Cancer Therapy Shortages -- Switch Can Harm Patients

Kristin Jenkins

April 12, 2017

Ongoing interruptions in the supply of generic injectable medications have left clinicians with pricey and "potentially less efficacious" second- and third-line chemotherapies that can result in the temporary discontinuance of treatment or in patients going straight to surgery, warn researchers.

Benjamin J. Davies, MD, Department of Urology, University of Pittsburgh and the Hillman Cancer Center, Pennsylvania, and colleagues illustrate the point with the example of intravesical bacillus Calmette-Guérin (BCG) immunotherapy, which is the gold standard for high-risk nonmuscle invasive bladder cancer (NMIBC).

In an essay published online April 12 in the New England Journal of Medicine, Dr Davies and colleagues note that shortages of BCG in 2012 and 2014 led to an increase in the use of an alternative, mitomycin (multiple brands), which then shot up in price.

The average wholesale price (AWP) for mitomycin jumped from $436.80 to $869.59 for a 40-mg dose. That represents a price increase of 99%, they note.

For a 5-mg dose, the AWP for mitomycin climbed even higher, from $67.20 to $165.60 — a whopping 146% price increase.

An analysis of Medicare data revealed that when patients were treated with mitomycin instead of BCG, the 20% co-pay insurance premium increased from $49 a year in 2012 to $155 in 2015.

At the same time, Medicare spending for mitomycin shot up from from $4.3 million in 2012 to $15.8 million in 2015. These price changes were passed along to patients and "were likely to translate into higher costs for payers and taxpayers," they say.

The researchers found similar trends in AWPs before and after disruptions in BCG supply for two other chemotherapies for bladder cancer: thiotepa (Thioplex, Immunex) and valrubicin (Valstar, Endo Pharmaceuticals).

Dr Davies and colleagues say BCG shortages illustrate just how vulnerable the supply of important generic drugs has become. What is more, the "cascading effect" can lead to shortages of alternative chemotherapeutic agents, they warn.

Since 2012, simultaneous shortages of mitomycin and thiotepa have been reported, they note.

Switch Can Harm Patients

It's not just a question of money ― the switch to other drugs can cause harm.

Intravesical treatment with BCG combined with TURBT is the gold standard for the management of patients with high-risk NMIBC, as well as for some patients with intermediate-risk NMIBC, noted Khurshid Guru, MD, vice chair of the Department of Urology and Robert P. Huben Endowed Professor of Oncology at Roswell Park Cancer Institute in Buffalo, New York, who was approached for comment. NMIBC can recur with the same stage and grade or it can progress to a higher stage or grade, he explained.

"BCG deficiency can lead to suboptimal management of these patients, resulting in higher rates of tumor recurrence and progression and, therefore, higher proportion of patients losing their bladders," Dr Guru told Medscape Medical News.

Dr Davies and colleagues note that profound clinical consequences of anticancer drug shortages have been experienced in other oncology settings. In one study of pediatric patients with lymphoma, drug substitutions for mechlorethamine (multiple brands) were associated with higher relapse rates. Had first-line therapy been available, these patients "might otherwise have been cured," they say.

Steep Price Increasess for Other Generics

Sudden, steep price increases have been seen with other generic injectables, such as glycopyrrolate (multiple brands), which is often used before surgery to reduce secretions. Dr Davis and collegues note that after problems with quality control forced one manufacturer to suspend production of glycopyrrolate, the remaining manufacturer increased its product's AWP by an unbelievable 855%, creating a new list price of $13.75 per 0.2-mg/mL dose, up from the previous price of $1.44.

The number of drug shortages has slowed somewhat since Congress passed the Food and Drug Administration Safety and Innovation Act in 2012, they write.

However, shortages of important generic drugs remain "unacceptably frequent," and the shortages are lasting longer, they say. This suggests that "policy efforts to date have not been sufficient in preventing supply disruptions." They note that since the bill passed, there have been more than 250 ongoing shortages. In 2015, 291 active national shortages were reported.

The need for new solutions is acute, but in the current political climate, payment reforms that stabilize the market for generic injectable agents may no longer be an option, the study authors admit. Importing BCG that was licensed abroad, providing incentives for companies that maintain drug production, and offering tax credits or preferential lending for manufacturers to upgrade facilities and build capacity are some of the ways in which the federal government could help, they say.

For now, Dr Davies told Medscape Medical News, "Our primary role is informational and lobbying Congress." The American Association of Clinical Urologists political action committee is building awareness and "getting politicians up to speed with the data," he said, noting that on the research side, clinical trials are testing new strains of BCG "that hopefully will help."

National organizations such as the American Urological Association and the Society of Urologic Oncology have also been actively monitoring availability of BCG in the United States and updating physicians, said Dr Guru. He agrees that finding acceptable drug replacements is the key. Rapid scientific progress has led to the introduction of newer drugs for bladder cancer in the past year, he pointed out, and there are "multiple studies in the pipeline to address the problem at different levels."

Dr Davies and Dr Guru have disclosed no relevant financial relationships.

N Engl J Med. Published online on April 13, 2017.

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