortunately, in many cases evidence-based recommendations are not available, as is the case with shortages of chemotherapy agents. Because chemotherapy regimens are studied in careful combinations, little data is available with regard to adverse effects and patient outcomes when substitutions are required.13 In one example, substituting cyclophosphamide for mechlorethamine during a shortage impacted event-free survival in children with Hodgkin Lymphoma.13

Ethical dilemmas frequently arise when it comes to making decisions about product rationing. Whenever possible, a multidisciplinary group in cooperation with an ethics committee should make the critical rationing decisions. Excellent resources are available to provide guidance for creating prospective approaches to rationing decisions (see online-only TABLE 1). In general, the best approach is to establish a plan for how decisions will be made in advance and then create a strategy for approvals and appeals, as well as a communication plan. 



In Conclusion
The overall drug shortage situation still qualifies as a public health crisis. While the FDA’s prevention strategies are working at reducing the rate of new drug shortages, the quality problems that caused the shortages in the first place are taking a long time to resolve, resulting in continued challenges for patients and clinicians.

References

  1. Food and Drug Administration Center for Drug Evaluation and Research. Strategic Plan for Preventing and Mitigating Drug Shortages. http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM372566.pdf. Food and Drug Administration. Accessed October 31, 2013.
  2. The White House. Executive Order 13588--Reducing Prescription Drug Shortages. http://www.whitehouse.gov/the-press-office/2011/10/31/executive-order-reducing-prescription-drug-shortages. The White House. Published October 31, 2011. Accessed October 31, 2013.
  3. Public Law 112-144. Food and Drug Administration Safety and Innovation Act. United States 112th Congress, 2012.
  4. Food and Drug Administration  Center for Drug Evaluation and Research. Approach to Addressing Drug Shortage; Public Workshop  http://www.fda.gov/Drugs/NewsEvents/ucm265968.htm. Food and Drug Administration. Published September 26, 2011. Accessed October 31, 2013.
  5. Ben Venue Laboratories Inc. Ben Venue Laboratories, Inc to Cease Production. http://www.benvenue.com/news_/october_3_2013.html. Ben Venue Laboratories. Published October 3, 2013. Accessed October 31, 2013. 
  6. Karlin S. Generic Rx Shortage Initiative Stuck: Too Few Manufacturers to Pick Up Slack. The Pink Sheet. July 8 2013: #00130708013.
  7. IMS Institute for Healthcare Informatics. Drug Shortages: A closer look at products, suppliers and volume volatility. http://www.imshealth.com/portal/site/ims/menuitem.edb2b81823f67dab41d84b903208c22a/?vgnextoid=a6fbcc0f68f73310VgnVCM100000ed152ca2RCRD. IMS Institute for Healthcare Informatics. Published November 2011. Accessed October 31, 2013.
  8. Woodcock J, Wosinska M. Economic and technological drivers of generic sterile injectable drug shortages. Clin Pharmacol Ther. 2013;93(2):170-176.
  9. Food and Drug Administration Center for Drug Evaluation and Research. Pharmacy Compounding. http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/pharmacycompounding/default.htm. Food and Drug Administration. Accessed October 31, 2013.
  10. Centers for Disease Control and Prevention. Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy - United States, 2012. MMWR. Morbidity and Mortality Weekly Report. Oct 19 2012;61:839-842.
  11. Food and Drug Administration Center for Drug Evaluation and Research.   Compounding Quality Act. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/. Accessed February 19, 2014.
  12. American Society for Parenteral and Enteral Nutrition. Information to Use in the Event of an Intravenous Multivitamin Shortage - May 2012. http://www.nutritioncare.org/lcontent.aspx?id=5346. Published May 2012. Accessed October 31, 2013.
  13. 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.

Erin R. Fox, PharmD, directs the Drug Information Service at the University of Utah Hospitals & Clinics and is associate professor (adjunct), at the Department of Pharmacotherapy, University of Utah College of Pharmacy. The University of Utah Drug Information Service provides content for the ASHP Drug Shortage Resource Center with support from Novation LLC. Erin has led the drug shortages project since the beginning of the partnership in 2001, and is recognized as an expert in drug shortages. She received an ISMP Cheers award and the ASHP Award of Excellence for her work on drug shortages. 

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