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FDA, Congress working to mitigate drug shortages

With drug shortages at an all-time high, members of Congress have proposed bipartisan legislation to address the issue, while the U.S. Food and Drug Administration (FDA) is taking action to mitigate future shortages and secure the prescription drug supply for the American public.

The number of reported drug shortages has nearly tripled from 61 in 2005 to 178 in 2010, according to the FDA. From January through October 2011, the agency had tracked 220 drug shortages. Approximately 80 percent of these involve sterile injectables, including anesthetics, oncology medications, antibiotics, and electrolyte/nutrition drugs.

Drug shortages are due primarily to manufacturing problems, such as glass shards, metal filings, and fungal or other contamination found in products, according to the FDA. Other reasons include a delay in the manufacturing or shipping of raw materials and components from suppliers, a shortage of active ingredients, the discontinuation of drugs and the consolidation of generic pharmaceutical firms. Older sterile injectable medications are more complicated to produce and more prone to manufacturing problems than other drugs. As a result, they are sometimes discontinued in favor of newer, more profitable drugs. Regarding consolidations, the top three generic injectable manufacturers hold 71 percent of the market by volume and most sterile injectables have one manufacturer that produces at least 90 percent of the drug. When a company encounters a problem or discontinues a drug, there aren’t many other firms to pick up the slack. Thus a shortage ensues.[pagebreak]

Shortages affecting dermatology

Particularly troubling to dermatologists are recent shortages of lidocaine 1 percent, fluocinolone/hydroquinone/tretinoin, bleomycin, methotrexate, and tetracycline. In some cases, these shortages can cause dermatologists to use potentially less-effective alternatives or off-label treatments that may have a greater risk profile — or require them to suspend a treatment completely. Substituting medications can also result in decreased patient compliance and convenience.

Fluocinolone/hydroquinone/tretinoin has been unavailable for the past 18 months, said Jacquelyn Garrett, MD, a dermatologist in private practice in St. Louis. “This is a major issue because a lot of my patients suffer from hyperpigmentation problems,” she said. Dr. Garrett has had to resort to other branded and generic hydroquinone-containing creams. But the alternatives must be applied twice daily as opposed to once daily, creating a potential patient compliance issue. In addition, all three ingredients worked together in a way that can’t be matched by products containing just one or two ingredients, she said. “So efficacy and patient convenience are compromised.”

Guy Webster, MD, PhD, clinical professor of dermatology at Jefferson Medical College in Philadelphia, concurs. He has had a problem obtaining fluocinolone/hydroquinone/tretinoin for the past two years. “That drug may never be back,” Dr. Webster lamented.

Another drug that he has been unable to get is colchicine. “The brand name is available at an obscene price and the generic is not available for reasons that I don’t understand,” Dr. Webster said. As there is no substitute for colchicine, his only option is to prescribe the brand name at a significantly higher cost to patients. “I’m unhappy because the patients are unhappy,” he added.

Although Dr. Webster doesn’t prescribe tetracycline, he has been told by many colleagues that they can’t get it. “It’s a shame because it’s a good and cheap drug,” he noted.

Dr. Garrett may be seeing the beginning of a tetracycline shortage, which the FDA says is due to manufacturing delays. Earlier this year, after prescribing it, she received a telephone call from the pharmacist saying the drug was unavailable. “That was the first I had heard that there was a problem getting tetracycline,” said Dr. Garrett, who had to prescribe an alternative medication. She doesn’t prescribe tetracycline often, favoring minocycline and doxycycline, but this particular patient had improved on a short cycle of tetracycline before.

Fortunately, there are alternatives for tetracycline, noted Mary Maloney, MD, chief of the division of dermatology at the University of Massachusetts. But she also points out that transitioning acne patients to other antibiotics can have serious implications. The alternatives may not be as effective and certainly may not be as cost-effective, Dr. Maloney said.

The lack of availability of bleomycin for more than one year has forced her to stop offering it as a treatment option for recalcitrant warts. “I use more destructive modalities, which I don’t think are as good for some patients,” Dr. Maloney noted.[pagebreak]

Although she has not experienced a shortage of lidocaine, Dr. Maloney knows of shortages in different regions of the country. As with tetracycline, there are long-acting local anesthetics and other substitutes for lidocaine, but they may not be quite as good.

Like Dr. Maloney, Dr. Garrett has not experienced a lidocaine shortage herself, but has received bulletins about its limited supply and is concerned about the potential impact on patients; companies that make lidocaine list it as being on back order or intermittent back order. Noting the importance of early detection in the survival of melanoma, Dr. Garrett said that delayed skin biopsies and skin cancer surgeries resulting from a lidocaine shortage could be devastating for patients.

A shortage of injectable methotrexate is creating a particular hardship for patients of Bruce Strober, MD, PhD, associate professor in the department of dermatology at the University of Connecticut, School of Medicine, in Farmington. He prefers the injectable form because it offers a better dosing approach, efficacy, and tolerability, and it is significantly less expensive than the oral formulation. Dr. Strober, who sees many patients with psoriasis, writes approximately 10 prescriptions for injectable methotrexate daily, which he acknowledges is not the norm for dermatology practices. The oral version, which is not in short supply, is more commonly prescribed.

“I have lost the ability to use a better formulation for most of my patients over the last couple of years,” Dr. Strober said. Two out of three patients can’t get the 2 cc vial, which is the standard dispensing size for dermatology. Some patients are able to get the 10 cc vial. “That’s more than one month’s supply of a drug that most of us would like to keep tight control of because the drug needs monitoring with blood tests on a regular basis,” he said. Given the larger amount, patients could skip return visits that are essential for the proper management of this drug.

For those responsible patients who Dr. Strober is confident will adhere to their scheduled visits and routine blood tests, he prescribes the 10 cc vial. For others, he is forced to prescribe the oral formulation, which does not offer 100 percent bioavailability and better tolerability like its injectable counterpart, Dr. Strober said. That means sometimes having to prescribe higher doses of the oral medication, which may contribute to side effects. Some studies have shown that the toxicity is greater with the oral drug than the injectable, he added. Some patients don’t respond to the oral formulation, but will improve using the same dose of the injectable, Dr. Strober said.

Injectable methotrexate with preservatives is more readily available than the drug without preservatives for reasons that he cannot explain. But after learning this, Dr. Strober specifies injectable methotrexate with preservatives on the prescription. “That way, the patient is more likely to get the drug.” There are no safety or efficacy issues with preservative-containing methotrexate to his knowledge. “This is an extremely critical issue for those of us who value methotrexate and use it frequently for the treatment of patients with moderate and severe psoriasis and other skin conditions that are very responsive to it,” he said. (To mitigate the methotrexate shortage, this spring the FDA allowed importation of a preservative-free methotrexate manufactured in Australia and approved in Canada.)[pagebreak]

Government intervention

In October 2011, President Obama issued an executive order directing the FDA, in cooperation with the Department of Justice, to help further reduce and prevent drug shortages, protect consumers, and prevent price gouging. In response, the FDA proposed establishing a database to collect and analyze drug shortage information, coordinating response activities, and expediting inspections, among other actions.

Two months later, the Department of Health and Human Services released an interim final rule regarding drug shortages. The rule requires sole manufacturers to notify the FDA at least six months prior to discontinuation of a drug that is life supporting, life-sustaining, or intended for use in the prevention of a debilitating disease or condition.

In the meantime, committees in both the House and Senate have conducted hearings about drug shortages. In addition, they have proposed various pieces of bipartisan legislation that expand the FDA’s authority to require early disruption notification. Currently, manufacturers are not required to notify the FDA of potential shortages, disclose the reason for them, or provide an estimated resolution date. This is being done only on a voluntary basis.

The AADA, which was asked to submit comments to the Senate Committee on Health, Education, Labor, and Pensions (HELP) on draft legislation concerning prescription drug shortages did so this past April, according to Amanda Grimm, the Academy’s senior specialist in regulatory policy. The AADA indicated its support for improving the notification and communication of ongoing and potential shortages to the patient and provider communities. Subsequent drug shortage legislation is expected to be incorporated into a larger bill known as the Prescription Drug User Fee Act rather than being passed individually. (The Academy continues to encourage members to report drug shortages to Grimm at agrimm@aad.org; the AADA uses the information gathered as it works with the FDA to mitigate such shortages as effectively as possible.)

New legislation mandating early disruption notification would allow the FDA to take immediate action to mitigate a drug shortage, rather than waiting to address it once it has become critical, said Dr. Maloney, who serves as the chair of the Academy’s Regulatory Policy Committee. “I’m very hopeful that the bipartisan nature of the bill will push it along,” she said.

Dr. Garrett is equally optimistic that the pending legislation, along with the executive order, will ensure that the American public has an ample supply of prescription medications.

Dr. Webster is not convinced that the FDA’s latest actions or new legislation will be effective in mitigating future drug shortages. “Drug shortages are something that happen when you have a complicated supply chain,” he said. “They have been going on as long as I have been practicing medicine. Congress is stirred up about it, but nothing will happen.”

Dr. Maloney, however, is reminded of the shortage of psoralens in 2010. “One and a half years ago, we didn’t have any psoralens for PUVA therapy throughout most of the country,” she explained. An ingredient became unavailable and no alternative sources existed. The FDA relaxed some restrictions on importations from Canada and worked to relicense the drug as soon as possible. “Although it took a fair amount of time, the FDA really did step up to try and help solve the problem,” she said. “The company has since obtained a solid supply of raw material from an approved source, so it’s back in business. Now we have psoralens again.”


Recent progress on drug shortage efforts

The Food and Drug Administration reports significant progress related to drug shortages, including:


  • Since October 2011, the FDA has prevented 96 drug shortages.
  • There has been a six-fold increase in voluntary notifications by drug manufacturers of potential shortages. Prior to October 2011, the FDA received approximately 10 voluntary notifications per month. Since then, the agency has received 61 notifications per month.
  • In 2012, the FDA expects to complete a database to monitor the number of, and reasons for, drug shortages.
  • The agency has started communicating recent reports of alleged stockpiling and price gouging to the Department of Justice.
  • The FDA is meeting with stakeholders, including the Generic Pharmaceutical Association, Pharmaceutical Research Manufacturers of America, and the Biotechnology Industry Organization, and with the three largest drug wholesalers, to discuss the development of strategies to prevent and reduce shortages.



Current drug shortages

The Food and Drug Administration maintains an online list of current drug shortage information from manufacturers at www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm. The page also includes links to information on reporting a drug shortage and a list of drug shortages that have been resolved.


 

Related Resources

Recent progress on drug shortage efforts
Current drug shortages