Medication shortages can create considerable disruptions in patient care depending on the availability of suitable therapeutic alternatives. Recently, the manufacturer of belatacept announced an impending shortage which could impact patient management at many transplant centers worldwide. Belatacept received the approval of Food and Drug Administration and European Medicines Agency in 2011, with an indication for de novo use after renal transplant. However, in many transplant centers, it has found use off label in conversion from calcineurin inhibitor (CNI)–based therapies. Although the use of belatacept in the United States is not reported in the most recent OPTN/SRTR Kidney Annual Data Report, it is believed by the authors that this agent is gaining traction in all approved countries as an alternative to or in conjunction with reduced doses of traditional maintenance immunosuppressants.1
Like most biological agents, the manufacturing of belatacept is difficult, time consuming, and expensive. To this end, the manufacturer of belatacept has been transitioning to a more efficient and higher yielding manufacturing process. Unfortunately, this transition has experienced a significant delay, but the reasons for this setback are unknown. It is important to note that the Food and Drug Administration mandates that when a change is made in drug manufacturing, before its approval for distribution, the manufacturer must validate any changes in identity, strength, quality, purity, and potency of the drug to assure there is no change in pharmacokinetics, safety, or efficacy.2 Based on the belatacept manufacturing delay, along with the growth in new prescriptions, the manufacturer anticipates that the current supply of belatacept will not be adequate to facilitate its use in new patients. To preserve the current supply for existing belatacept-treated patients, the manufacturer established a restrictive distribution program. All patients currently receiving belatacept must have registered with the distribution program to continue to have access to this drug after March 15, 2017. The manufacturer anticipates that, subject to regulatory approval, the transition to the new manufacturing process will be successfully completed in late 2017, resulting in a significant increase in supply that will be able to sustain both existing and new patients starting in 2018.
Despite its slow uptake in many transplant centers since its regulatory approval, belatacept has positioned itself as an alternative to both CNI and mammalian target of rapamycin inhibitors. Patients that have used belatacept de novo or via conversion may have experienced similar graft survival but with better kidney transplant function. Treatment with belatacept is also associated with improved blood pressure and lipid profiles, as well as less diabetes when compared with CNI-based regimens.3,4 Not having belatacept available as an alternative to traditional immunosuppression, even for several months, could therefore significantly impact the management of transplant recipients. It is understood why the manufacturer felt the need to implement the belatacept distribution program, but such a program places a burden on transplant clinicians and center personnel. Managing the proper movement of patient-specific supplies and communication with transplant physicians, pharmacists, coordinators, infusion centers, and patients will provide a challenge to transplant centers.
Overall, it has been well documented that both the United States and Europe have experienced an increased frequency of drug shortages, which have resulted in difficulties for patients, practitioners, healthcare facilities, and even federal regulators.5-7 There are many factors that contribute to drug shortages, including reduced availability of raw materials, manufacturing difficulties, regulatory issues, and manufacturer marketing decisions, to name a few. Importantly, tendering, as a method of cost-containment has also been identified as a cause of drug shortages. Tendering is a process in which payers (ie, private or government insurance) negotiates the lowest price for a medication with multiple producers. The supplier who offers the lowest price has their medications available on the payers’ insurance plans for the duration of the contract. The low drug prices resulting from tendering can reduce the number of suppliers, making drugs more susceptible to shortages.
Production of pharmaceuticals is becoming more and more concentrated, to increase efficiency. Thus, there may be only one active producer worldwide. If this sole production site has a problem, it immediately becomes a global issue. Additionally, because of the complexity of the production process, high-quality requirements, and small margin for errors, injectable drugs may be more susceptible to manufacturing problems or quality issues than capsules or tablets.5-7
Currently, drug shortages span across all major therapeutic areas, and medications used in solid organ transplantation are no exception. In the United States, over the past 10 years alone, almost every major transplant immunosuppressant has been affected by a drug shortage8:
- – Intravenous methylprednisolone (2000‐2011; frequent shortages due to decreased production by several manufacturers)
- – Intravenous cyclosporine (2011; shortage due to manufacturer discontinuation)
- – Cyclosporine modified capsules (2012; shortage due to manufacturing delays)
- – Enteric-coated mycophenolic acid tablets (2012; no known reason for shortage)
- – Alemtuzumab (2012; shortage due to the drug being voluntarily withdrawn from the market and a restrictive distribution program being initialized for its use in organ transplantation)
- – Azathioprine tablets (2015; shortage due to manufacturer discontinuation)
- – Tacrolimus capsules (2015; shortage due to manufacturer discontinuation and manufacturing delays)
- – Intravenous azathioprine (2016; shortage due to discontinuation by the lone manufacturer)
- – Over a similar period, transplant centers have also experienced shortages in sulfamethoxazole-trimethoprim, ganciclovir, acyclovir, and intravenous immunoglobulin.
One of the biggest differences between many of the shortages previously listed and the current belatacept shortage is the up-front communication of this issue by the manufacturer to transplant practitioners and institutions of a restrictive distribution program to ensure that preexisting belatacept-treated patients remain on this medication. Although not being able to use belatacept in new transplant patients until the manufacturing transition is complete is far from ideal, with the steps taken by the manufacturer, transplant practitioners had the time to take care of existing patients and plan for future patients.
In June 2013, the International Pharmaceutical Federation convened an International Summit on Medicine Shortage. A large number of solutions and best practices to prevent and mitigate shortages are suggested, both on the demand and supply side.9 However, it is to be expected that drug shortages will continue to have a significant impact on patient management, including organ transplant recipients. Moving forward, manufacturers can help mitigate drug shortages through proper communication with federal agencies when changes in manufacturing processes or shortages in raw materials are noted. For practitioners, it is imperative that they be cognizant of current shortages and adequately respond to new shortages of transplant immunosuppressants.
1. Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2015 annual data report: kidney. Am J Transplant
. 2017;17:21–116 [published online January 3 2017].
2. Food and Drug Administration. Guidance for industry changes to an approved NDA or ANDA. Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM077097.pdf
. Updated September 2009. Accessed March 9, 2017.
3. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med
4. Rostaing L, Massari P, Garcia VD, et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. Clin J Am Soc Nephrol
5. Gupta DK, Huang SM. Drug shortages in the United States: a critical evaluation of root causes and the need for action. Clin Pharmacol Ther
6. Pauwels K, Simoens S, Casteels M, et al. Insights into European drug shortages: a survey of hospital pharmacists. PLoS One
7. Krisl JC, Fortier CR, Taber DJ. Disruptions in the supply of medications used in transplantation: implications and management strategies for the transplant clinician. Am J Transplant
8. American Society of Health-System Pharmacists. Current Drug Shortages. Available at: https://www.ashp.org/drug-shortages/current-shortages
. Updated March 2017. Accessed March 9, 2017.
9. International Pharmaceutical Federation. Report of the International Summit on Medicines Shortage. Available at: https://www.fip.org/files/fip/publications/FIP_Summit_on_Medicines_Shortage.pdf
. Updated September 2013. Accessed March 9, 2017.