Drug Shortages: Has the FDA Response Made an Impact?

Rationing of much needed medications for patients is a scary thought for me as a healthcare professional. I can understand when an orphan drug may go in short supply for a rare disease, but when commonly used medications like antibiotics and intravenous fluids become scarce, I wonder what the forces are that cause this to happen, and why can’t it be prevented? Worse yet, how could a patient even begin to understand or combat such a specific ordeal?

Drug shortages in the U.S. continue to occupy headline news. In some instances, the shortages are for commonplace treatments like intravenous (IV) normal saline solutions, IV nitroglycerin, anesthesia drugs, IV multivitamins, and antibiotics. Other drugs in short supply have included life-saving cancer medicines, and treatments for tuberculosis, Lyme disease, and ADHD. Take note: these are not orphan drugs or orphan diseases, but everyday treatments used for common ailments.

Why are there drug shortages?

There is no one easy answer to this question. First, it’s important to understand how a drug shortage is defined. According to FDA, “a shortage is considered to be the period of time when the demand for the drug within the U.S. exceeds the supply of the drug.” For the FDA, identified drug shortages would involve medically necessary products that have a significant effect on public health. A medically necessary drug is used to treat or prevent a serious disease or medical condition and for which no acceptable drug alternative is available in adequate supply. However, the agency does consider all possible drug shortages to determine if they are medically necessary. The American Society of Health-System Pharmacists (ASHP) considers a drug product to be in a shortage once it is verified with manufacturers, regardless of whether the product is or is not medically necessary.

The reasons behind drug shortages are as varied as the drugs themselves. Top reasons include:

• Quality: manufacturing delays or quality issues.
• Raw materials may be in short supply.
• Demand for the drug may increase.
• Loss of drug manufacturing site or production line.
• Drug discontinuation or lack of financial incentive.

The manufacturing process for pharmaceutical agents, especially sterile IV products can be especially complicated and may involve many steps. According to a recent infographic supplied by FDA, quality issues are the top reason for lack of treatment and affect 67% of all drug shortages. Twenty-seven percent of the time raw material may simply not be available. An uptick in public demand can also result in drug shortages, as has occurred in the past with flu vaccines and antiviral treatments.

Drug discontinuation and lack of financial incentive is especially concerning. While the FDA has the authority to seek alternative sources for a needed drug in short supply, FDA cannot force a manufacturer to supply a drug it decides to discontinue. It is costly for a manufacturer to research, develop, and market a drug that is not in high demand, especially if it is a generic product or an older sterile injectable medication. The company may make a business decision that older drugs should be removed from their portfolio in favor of newly-branded and more profitable medications.

What are the impacts of drug shortages?

Patient safety issues for drug shortages can be immense. Besides the lack of effective drug treatment, other areas of medical care that are impacted include:

• Medical procedure and drug treatment protocol delays.
• Higher rates of relapse among patients with cancer or other chronic disease.
• Elevated rates of medication errors, possibly due to lack of study data on drug substitutes.
• Ethical questions or bias when determining how to distribute drugs in short supply.
• Healthcare providers may not have experience with dosing or preparation of required therapeutic alternatives.
• Reduced patient health outcomes.
• Spikes in drug procurement cost.
• Patients may decide to purchase needed drugs online or from foreign countries.

A survey conducted with pharmacists by The Institute for Safe Medication Practices (ISMP) in 2012 revealed medications most commonly involved in side effects due to drug shortages:

• Chemotherapy (27%), particularly doxorubicin.
• Opioid analgesics (17%), mostly fentanyl and morphine
• Electrolytes (7%)
• Antibiotics (5%)
• Phentolamine (4%)
• Phytonadione (4%)

However, the FDA has implemented legal regulations with manufacturers to curtail these impacts. Title X of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 now requires all drug makers to give advanced notice to the FDA about impending critical drug discontinuations (at least 6 months in advance) or production interruptions (as soon as possible). This allows the FDA to work with the manufacturers to help prevent unknown, possible life-threatening drug shortages. As noted by ASHP this includes drugs that are:

• Life-supporting or life-sustaining
• Use to prevent or treat a debilitating disease or condition
• Used in emergency medical care or during surgery

The FDA may also quicken the review of a manufacturer’s new drug application in order to mitigate possible shortages. To enforce the new law, the FDA follows up with the manufacturer in the case of noncompliance and the manufacturer must reply within 30 days. In addition, the FDA must give an annual report to Congress on drug shortages, outlining manufacturers who do not notify of impending shortages, plus any FDA actions taken to lessen drug shortages, coordination with the DEA, and other measures.

Manufacturers are required to report drug discontinuances to FDA regardless of whether they intend to remove the product from the market permanently or only have an interruption of supply. However, FDA encourages firms to notify them of any potential supply issues at any point in the manufacturing process. The FDA is now required to maintain an up-to-date list of drugs in short supply. ASHP also maintains a more inclusive list of drug shortages.

Case examples

• IV sodium chloride (saline)

A shortage of 0.9% sodium chloride solution used to replace electrolytes or administer medications has taken a toll since increase demand started in the 2013-2014 flu season. Normal saline, a dilute salt and water solution, is used frequently in hospitals and clinics for irrigating wounds, rehydrating patients, and serving as a diluent for IV medications like chemotherapy and antibiotics, among many other uses. According to Baxter, a top supplier, over 740 units of saline and other sterile solution are used every 60 seconds across the United States. Shortages of normal saline have resulted in pharmacists and nurses having to limit their use of the IV solution and creating workarounds to ensure ample supply. Currently, the most affected product is the 1,000 milliliter bag of sodium chloride.

FDA has intervened to help address the normal saline shortage. Alternate sources of normal saline were identified from oversea suppliers. FDA is also working with other American manufacturers, including Baxter Healthcare Corp., Fresenius Kabi USA, LLC., and Hospira Inc., to restore an adequate supply of normal saline for U.S. hospitals and health clinics.

• Antibiotics and Anti-Infectives

Shortages of antibiotics in the U.S. are an ongoing concern. In fact, according to experts, antibiotics are being removed from the market six times faster than new ones are being produced. Between 2001 and 2013, there were shortages of 148 antibiotics. This is of great concern to the FDA and the healthcare community as many of these antibiotics are the sole drugs to treat certain antibiotic-resistant infections or for certain pediatric infectious diseases. Another concern: many of these life-threatening infections picked up from a hospital (nosocomial infection) or outpatient surgical clinic require these last-line medications.

In a 2015 study done at George Washington University, nearly half the shortages were for antibiotics needed to treat severe and resistant infections, including:

• Clostridium difficille
• Carbapenem-resistant Enterobacteriaceae (CRE)
• Methicillin-resistant Staphylococcus aureus (MRSA)
• Pseudomonas aeruginosa

Even more common drugs, like aztreonam used to treat serious infections in patients allergic to penicillin, and trimethoprim/sulfamethoxazole, used to treat pneumocystis pneumonia, were in short supply with no alternate manufacturers.

What has the response been to the new regulations?

FDA has made a significant impact on drug shortages. FDA address shortages by:

• Working with firms to resolve manufacturing issues to allow medications to return to the market.
• Speeding up FDA’s review process so that new manufacturers can supply needed products as soon as possible.
• Helping firms get new sources of raw material.
• Expediting review of pharmaceutical manufacturing lines.
• Extend expiration dates if data can confirm safety and effectiveness.
• Procuring critical drugs from foreign manufacturing plants that meet FDA quality standards.
• Development of a long-term strategic action that manufacturers can take to help prevent future shortages.

According to the FDA, drug shortages peaked in 2011 with 251 shortages. Up until that time shortages had been steadily increasing since 2006 when there were 56 reported shortages. However, in 2013 and 2014, there were only 44 newly reported drug shortages in each year, the lowest in over a decade. Most importantly, in the time between 2011 to 2013, FDA was able to help avert over 740 drug shortages. The new regulations requiring early notification from drug manufacturers have been able to positively impact these numbers.

Healthcare systems, including hospitals and pharmacy benefit managers (PBMs) are also addressing drug shortages by developing their own internal protocols, ethical standards, and review process to combat drug shortages.

What actions should a patient take?

• If you have a concern that a drug you or a family member requires may be in short supply, talk with your doctor. There may be alternatives available.
• Ask your healthcare provider or insurance if their associated hospitals or organizations, such as Pharmacy Benefit Managers (PBMs), have a policy in place for drug shortage management.
• Do not buy substitute medications on the Internet or from a foreign country due to lack of quality assurance, potential fraud, and risk for toxicity.
• Visit the Drugs.com Current U.S. Drug Shortages page to see if a drug you are questioning is listed.
• If your drug is not on the list, email the name and dose of the drug, along with your contact information to the FDA at: drugshortages@fda.hhs.gov.