To Ease IV Fluid Shortage, FDA Allows Baxter to Import from Spain

An intravenous fluid shortage has prompted the US Food and Drug Administration to allow importation of saline from a Spanish plant run by a US company. Image: ©

An intravenous fluid shortage has prompted the US Food and Drug Administration to allow importation of saline from a Spanish plant run by a US company. Image: ©

The US Food and Drug Administration (FDA) is allowing Baxter Healthcare Corporation to temporarily import intravenous (IV) saline from its manufacturing plant in Spain to help ease an ongoing IV fluid shortage in the United States. The agency is also permitting the importation of a saline product from Norway.

The temporary easing of restrictions on imports on these products is intended to help ease an ongoing shortage of IV fluids. A recent JAMA article noted the shortage had affected two-thirds of US hospitals as of February, and outlined how hospitals and other health care facilities are coping with the shortage. Many are taking extraordinary measures to minimize patient harm, such as giving water or alternative fluids to patients who are capable of drinking rather than IV fluid. About half of the hospitals reported that efforts to conserve IV supplies were preventing patient harm from the shortage. However, the hours involved in regularly calling suppliers and carefully managing supplies costs the hospitals valuable staff time, even when patients are not harmed.

Temporarily allowing the import of saline from Baxter’s Spanish facility will not end the IV fluid shortage, but may ease disruptions in the availability of 0.9% saline, according to the FDA. The agency has inspected the saline plant in Spain to ensure that it can meet the agency’s standards for safety and quality.

Importing pharmaceuticals from other countries has become an increasingly common strategy for drug makers, with most drug ingredients used in US drugs now coming from China and India. However, serious quality problems have occurred, such as the importation of adulterated raw material for heparin into the United States, which resulted in major recalls of the product in 2008. Many foreign countries lack the regulatory capabilities of the FDA. The FDA has slowly been growing its workforce in countries like China and India, but still is unable to inspect all foreign facilities.

On a recent visit to India, FDA Commissioner Margaret Hamburg, MD, emphasized the need for drug makers who wish to export drugs or ingredients to the United States to meet US standards. One major Indian drug and drug ingredient manufacturer, Ranbaxy, was targeted by the FDA in January. The agency barred the use of pharmaceutical ingredients produced at the company’s plant in Toansa, India, in FDA-regulated products, and required 2 of the companies’ other factories to comply with FDA standards.

FDA Plans to Reduce Liver Damage Risk by Asking Physicians to Stop Prescribing High-Dose Acetaminophen Products

The US Food and Drug Administration is asking physicians to stop prescribing and dispensing medications containing high doses of acetaminophen to reduce the risk of liver damage. (Credit: JAMA, ©AMA)

To reduce the risk of liver damage, the US Food and Drug Administration is asking physicians to stop prescribing and dispensing medications containing high doses of acetaminophen. (Credit: JAMA, ©AMA)

After only limited success in persuading drug manufacturers to reduce the amount of the painkiller acetaminophen in prescription combination products, the US Food and Drug Administration (FDA) has now called on physicians to avoid prescribing these products if the acetaminophen content is too high. Liver failure, a need for liver transplantation, or death can occur when individuals exceed a certain daily dosage.

In 2011, the FDA gave manufacturers 3 years to voluntarily limit the amount of  acetaminophen in prescription combination drugs to no more than 325 mg in each tablet or capsule. The 3-year window closed this week, and although more than half of manufacturers have complied, some have not.

Acetaminophen, used to relieve pain and fever, can be found in over-the- counter products, such as Tylenol, and in prescription products combined with other ingredients, usually opioids such as codeine (Tylenol with Codeine), oxycodone (Percocet), and hydrocodone (Vicodin).

However, severe liver injury can occur when acetaminophen use exceeds maximum dosage (currently 4000 mg within a 24-hour period) or when an individual takes the drug and also consumes alcohol. Researchers estimate that in the United States, there are about 44 000 acetaminophen overdose–related emergency department visits each year, with about half being unintentional.

This week, the FDA issued a recommendation to physicians and other health care professionals to discontinue prescribing and dispensing prescription combination drug products that contain more than 325 mg of acetaminophen. The agency noted that no available data show that taking higher doses per pill or tablet provides additional benefit that outweighs the added risks for liver injury. This limitation should help reduce the risk of severe liver injury from inadvertent acetaminophen overdose.

The FDA said that it will soon begin proceedings to withdraw approval of prescription combination drug products containing more than 325 mg of acetaminophen per dosage unit that remain on the market.

The FDA’s action this week does not apply to products sold over the counter that contain acetaminophen as the sole active ingredient or combined with other drugs, such as ingredients found in cough and cold medicine. As ProPublica, an independent, nonprofit news group points out, some over-the-counter products contain as much as 625 mg of acetaminophen per dose. However, the agency said it will address over-the-counter acetaminophen products in another regulatory action because many consumers are unaware that overuse of acetaminophen poses a liver damage risk.

Author Insights: Physicians Often Flying Blind on Use of Medications for Premature Infants

Matthew M. Laughon, MD, MPH, of department of pediatrics at the University of North Carolina, and colleagues found little information available to help physicians safely and effectively use medications in neonates. Image: University of North Carolina

Matthew M. Laughon, MD, MPH, of department of pediatrics at the University of North Carolina, and colleagues found little information available to help physicians safely and effectively use medications in neonates. Image: University of North Carolina

Despite government efforts to promote research on medications used in children, huge gaps persist in knowledge about whether medications are safe and effective for the most vulnerable—newborns receiving care in neonatal intensive care units (NICUs)—according to a study published today in JAMA Pediatrics.

Matthew M. Laughon, MD, MPH, of the department of pediatrics at the University of North Carolina at Chapel Hill, and his colleagues found large gaps in the information available about medications used in neonates. They reported that medication use is very common in this population: in a cohort of nearly half a million hospitalized infants, 399 drugs were used and there were more than 1.5 million drug exposures in just the first 28 days of life for this group. Yet when the researchers reviewed US Food and Drug Administration (FDA) databases to identify medications studied in neonates and whether the studies resulted in new information on the drugs’ labels, they found that only 28 drugs had been studied in this population, resulting in labeling changes for only 24. Only 11 of the label changes provided information about the safety and efficacy of the drug for premature infants and 13 of the drugs studied were not used in NICUs, where most neonatal drug exposure occurs. Eight of the drugs were used in fewer than 60 preemies.

Laughon discussed the findings with news@JAMA.

news@JAMA: Why did you decide to do this study?

Dr Laughon: We knew anecdotally and experientially that federal legislation designed to increase the amount of information on drugs used to treat children didn’t do much to address the need for information on neonates. We wanted to quantify that.

news@JAMA: Which laws are you talking about?

Dr Laughon: Prior to 1997, there was very little incentive for drug companies to study pharmaceuticals in children. In 1997, the US Food and Drug Administration Modernization Act was passed and then the Best Pharmaceuticals for Children Act [BPCA] was passed in 2002. These laws helped increase the study of drugs in children, which is great. Last year, the Food and Drug Administration Safety and Innovation Act was passed, designating neonates as a special population. As a result the FDA has hired a neonatologist.

news@JAMA: What has been the effect of these laws on data about drugs for neonates?

Dr Laughon: Since the laws went into effect, there have been between 400 to 500 pediatric labeling changes on drugs, but only a minority related to neonates. A lot of the label changes related to neonates did not include safety and efficacy information. There were only 14 where safety and efficacy were established for neonates, but these drugs were hardly used in neonates, often not in the NICU. Even though the safety and efficacy of many drugs have not been established, physicians are still using these drugs on neonates without evidence of benefits, knowing there are side effects since all drugs have side effects.

news@JAMA: Why do you think information about neonatal medication use has lagged?

Dr Laughon: They are a real tough population to study. Parents are often reluctant to consent to participation. There are physiologic changes that occur in neonates that don’t occur at any other time of life. Over the first month of life, there may be rapid changes in drug metabolism in these neonates. That’s really challenging. You need special pharmacokinetic techniques to make sense of the data. There is not much expertise available, with fewer than 10 individuals in the United States who are true experts on drug metabolism in neonates. The National Institutes of Health [NIH] is trying to beef up expertise in pediatric pharmacokinetics, including neonatal pharmacokinetics.

Neonates also have low circulating blood volume, so you can’t take much blood. You need very sensitive assays to detect a drug in small amounts of blood.

news@JAMA: What can be done to promote more study of medication use in neonates?

Dr Laughon: On the industry side, new drugs are usually developed for adults, then passed down to children and then to neonates. Some federal programs give 6-month patent extensions to companies who study their new drugs in children. For old drugs that are off patent, there is not a lot of incentive for pharmaceutical companies to study the drugs in children. The BPCA has designated funding to NIH for the Pediatric Trials Network to study off-patent and off-label medication use in children. The network has done a wonderful job studying drugs in children, with a fair number of the studies in neonates.

news@JAMA: What do you hope your study contributes?

Dr Laughon: This article is about awareness. Very few physicians have read an FDA label; it is important to know where this information comes from. They should be willing to participate in studies to help generate new information. We need parents’ help to enroll their neonate child in studies. We are thankful to the parents who have agreed to enroll in past studies; they have helped us improve the care of neonates. We have learned, for example, that the doses of fluconazole we were giving neonates were not right, so now when we have neonates with candida [a fungal infection], we can give them the right dose.

Study Suggests Interrupted Sleep Might Not Impair Performance of Practicing Surgeons

Surgeons who operate overnight do not necessary perform worse with laparoscopic surgery the next day. Image:

Surgeons with interrupted sleep from operating overnight do not necessarily perform worse with laparoscopic surgery the next day. Image:

There was a time when sleep deprivation among physicians was considered an unquestioned reality, then a time when it became an unnecessary risk for both physicians and patients. Now, the debate continues, with new findings suggesting that sleep interruption may be more benign that previously suspected—at least among experienced surgeons.

A study released in JAMA this week suggests that surgeons performing daytime surgeries after they operated the night before do not perform worse than when they did not operate overnight.

A group of researchers in Ontario, Canada looked at administrative data on 2078 nonemergency cholecystectomies (gallbladder removal surgeries) that were performed during the daytime by a surgeon whose billing records indicated that he or she had also performed emergency surgery the night before (between midnight and 7 am). To take individual surgeon variability into account, each “at-risk” cholecystectomy performed by a surgeon who had operated the night before was compared to 4 “control” cholecystectomies performed by the same surgeon when he or she had not operated the night before. The 133 surgeons in the study operated at 102 different community hospitals in Ontario; all teaching hospitals involving residents (physicians in training) were excluded.

Researchers compared the complication rates of the at-risk vs control cholecystectomies, defining the main “complication” as the surgeon’s decision to switch midstream from performing the standard laparoscopic keyhole procedure to a more invasive open procedure involving a larger incision into the abdomen. This conversion from laparoscopic to open surgery is a plausible result of surgeon fatigue leading to error during laparoscopy and represents a generally undesirable outcome for both patients and physicians.

Results showed that there was no difference in rates of conversion from laparoscopic to open surgery between the 2 groups: 2.2% in the at-risk group vs 1.9% in the control group.

However, the new findings have an important limitation: there was no information on the actual amount of sleep deprivation experienced by the surgeons. Researchers did not know when the nighttime operations performed by the surgeons occurred, when the subsequent daytime operations occurred, or how many hours of sleep the surgeons were able to get in between. When it comes to physician performance, even a 1-hour nap can make a big difference.

Additionally, the study looked solely at physicians in practice in the community, so its findings should not be extrapolated to residents, who arguably represent the most sleep-deprived group of physicians. Following concerns about poor performance and medical errors resulting from resident fatigue, in 2003 the Accreditation Council for Graduate Medical Education (ACGME) limited work hours of medical residents in the United States to a maximum 80-hour work week and 30-hour consecutive shift. In 2011, this 30-hour shift was further cut down to a 16-hour maximum for first-year residents (interns) and a 28-hour maximum for all other residents.

There has been some talk of instituting similar work-hour restrictions for attending physicians who have completed their residency training, but currently no such restrictions exist. Because there is much opposition among attending physicians to the idea of restricting their work hours, the findings from this study, which confirm those of another recent study of surgeons after an overnight trauma shift, are already being heralded as key evidence against the need for this.

Furthermore, many opponents of work-hour restrictions also feel that current resident work-hour restrictions should be made less stringent. Indeed, since 2011 the ACGME has been under intense pressure to review (and possibly reverse) the new resident work-hour restrictions, which have been much criticized in the medical education community, both in surgical and nonsurgical specialties of medicine. Editorials have been published by the dozens—from the New York Times to the JAMA Network itself—discussing how after the institution of the 16-hour rule, continuity of care for patients has declined, and interns are learning less, making more errors, and not actually sleeping more.

Since the majority of studies on this topic have only looked at attending physicians, current and future studies specifically looking at resident fatigue and performance under the new guidelines will be crucial over the next several years in reevaluating work-hour restrictions for residents.

Updated Rules for Clinical Research Strengthen Patient Protections

Ramin W. Parsa-Parsi, MD, MPH, of the German Medical Association, said changes in the World Medical Association’s revised Declaration of Helsinki are intended to bolster protection for participants in research involving humans while still promoting quality research.

Ramin W. Parsa-Parsi, MD, MPH, of the German Medical Association, said changes in the World Medical Association’s revised Declaration of Helsinki are intended to bolster protection for participants in research involving humans while still promoting quality research.

The rights and interests of patients must always trump medical researchers’ drive to generate knowledge, according to updated guidelines for the ethical conduct of clinical research from the World Medical Association (WMA).

The WMA’s Declaration of Helsinki has set the worldwide standard for ethics in research involving humans for nearly 50 years. First drafted in 1964, the declaration is used by researchers, funders, ethics oversight bodies, and research participants to assess whether clinical research is hewing to appropriate ethical standards. One notable exception is the US Food and Drug Administration’s decision in 2009 to follow a different standard, a move that some speculated may be linked to the declaration’s guidance that the best possible treatment be used instead of placebos.

The updated version is designed to be more easily accessible, grouping recommendations by subject matter, with specific sections dedicated to informed consent, the use of placebos, and the conduct of research on vulnerable groups. It also includes several revisions aimed at strengthening protections for research subjects.

In a video interview, Heikki Pälve, MD, PhD, chief executive officer of the Finnish Medical Association, explained that the most important recommendation is number 8, which says, “While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects.”

Pälve said that putting patient rights first is crucial to ensuring the future of clinical research by protecting the public’s trust in the enterprise. For the first time, the declaration requires that participants who are harmed in the course of research be compensated and provided with appropriate treatment. The declaration also requires researchers to share the overall study results with participants. Ramin W. Parsa-Parsi, MD, MPH, of the German Medical Association, who also participated in the interview said, “We believe that this revised document achieves a good balance between strengthing safeguards for patients while promoting good quality research.”

Several changes were also made to protect the interests of research participants in resource-poor countries, which are increasingly used as sites for clinical trial research. In a Viewpoint accompanying the declaration in JAMA, Paul Ndebele, PhD, of the Medical Research Council of Zimbabwe, said the revised declaration addresses some of the ethical issues specific to studies conducted in middle- and low-income countries. For example, it requires that researchers provide for ongoing access to effective interventions and care after trial completion.

But some questioned whether the revised declaration went too far in protecting patients. A second JAMA Viewpoint, by Joseph Millum, PhD, and colleagues, argues that the document doesn’t provide for situations when it might be appropriate to forego informed consent or where very broad consent may be given for use of biomedical samples. The Viewpoint also questions whether the guideline is too restrictive about exposing patients to risk in the context of clinical research: “The declaration’s lack of clear and consistent guidance regarding when net risks are acceptable creates unnecessary confusion and fuels the unfounded concern that all medical research is inherently exploitative.”

Author Insights: Using Detection of Postsurgical Blood Clots as a Quality Measure May Be Misguided

Karl Y. Bilimoria, MD, MS, of Northwestern University and Northwestern Memorial Hospital in Chicago, and colleagues suggest surveillance bias limits the usefulness of postsurgical blood clot rates as a quality-of-care measure. (Image: Northwestern Memorial Hospital)

Karl Y. Bilimoria, MD, MS, of Northwestern University and Northwestern Memorial Hospital in Chicago, and colleagues suggest surveillance bias limits the usefulness of postsurgical blood clot rates as a quality-of-care measure. (Image: Northwestern Memorial Hospital)

Sometimes good intentions have unintended consequences. Take, for example, using rates of blood clots (venous thromboembolisms, or VTEs) after surgery as a quality measure, with higher rates theoretically pointing to suboptimal preventive measures.

Developing blood clots after surgery is a common complication, and the postoperative morbidity and death associated with VTEs are potentially preventable through such measures as anticlotting drugs and getting patients moving around soon after surgery. To assess whether physicians and hospitals are reducing preventable blood clot formation after surgery, the Agency for Healthcare Research and Quality developed a risk-adjusted postoperative blood clot rate measure that was endorsed by the National Quality Forum and has been incorporated into numerous quality improvement programs and public reporting initiatives.

But a study appearing today in JAMA suggests such a measure might be flawed because of “surveillance bias”—which means you might find more of something not because it’s become more common but because you’ve stepped up efforts to find it. In the case of VTEs, the study suggests, some hospitals might find more VTEs in their patients because of increased efforts to look for VTEs, not because the number of blood clots has actually increased.

Researchers using data from 2838 hospitals and Medicare claims data from 954926 surgical patient discharges from 2786 hospitals found that institutions with increasing quality scores had higher rates of using measures to prevent VTE but also higher rates of blood clots. In addition, they found increased hospital VTE event rates were associated with increasing hospital VTE imaging rates.

Lead author Karl Y. Bilimoria, MD, MS, of Northwestern University and Northwestern Memorial Hospital in Chicago, discusses his team’s findings.

news@JAMA: Why did you do this study?

Dr Bilimoria: We heard from a number of institutions saying that no matter what they did, they couldn’t drive down their VTE rates. Here at Northwestern, we’ve worked on this for the past 4 or 5 years, and it seemed we got worse over time.

news@JAMA: Why did it seem to get worse?

Dr Bilimoria: What happened was we were putting so much emphasis on VTEs that we started finding more, and this created a vicious cycle. And we heard this from other top-quality hospitals. How frequently hospitals use imaging to detect a VTE is strongly associated with the number of VTEs they find, which makes them look worse on the rankings. All this suggests is that there is a surveillance bias around the measurement.

news@JAMA: So postsurgical blood clot development should not be a quality measure?

Dr Bilimoria
: Everybody wants to measure quality around hospital care and VTE is one of the most common metrics used in public reporting sites and internal sites, so it has huge implications for hospitals. We’re not saying you shouldn’t look for VTEs, but to assess quality [associated with VTE prevention], it may be better to look at process measures or adherence to guidelines.

news@JAMA: Does this surveillance bias have ramifications for patients?

Dr Bilimoria: If you’re a patient and look at these hospital quality rankings and find one has more blood clots after surgery, you may not go there. But that hospital may be more vigilant and have the ability to act better than the one you end up choosing.

news@JAMA: Does the surveillance bias have ramifications for physicians?

Dr Bilimoria: There is a huge potential for adverse consequences. If you get knocked for finding more VTEs, then maybe you look for them less or you use prophylaxis inappropriately in low-risk patients, and that is not without risk.

Bacterial Infections Prompt Another Compounding Pharmacy Recall

Bacterial infections have been linked to drug infusions produced by a compounding pharmacy in Texas. Image: teetuey/

Bacterial infections have been linked to drug infusions produced by a compounding pharmacy in Texas. Image: teetuey/

The emergence of bacterial infections in 15 patients who received drug infusions made by a Texas compounding pharmacy has prompted a nationwide recall of the company’s products, according to an alert issued by the US Food and Drug Administration (FDA).

According to the FDA, 15 patients at 2 Texas hospitals have developed bloodstream infections after receiving infusions of calcium gluconate produced by Specialty Compounding, of Cedar Park, Texas. The infections were caused by the bacterium Rhodococcus equi. Cultures of samples of calcium gluconate provided evidence that Rhodococcus bacteria were present.

The company has recalled all of its sterile products. According to a company news release, such products were distributed to hospitals and physicians in Texas and directly to patients in other states. The FDA advises that use of sterile products from this pharmacy be stopped immediately and the products returned to Specialty Compounding.

“The FDA believes that use of these products would create an unacceptable risk for patients,” said Janet Woodcock, MD, director of FDA’s Center for Drug Evaluation and Research, in a statement. “Giving a patient a contaminated injectable drug could result in a life-threatening infection.”

The recall and infections were the latest public health problem linked to compounded drugs. In late September 2012, the New England Compounding Center (NECC) in Framingham, Massachusetts, issued a nationwide recall after cases of fungal meningitis began emerging among patients who received spinal injections of steroids produced by the company. To date, there have been 749 infections, including 63 deaths, linked with contaminated products from the NECC, according to the US Centers for Disease Control and Prevention’s website. A subsequent FDA inspection of another major supplier of compounded drugs, also in Massachusetts, documented serious sterility lapses, including a leaky roof. In May, the FDA warned of fungal infections associated with steroids from a Tennessee-based compounding pharmacy.