The Food and Drug Administration (FDA) is responsible for protecting the public health by ensuring the safety of the nation’s drug supply, and considers the impact of shortages on patient care and access as a part of that charge. In 2010, the FDA reported that there was a record number of drug shortages, which increased in 2011 and, although there was a noted decline in 2012, shortages of critically needed drugs began to affect the provision of care and emergency treatment.
According to data collected by the FDA’s Drug Shortage Program, a higher percentage of the drugs in short supply are sterile injectables. Although in 2012, there were fewer reported drug shortages, the FDA continues to see shortages involving older sterile injectable drugs. These shortages have involved cancer drugs, anesthetics used for patients undergoing surgery, as well as drugs needed for emergency medicine and electrolytes needed for patients on IV feeding.
Fortunately, the FDA also has been able to prevent a significant number of drug shortages. In 2011, the FDA was able to help prevent 195 drug shortages. And in 2012, 282 drug shortages were prevented. The agency’s ability to prevent shortages has been greatly facilitated by increased early notifications from manufacturers.
The FDA defines a drug shortage as a situation in which the total supply of all clinically interchangeable versions of an FDA-regulated drug is inadequate to meet the current or projected demand at the patient level. In 1999, the FDA Center for Drug Evaluation and Research (CDER) began the Drug Shortage Program (DSP) charged with a mission to detect potential and actual drug shortages in the United States. DSP reports that drug shortages have risen from 61 in 2005 to 178 in 2010. The FDA notes that the major reason for recent drug shortages has been unanticipated manufacturing problems. These problems have affected product quality and sometimes caused firms to voluntarily halt production. Some problems may involve lower risks, such as the wrong expiration date on the package or significant issues such as particulates in the product or sterility problems.
Stakeholders holding a Drug Shortages Summit in the fall of 2010 proposed that there were additional correlating factors involved contributing to the deficiencies in the supply chain. In a summary report of the summit they listed regulatory barriers and ambiguities, including the lack of the FDA authority to require notification and other actions, were considered significant contributors to drug shortages. They noted that several drug shortages have been precipitated by actual or anticipated action by the FDA as part of the Unapproved Drug Initiative, which is designed to increase enforcement against drugs that lack FDA approval to be marketed in the United States. Raw materials sourcing and manufacturer factors, business, marketing, and distribution factors were also cited in the report.
Medical Care and Public Health Issues
How may these shortages affect the provision of medical care and even ultimately public health at large? According to Dr. Robert S. DiPaola, director of the Cancer Institute of New Jersey, these shortages are now affecting clinical trial options for patients with cancer. In his testimony during the Sept. 23, 2011, hearing before the House Committee on Energy and Commerce, he explained that many of these drugs that are in short supply are a part of the standard clinical trial regimens. New treatments are often added or compared to these drugs within the trial. These drugs are used in large national cooperative group trials. The Coalition of Cancer Cooperative Groups has reported that approximately 50 percent of the active cooperative group cancer clinical trials involve drugs subject to shortages.
DiPaola went on to explain that drug shortages today will also have long-term effects on cancer research. New drugs administered in clinical trials represent the final step of a long process of developing new therapies and are often best added to an existing treatment for comparisons to the best current treatment. When these drugs run out it could alter trial results and ultimately delay results for years.
Drug shortages have also driven purchasers to the “gray market” for critically needed drugs. In the context of drug shortages, the term gray market is often used to reference the downstream distribution of approved drug products at significantly marked-up prices. A shortage offers a unique opportunity for this to occur, because large-scale buyers are often willing to pay any price to obtain a much-needed product. When a gray market distributor handles a product that it normally would not distribute, there can also be safety issues that put patients at risk—if, for example, the product is not stored or handled appropriately. These activities do not cause shortages, but may exacerbate the impact of an existing shortage. To put this into perspective, during a meeting of representatives from the state pharmacy boards and the FDA in December 2012, representatives of the state boards voiced concerns that the multistate outbreak of fungal meningitis from contaminated steroid medications in the fall of 2012 was generated from a gray market product. Unfortunately shortages in certain sterile products, and other products has led to the creation of an entirely new and unregulated segment of the pharmaceutical industry in the form of the nontraditional large scale compounding pharmacies as in the case of the 2012 outbreak.
Strategic Plan for Preventing and Mitigating Drug Shortages
On July 9, 2012, the president signed into law the Food and Drug Administration Safety and Innovation Act (FDASIA). Among other provisions, FDASIA directs the FDA to establish a task force on drug shortages to develop and submit to congress a Strategic Plan to enhance FDA’s response to preventing and mitigating drug shortages. If given the time to plan, the FDA believes it can be more effective in its response. For example, increased notifications combined with allocation of additional FDA resources resulted in real progress in addressing shortages—FDA helped prevent close to 200 drug shortages in 2011 and more than 280 in 2012. If notified in advance of potential disruptions in production, the FDA anticipates it can take a number of steps to help prevent or mitigate a shortage, including:
- Determining if other manufacturers are willing and able to increase production.
- Expediting inspections and reviews for submissions.
- Exercising temporary enforcement discretion for new sources of medically necessary drugs.
- Working with the manufacturer to ensure adequate investigation into the root cause of the shortage.
In its Drug Shortage Strategic Plan, the FDA identified two central goals to address drug shortage: improving their mitigation response to imminent or existing shortages, and implementing strategies for the long-term prevention of shortages by focusing on the root causes of shortage.
Recognizing the emerging problem, the FDA established their Drug Shortage Program (DSP) in 1999 as a means of support to the industry. The FDA is limited in their authority when it comes to drug shortages. When a shortage occurs, the agency has no authority to compel a manufacturer to produce a particular drug, or report a disruption in production. When FDASIA became law manufacturers that produce certain drugs were required to report permanent discontinuance or an interruption in manufacturing of these drugs six months in advance of action, or as soon as practicable. FDASIA also required the FDA to maintain a current list of drugs that are determined by the FDA to be in shortage in the United States, and to include on that public list certain information about those shortages. Finally, FDASIA requires the FDA to issue a final rule implementing certain drug shortage provisions in FDASIA by Jan. 9, 2014.
The FDA published a proposed rule Nov. 4, 2014, requiring all applicants of certain approved drugs or biological products, to notify the FDA electronically of a permanent discontinuance or an interruption in manufacturing of the product that is likely to lead to a meaningful disruption in supply of the product in the United States. This particularly applies if the drug or biological product is a prescription product that is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including any such drug used in emergency medical care or during surgery, and excluding radiopharmaceutical products. The rule would require notification to the FDA at least six months prior to date of the permanent discontinuance or interruption in manufacturing, or as soon as practicable but in no case less than five business days after the action is taken. The FDA feels it can be most effective when there is time to plan for these disruptions and to work with the manufacturers to restore supplies to meet the need. Comments will be accepted until Jan. 4, 2014.