19 September 2016

How Physicians, Hospitals and Health Systems Are Dealing With the U.S. Drug Shortage Crisis

The ongoing drug shortage crisis in the U.S. is sending prices for some medications skyrocketing, forcing hospitals and physicians to scramble for alternatives and threatening the safety of patients. These shortages have been causing major problems nationwide for several years, but the causes are complex and not easily fixed, and doctors, hospitals, health systems and acute-care facilities continue to struggle to find effective workarounds.

The number of drugs in short supply in this country has more than tripled in the past decade. Since 2012 when the Food and Drug Administration Safety and Innovation Act (FDASIA) took effect, that number has decreased overall. Yet shortages of drugs commonly used for unscheduled acute care in emergency rooms, intensive care units and other health care facilities have continued to increase in both number and length, with an approximately eight-month median duration. 

Multiple Causes Make Drug Shortages Hard to Fix or Prevent

Most U.S. drug shortages are caused by one or more of the following:

  • Manufacturing / production issues:
    • ​Quality control problems
    • Lack of availability of raw materials
    • Shipping delays
    • Production capacities that either cannot or have not yet ramped up to meet increases in demand
  • Economic issues / business decisions: 
    • ​Market share erosion that causes brand-name drug manufacturers to discontinue production when generic versions enter the market
    • Mergers or acquisitions involving pharmaceutical companies that manufacture the same medication, which typically results in one of those drugs being discontinued for business reasons
    • Discontinuation of older medications in favor of newer, more profitable ones
  • Regulatory issues:
    • Slow FDA approvals for new drugs
    • Pricing constraints tied to federal reimbursements
    • FDA warnings and bans that result in the temporary suspension of production at particular plants or permanent discontinuations of certain products, including commonly used injectable opioids such as morphine and oxycodone and injectable benzodiazepines such as diazepam, midazolam and lorazepam

The Sterile Injectable Drugs Shortage: A Perfect Storm

Sometimes more than one of these factors contributes to the shortage of a particular drug or type of drug. The persistent shortage of sterile injectables – including essential drugs like sterile saline solution and antibiotics that can be effective against superbugs – is the result of a perfect storm of manufacturing, economic and regulatory issues. 

According to a recent article in Forbes, sterile injectable drugs are more expensive to manufacture and notoriously difficult to produce safely, yet because they are subject to federal Medicare and Medicaid reimbursement policies they often have artificially low selling prices. In addition, the FDA’s increased scrutiny of sterile IV fluid manufacturers after particulate matter was found in some products a few years ago has led to recalls, manufacturing delays, and product discontinuations of some sterile injectables. 

Shortages of injectable antibiotics that have been shown to be effective in treating drug-resistant bacteria present another serious challenge, especially in light of the alarming evolution of superbugs. A recent example is this year’s shortage of amikacin sulfate. Amikacin has been shown to be active against certain gram-positive and gram-negative bacteria including Staphylococcus series, Klebsiella series and E. coli, both in vitro and in clinical infections. It also may be the aminoglycoside of choice for serious nosocomial gram-negative infections in areas where resistance to gentamicin or tobramycin is present. Teva Pharmaceuticals is one of the few companies that manufacture amikacin. FDA inspectors who visited Teva’s sterile injectables plant in Hungary in January cited issues with the “current good manufacturing practices” (CGMPs), the regulations for pharmaceutical manufacturing processes and facilities that the FDA enforces. Teva responded by suspending production of all but two of the roughly 200 drugs that were being made there “as a precaution” while it continues to work to resolve those issues to the FDA’s satisfaction. Only amikacin and bleomycin, a cancer treatment drug, continued to be produced at the facility. The FDA subsequently issued an import alert banning all the products made at that plant from the U.S., with the exception of amikacin and bleomycin. But on August 2, Teva announced a voluntary recall of seven lots of amikacin sulfate, citing concerns about the potential presence of glass particulate matter, and as of August 31 the ASHP current drug shortages page includes both amikacin and bleomycin. 

Other manufacturers of sterile injectables have also been forced to halt production at plants outside the U.S. while they address FDA warnings and concerns. Over the past several years, FDA warnings for Hospira plants in Europe, North America, Asia and Australia have caused production stoppages. Pfizer, which acquired Hospira last year, announced a temporary production halt at a plant in India last month after a team of inspectors from four of the world’s leading regulatory agencies, including the FDA, found a number of lapses in good manufacturing practices. 

Price Gouging Exacerbates the Problem

Shortages and discontinuations of drugs that have unique applications or are produced by only one manufacturer have even more severe repercussions. And manufacturer price gouging for these medications is becoming a huge problem. The FDA has been slow to approve new medications that could provide market competition that would drive down prices as well as create alternative options for health care providers during shortages of either drug. 

Another emerging source of price gouging is the misuse of the Orphan Drug Act (ODA). More and more companies are purchasing the rights to existing drugs and submitting them to the FDA for approval as orphan drugs for a different use, to treat diseases that affect fewer than 200,000 people in the U.S. Under ODA, makers of approved orphan drugs get tax credits for half the cost of clinical development (even though companies that purchase the older drugs didn’t pay for the development costs), seven years of exclusivity, and waived fees. So once the FDA approves the drug as an orphan, the drug makers relaunch them under a different name and charge exorbitant prices. 

This trend has a wider impact than it might appear because many of those “orphan” drugs are frequently used off-label to treat much more common conditions, making this practice even more profitable for drug makers. And repeated attempts to curb misuse of the law by ending drugs’ ODA status and benefits once the drug’s target population or sales exceeded a certain threshold have been blocked.

International Politics Have Led to Shortages of Sedatives, Paralytics, Anesthetics and Other Drugs

Commonly used sedatives, paralytics, anesthetics and other drugs that have been used not only by hospitals for medical purposes but also by U.S. correctional facilities as anesthetics for lethal injections have become limited or discontinued. A global campaign by opponents of the death penalty or lethal injections against makers of drugs used for that purpose brought intense pressure to bear, causing many of the manufacturers to stop producing them or severely restrict their distribution. That has left physicians and hospitals scrambling for alternate sources as well as alternative medications.

Hospira, the only U.S. manufacturer of sodium thiopental (Pentothal), is one example. The company had halted production of the drug in 2009 because of manufacturing issues in a North Carolina plant, and after spending two years trying to bring the closed facility into compliance with the FDA CGMPs, had planned to shift production to a plant in Italy. But Hospira was forced to exit the market permanently in 2011 instead after Italian officials said they would not permit the product to be released out of Italy if it could potentially be used for lethal injections.

Some paralytic agents also are no longer being produced for similar reasons, and those that are in production are extremely expensive. There also has been a shortage of agents used to reverse those paralytics, and the prices of those that are available have gone up dramatically; a drug that used to cost roughly $10 per vial can now cost close to $100. 

The FDA’s Dilemma: Balancing Quality and Supply

The FDA is under tremendous fire from two opposing factions: those who argue that the agency’s more zealous inspections and enforcement actions in recent years have been largely responsible for the drug shortage problem, and those who say that zeal must be maintained to protect this country’s patients by ensuring the safety and efficacy of the U.S. drug supply. The FDA’s efforts to straddle this supply/quality tightrope by making exceptions or finding loopholes in the enforcement of its good manufacturing quality practices have often been met with criticism. 

Faced with the sudden shortage of sodium thiopental in 2011, several U.S. states imported untested sodium thiopental for use in lethal injections from a questionable distributor in the U.K., leading the British government to ban the sale of sodium thiopental from the U.K. And a federal appeals court later prohibited the FDA from letting sodium thiopental from foreign suppliers into the country.

In another example, when the agency issued an indefinite ban on a factory belonging to one of China’s leading exporters of pharmaceuticals products last year, the FDA made a highly controversial decision to allow the banned plant to continue exporting about 15 ingredients for use in finished drugs in the U.S., including widely used chemotherapy ingredients doxorubicin and daunorubicin, to avoid possible shortages of key drugs. 

FDA’s Push to Modernize the Pharmaceutical Manufacturing

The FDA has begun working with drug makers to modernize manufacturing methods. This proactive collaboration with drug makers is a new approach “to help the industry adopt scientifically sound, novel technologies to produce quality medicines that are consistently safe and effective — with an eye toward avoiding drug shortages.” The agency says it is encouraging pharmaceutical industry to develop advanced manufacturing technologies, as other industries have done, in order to “create a more robust drug manufacturing process with fewer interruptions. This will minimize product failures and provide greater assurance that the product will consistently deliver the expected clinical performance.” The FDA has established an Emerging Technology Team (ETT) that is providing guidance to drug companies pursuing new technologies, engaging in a dialogue with them early in the technology development process to help identify and resolve scientific issues for new technologies before a drug application is submitted. The agency says it worked closely with the manufacturer of the first-ever 3D printed pill, for epilepsy drug Spritam (levetiracetam), to make the use of 3D printing technology for this application a reality. The agency recently approved the pill, which it says “can disintegrate more rapidly in a patient’s mouth, greatly aiding those who have trouble swallowing.” 

What Can Physicians, Hospitals and Health Systems Do?

Until long-term solutions to the underlying problems causing ongoing drug shortages are agreed upon and implemented, physicians, hospitals and health systems need to continue to develop strategies to acquire vital medications in short supply and workarounds for those that are unavailable. They can also become active in advocacy efforts to help shape effective solutions. 

Use Group Purchasing Organizations (GPOs)

Many hospitals belong to group purchasing organizations (GPOs) that leverage member organizations’ aggregated buying power to drive down prices of products in the health care supply chain, including medications. Pharmaceutical companies often give GPOs preferential treatment when shipping drugs in short supply, so GPO member hospitals acquire more of those medications more quickly than non-member hospitals, exacerbating the shortage of those drugs at those facilities. GPOs have been consolidating to further increase their negotiating power with manufacturers, vendors and distributors. 

There are those who blame drug shortages on these large purchasing groups, notably Physicians Against Drug Shortages, a small, nonprofit advocacy group that has been extremely vocal on this subject. 

Purchase Directly From Pharmaceutical Companies

Many of the drugs that have chronically been in short supply are vital, especially for emergency and acute care. More and more health systems have forged direct relationships with drug makers to procure some of those hard-to-get, critically important products, even though one-off purchases may cost more than buying through a GPO or distributor. GPOs are concerned about the increase in direct purchasing contracts, which threaten the long-standing distribution model and the GPO administrative fees that fund those buying groups.

As a last resort, hospitals and health systems sometimes try to import drugs directly from other countries.

Use or Purchase Alternative Medications

When ready-to-administer doses of a medication are unavailable, the drug may be available in a form that requires the doctor or nurse to fill syringes or make other preparations before administering it to patients.

 In many cases, there are medications with similar uses and effectiveness to drugs in short supply that can be used as temporary alternatives. But they often cost more – sometimes many times more – than the unavailable drug. In some cases, doctors who have no other choice may be forced to use older medications that may not be as effective as the drug of choice or may involve more, or more harmful, side effects.

A team of Yale researchers found that using alternative medications in acute and emergency situations raises the risk of medical error, so it may be advisable to familiarize medical staff with the proper procedures, uses and potential side effects of alternative drugs used in acute and emergent care.  

Use Alternative Techniques

When either paralytic agents are in short supply, or cannot be used because of a shortage of paralytic reversal agents, there are alternative techniques such as regional, spinal or epidural anesthesia or nerve blocks that can be used in some cases to reduce the need for paralytic agents. 

Anticipate Shortages at Health Care Facilities

By monitoring hospital pharmacy inventory and tracking drug usage, hospitals and health systems can sometimes predict which drugs will be in short supply and seek alternative sources in advance. If hospitals know that the price of a drug will be going up or going on shortage, pharmacies can sometimes buy up those drugs far enough in advance to maintain a good supply before the price increases or to tide them over during the anticipated shortage. Sheridan meets with its hospital partners’ pharmacies on a regular basis and helps advise them on the best strategies to address specific current and anticipated shortages.

Participate in Advocacy Efforts to Fix the Problem 

The issues causing ongoing drug shortages are complex and interrelated. Arriving at successful short-term and long-term solutions to the drug shortage crisis will likely require the collective input and collaborative efforts of health care providers and facilities, patients, pharmaceutical companies and local and federal government. More physicians need to be vocal advocates for changes to fix the broken U.S. health care supply chain and rethink current regulatory oversight for the ultimate benefit of patients. 

At the national level, Sheridan’s physician leaders are active in the American Medical Association (AMA), the American Society of Anesthesiologists (ASA), the Society of Critical Care Anesthesiologists (SOCCA) and other organizations that have led physician efforts to deal with the drug shortage issue, including lobbying the federal government (including the FDA) and the pharma industry. Although not all of their advocacy efforts have met with success, some have positively influenced federal policy. For example, the FDA’s 2013 Strategic Plan for Preventing and Mitigating Drug Shortages incorporated several AMA policy elements

Physicians can also participate in these efforts at the state level. Many Sheridan anesthesiologists are extremely active in the Florida Society of Anesthesiologists (FSA), a state component society of the ASA, and a number of those physicians have served on the society’s board of directors.