Pediatric drug shortages continue to frustrate clinicians, patients

Clinicians in all facets of pediatric medicine likely face a shortage of at least one type of medication that their patients could use.

Although a number of measures are being implemented to alleviate some of the burden from shortages — including passage of legislation that would help identify critical drugs in short supply — relief is not coming fast enough for some, according to many pediatricians.

Where the problem begins

The problem of medication shortages is multifaceted. Despite changes in laws that have prompted more research into drug development, such as the Best Pharmaceuticals for Children Act (BCPA) and the Pediatric Equity Act passed in 2007, pharmaceutical companies remain hesitant to test newer medications in children. The manufacturers cite the vast number of governmental hurdles that must be surmounted to have a medication approved for pediatric use.

Also, the manufacturing processes involved often leads to enormous financial output with little financial gain — as the market for these medications is often limited. The economic burden also leads to some corner-cutting on the part of manufacturers, which can lead to widespread health problems, and shutdowns of those manufacturing facilities.

“I think the newer laws, like Best Pharmaceuticals for Children and the Pediatric Equity Act, have helped, in that they’ve provided a nice incentive for pharmaceutical companies to develop newer medications,” said A.Kim Ritchey, MD, professor of pediatrics and chief of the division of pediatric hematology/oncology at the University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh of UPMC. “But they don’t address the shortage problem. That has to do with manufacturing, and how much can they continue to make a certain drug that has a relatively low yield in terms of market demand. It becomes a question of, ‘Do we cut our losses, and not make it anymore?’”

Shortages in all areas, related problems

Ritchey and other clinicians interviewed by Infectious Diseases in Children agreed that the problem of shortages is most pronounced in the area of pediatric oncology, but the problem extends well beyond oncology medications.

Constance Houck, MD, a principal investigator in the Anesthesia Clinical Research Unit at Boston Children’s Hospital, said she noticed the problem becoming more pronounced with the propofol shortage. The problem with propofol began because of manufacturing delays.

“At that time, a lot of drugs had gone off the market, and that left us with no induction anesthetics at all,” Houck said. “There still was sodium thiopental, but that has also gone off the market because it was being used for executions. An Italian company (Hospira) manufactured the product, and they stopped manufacturing it because of the death penalty issue. That left a huge shortage.”

Houck said that what became very noticeable in light of all these shortages was hoarding among hospitals for the last of the injectable anesthetics.

“I think the pharmacists are doing a lot better working together to get the medications out, but it is tough with things in such short supply,” Houck said.

During the most recent shortage, clinicians were also forced to order more commonly from overseas — and that has its own set of issues because manufacturing and storage are often different than American manufacturers, Houck said.

Ritchey said he noticed similar problems in oncology.

“About a year ago, we had a critical shortage of methotrexate, to the point where we clinicians were making decisions about which child was getting the medication and which was not,” he said.

The American Society of Health-System Pharmacists recently issued a bulletin detailing myriad reasons for the methotrexate shortage, including manufacturing suspensions and delays.

Besides methotrexate, a shortage of another cancer drug — mechlorethamine — may have actually led to relapses in patients after shortages of the drug in 2010. Treatment regimens with cyclophosphamide, which was used as a substitute for mechlorethamine, led to an estimated 2-year event-free survival decline from 88% to 75%.

“As a parent of a child with leukemia, you can’t imagine what it would be like to know that there are lifesaving drugs available, but we can’t get them for their child. It just adds to this incredibly stressful situation that they are already in,” Ritchey said.

Shrinking drug pipeline

Discussing pediatric infectious disease treatments during the 25th Annual Infectious Diseases in Children Symposium, George McCracken Jr., MD, of UT Southwestern Medical Center, said the main problem is a lack of new drugs in the pipeline.

McCracken said there are only a few drugs — ceftaroline and doripenem — specifically for children in the pipeline that will have broad-spectrum activity.

Looking ahead at the pipeline in general, McCracken said there will likely be more research into newer fluoroquinolones, oxazolidinones, carbapenems, macrolides, beta-lactamase inhibitors, as well as aerosol formulations, but the number of medications likely to be approved for children is low.

Ritchey said it is not likely that many drugs in the oncology market would be specifically marketed for children either. He is aware of only one cancer medication that was specifically developed for a pediatric cancer indication.

“We often use cancer medications off-label for children, but we haven’t done it ‘willy-nilly,’” Ritchey said. “There are often dozens of trials and anecdotal reports that show they are safe and effective, but these frequently don’t have FDA approval because the companies won’t go through the process to get them approved for use in children.”

This is the case, Ritchey said, with many medications used in pediatrics.

Challenges for manufacturers

Daniel Benjamin, MD, PhD, who is chair of the Pediatric Trials Network of the National Institutes of Health, told Infectious Diseases in Children that the pharmaceutical approval process for medication use in children is a challenge, particularly in a market where there is relatively low market yield.

In contrast, Benjamin said: “You are not going to see a drug shortage for a medication like Viagra.”

Lisa Kubaska, PharmD, from the FDA’s Center for Drug Evaluation and Research, added that drugs are complex to manufacture, and sterile manufacturing operations are difficult to design and maintain in a state of control.

“Such operations are, frankly, highly vulnerable to inadequate maintenance and sanitation programs,” she said.

Kubaska said some of the more recent shortages — particularly those of generic injectables — were caused by a breakdown in quality control over manufacturing operations. These quality issues have led to compromised sterility and the presence of foreign contamination (eg, glass, metal and other material) inside vials of injectable drugs. Many of these facilities were older and the building and equipment were not properly maintained, according to Kubaska.

Complicating the issue, she said, is that generic drug manufacturers often have little excess production capacity. Therefore, when one manufacturer has to temporarily cease production, the other manufacturers may not be able to increase production quickly enough to avert a shortage. In general, brand name drug manufacturers often have backup lines to produce their drug should there be a delay or temporary loss in supply.

Finally, Kubaska said, failing to address the issues that FDA identifies during inspections — or even those issues a manufacture’s self-inspection may uncover — has become a frequent problem with some drugmakers.

“Pharmaceutical manufacturers need to make a commitment to quality. This commitment needs to come from [senior management] and be integrated into every aspect of the manufacturer’s operations,” Kubaska said. “When management with executive responsibility undertakes adequate oversight and resources a robust quality system, the company will likely avoid serious manufacturing problems of the type that cause shortages, make the evening news, and lead to compliance actions by the agency.”

Hope ahead

One initiative Kubaska mentioned that could help address some of these issues is the Drug Shortage Prevention Act (H.R.3839). This legislation may help identify critical drugs in short supply and give the FDA more authority and information to address the issue.

Another initiative, the Creating Hope Act, which is aimed at stimulating drug development, creates a market-based incentive to spur pediatric cancer drug development. This act was signed into federal law in July 2012 as Section 908 of the FDA Safety and Innovation Act.

Finally, it is the hope of many physician organizations that other legislation, like the BPCA, will also spur research into newer medications, which may at least provide alternatives in the event of shortages.

Robert W. Block, MD, FAAP, recent past-president of the AAP and past chair of the department of pediatrics at the University of Oklahoma Health Sciences Center, and leaders from other pediatric organizations wrote a paper in Pediatrics for the 113th Congress detailing priorities for the health of the nation’s children.

In the paper, each institution outlined its priorities, with the AAP focusing on more legislation that makes children a priority — like the BPCA — and the others calling for more training, diversifying workforces, biomedical research in the pediatric arena, and ending childhood poverty.

“Although most agree that children are our most precious resource, they are often forgotten when it comes to the overall priorities of Congress,” Block and colleagues wrote. “The message here is clear: We must provide for the future health and well-being of our children by guaranteeing access to quality health care, which is provided by a culturally diverse primary care and specialty workforce that is adequate to meet their medical and social needs.” — by Colleen Zacharyczuk

References:

Block R. Pediatrics. 2013;131:109-119.
Metzger M. N Engl J Med. 2012;367:2461-2463.

For more information:

Daniel Benjamin, MD, PhD, can be reached at PO Box 17969, Durham, NC 27715; email: danny.benjamin@duke.edu.
Constance Houck, MD, can be reached at: constance.houck@childrens.harvard.edu.
A. Kim Ritchey, MD, can be reached at: Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Ave., Pittsburgh, PA 15224.

Disclosure: Benjamin, Houck, Kubaska, McCracken and Ritchey report no relevant financial disclosures.

What needs to be addressed to deal with ongoing drug shortage problems?

Communication between medical and pharmacy staff.

Drug shortages have been a significant problem in recent years. Increased attention is being given to drug shortages, and clinicians can track shortages of specific medications on several good Internet sites, including the FDA (www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm) and the American Society of Health Systems Pharmacists (www.ashp.org/shortages).

The reasons for drug shortages are complex, including quality and manufacturing difficulties, among other reasons. Many injectable, sterile drugs are affected, including medications for oncologic use and analgesics. Not as many antibiotics have been newly introduced in recent years, although reasons for this relate to other factors, such as profitability (as compared to chronically prescribed medications).

Communication between medical and pharmacy staff is important when shortages occur, to describe alternative medications and expected shortage resolutions.

Edward A. Bell, PharmD, BCPS, is Professor of Clinical Sciences at Drake University College of Pharmacy, Blank Children’s Hospital, in Des Moines, Iowa. He is also a member of the Infectious Diseases in Children Editorial Board. Bell can be reached at: Drake University College of Pharmacy, 2507 University Ave, Des Moines, IA 50311; email: ed.bell@drake.edu. Disclosure: Bell reports no relevant financial disclosures.

Awareness and education are key.

I am extremely concerned about all medication shortages among the pediatric population. It is difficult to prioritize which shortages are most concerning; they are all troubling and are all too real when you are struggling to find solutions for your own children or patients, especially when comparable substitutions are not available.

I am extremely concerned about all medication shortages among the pediatric population. It is difficult to prioritize which shortages are most concerning; they are all troubling and are all too real when you are struggling to find solutions for your own children or patients, especially when comparable substitutions are not available.

Awareness is often limited to those affected; it is imperative to educate all providers, parents and local and national leaders and arm them with the tools to advocate for children’s health.

Amy B. Middleman, MD, MSEd, MPH, is associate professor of pediatrics in the adolescent medicine and sports medicine section at Baylor College of Medicine. She is also Director of Adolescent and Young Adult Immunization at Texas Children’s Center for Vaccine Awareness & Research. In addition, Middleman is a member of the Infectious Diseases in Children Editorial Board. Middleman can be reached at abmiddle@texaschildrens.org. Disclosure: Middleman reports no relevant financial disclosures.