Author Insights: Medications Help Curb Alcohol Use Disorders

Daniel E. Jonas, MD, MPH, of the University of North Carolina at Chapel Hill, and colleagues found drugs that help individuals with alcohol use disorders abstain from drinking.  Image: Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill

Daniel E. Jonas, MD, MPH, of the University of North Carolina at Chapel Hill, and colleagues found drugs that help individuals with alcohol use disorders abstain from drinking. Image: Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill

Quitting drinking can be a difficult task for individuals with alcohol use disorders, but a pair of drugs may help, finds an analysis of more than 100 studies examining the use of medications to treat these conditions.

Alcohol use disorders are common in the United States, affecting an estimated 17 million people in the United States. These disorders have severe consequences for patients’ health, contributing to increased cancer risk, liver disease, and other health problems. Individuals with these disorders may also face steep social and economic costs, including job loss or family estrangement. Yet, less than one-third are ever treated and only 10% take medication for the conditions, despite a large body of evidence on the effectiveness of these interventions.

Lead author Daniel E. Jonas, MD, MPH, of the University of North Carolina at Chapel Hill, explained that sometimes having a large body of evidence on numerous drugs can create confusion about what works and what doesn’t. To provide clearer information about the benefits and harms of the available medications, he and his colleagues reviewed data from 122 randomized clinical trials and 1 cohort study involving a total of 22 803 participants. The studies were, on average, 12 weeks long. They found that either oral naltrexone or acamprosate helped patients refrain from drinking. To prevent 1 person from resuming drinking, 12 patients would have to be treated with acamprosate (the number needed to treat) or 20 would have to be treated with oral naltrexone. Treatment with oral naltrexone also helped reduce the risk of a return to heavy drinking, with 1 patient benefiting for every 12 treated. Injectable naltrexone was associated with reduced drinking days, but not abstinence.

Jonas discussed the findings with news@JAMA.

news@JAMA: What do the numbers needed to treat tell us?

Dr Jonas: We have to treat 12 people with naltrexone to get 1 to successfully reduce drinking. People look at that 2 ways—some may not view it as very good, but those numbers are pretty good compared with other medications that have wide support.

news@JAMA: Are physicians using medications to treat alcoholism?

Dr Jonas: No. These treatments are underused and there’s a lot of room for improvement. Most primary care physicians—I’m a primary care physician—are trained to refer people with alcohol use disorders to specialists. They are not really trained to treat them by providing psychosocial interventions or medicine. Many communities don’t have specialist care that physicians can refer patients to.

news@JAMA: Do you have any explanation for why the results would be different for oral or injectable naltrexone?

Dr Jonas: There are some pharmacokinetic reasons why it may not work when you convert the drug to an injectable. It’s also monthly, there’s a lot of challenges in getting a drug to last for a month. But there is not yet that much evidence on the injectable. It’s possible additional studies will show the injectable form may work.

news@JAMA: Why might acamprosate reduce the risk of having a drink but not of a return to heavy drinking?

Dr Jonas: I don’t know the answer. Some theories are tied to the mechanism of action. Naltrexone reduces craving, while acamprosate works on through other mechanisms. There’s some thinking naltrexone may be better for preventing a return to heavy drinking, but acamprosate is better for avoiding drinking.

news@JAMA: How do the results for naltrexone and acamprosate compare with disulfiram?

Dr Jonas: Disulfiram has been around the longest. Well-controlled studies don’t really show that it works. There are fewer good studies of disulfiram. When you look at naltrexone or acamprosate we have more and better evidence.

news@JAMA: What did you learn about adverse effects and tolerability?

Dr Jonas: The evidence on harms wasn’t as good as evidence on benefits. A number of adverse events are slightly increased compared with placebo for the 2 drugs. Acamprosate was a most commonly associated with anxiety, diarrhea, and vomiting. Naltrexone was associated with a higher risk of dizziness, nausea, and vomiting.

news@JAMA: Are there any other cost or convenience differences between the 2 drugs?

Dr Jonas: Everyone wants to know how to pick which drug to use. Naltrexone is 1 pill once a day. Acamprosate is 2 pills 3 times a day. It’s really hard for anyone to take 2 pills 3 times a day reliably. So unless the patient has a contraindication, many physicians will try naltrexone first. Both are available in generic. Wholesale naltrexone is cheaper. Injectable naltrexone is the only one with a high cost, about $1200 a month.

news@JAMA: Which of the off-label treatments have the strongest evidence base favoring effectiveness?

Dr Jonas: Just 2 had moderate effects, topiramate and nalmefene. Nalmefene is approved in other countries; it is similar to naltrexone. There is not as much evidence for either of these as for naltrexone and acamprosate.

Topiramate is a really used for a lot of off-label things. It has adverse effects that can lead to cognitive dysfunction, paresthesia, and taste abnormalities. It has a long list of common adverse effects.

news@JAMA: What do you think is the main take-home message?

Dr Jonas: We have some medicines that can be a useful component of treatment. These are so underused. The related question, is whether primary care needs to start doing more treatment rather than referring. There just isn’t an adequate supply of specialists who take care of people with alcohol use disorders.

Additionally, there are barriers to getting to a specialist and people may not want to go. Lots of patients with alcohol use disorders have comorbid depression and anxiety that often prevents them from seeing another physician they don’t know.

Author Insights: Studies Disclose Motivations When Comparing Treatment Costs

Franklin G Miller, PhD, of the National Institutes of Health Department of Bioethics, and colleagues suggests making the cost motivations in comparative-effectiveness studies clear on consent forms. Image: NIH

Research participants should be informed when studies are being conducted to determine which treatments provide the best bang for the buck, argue the authors of a Viewpoint in today’s issue of JAMA.

Health care reform and the urgent need to cut rising health care costs have led to a growing number of comparative-effectiveness studies that may pit treatments against each other to assess the relative risks, benefits, and costs of the treatments. Franklin G. Miller, PhD, National Institutes of Health Department of Bioethics, and colleagues argue that when treatment costs are a motivating factor behind a study, participants have a right to know.

Miller and colleagues highlighted the Comparison of the Age-Related Macular Degeneration Treatment Trials (CATT) as an example of study motivated in part by differential drug costs. The CATT compared the relative costs, safety, and effectiveness of 2 drugs used to treat macular degeneration. Ranibizumab has been approved by the US Food and Drug Administration (FDA) as a macular degeneration treatment, but  many clinicians use a similar drug bevacizumab, which was originally approved as a cancer treatment, in part because it is 40 times cheaper. A report from the US Department of Health and Human Services’ Office of Inspector General (OIG) found, for example, that between 2008 and 2009, Medicare Part B “paid physicians $40 million for 936 382 Avastin (bevacizumab) treatments and $1.1 billion for 696 927 Lucentis (Ranibizumab) treatmetnts.”*

The CATT study mentioned the cost differential but did not spell out that costs were one of the motivating factors behind the study. The study by Miller and colleagues suggests simple language that could be used to let study participants know that cost is a motivating factor. Miller discussed his and his colleagues’ views with news@JAMA.

news@JAMA: Why did you decide to write this Viewpoint?

Dr Miller: There are more comparative effectiveness studies being conducted and one of the background motivations for the studies is the relative costs of treatments. A lot of drugs are expensive, and there is some real value in seeing how these stack up. They rarely are done solely for cost. There are usually other clinical considerations. It was my perception that cost motivation is not routinely described to patients as a reason why a study is done.

news@JAMA: What makes the CATT study such a good case study?

Dr Miller: It’s an excellent study. It stands out in that you have 2 treatments that are biologically almost essentially the same—one is FDA-approved, and one is [prescribed] off label. The FDA-approved drug is 40 times more expensive. With the newly released data about Medicare payments to physicians, it turns out that ophthalmologists are among the highest paid. A fair amount of that has to do with Lucentis [ranibizumab]. I think most ophthalmologists prescribe the cheaper option.

We weren’t trying to criticize the study, it’s a very valuable study. The cost wasn’t fully described as a motivation, but that is really the norm. I was on data safety monitoring committee for the study, and we approved the consent form.

news@JAMA: What did the CATT study ultimately find?

Dr Miller: There was no difference in the safety and effectiveness of the two. This is not surprising because of the biological similarity.

news@JAMA: How might informing participants about cost motivations affect their behavior?

Dr Miller: That’s a question we don’t have an answer to. For patients with chronic conditions it might be better for them to get an equivalent, but cheaper treatment. They might be more motivated to participate, and some are altruistically motivated. There might be some who could be turned off.

news@JAMA: What is the main take-home message you’d like to pass along to researchers and potential research participants?

Dr Miller: When a part of the motivation to do a randomized study has to do with the relative costs of treatment it should be clearly laid out. We suggested some simple language.

*This blog has been updated with information from the OIG report.

Inexpensive Lifesaving Therapy for Diarrheal Illness in African Children Is Underused by For-Profit Clinics

Neeraj Sood, PhD, of the University of Southern California, and Zachary Wagner, a doctoral student at University of California, Berkeley, found that for-profit health facilities in sub-Saharan Africa are less likely than large public hospitals to provide lifesaving rehydration to children with diarrhea. Image: University of Southern California

Neeraj Sood, PhD, of the University of Southern California, and Zachary Wagner, a doctoral student at University of California, Berkeley, found that for-profit health facilities in sub-Saharan Africa are less likely than large public hospitals to provide lifesaving rehydration to children with diarrhea. Image: University of Southern California

Although oral rehydration can mean the difference between life and death for children with diarrheal illnesses in sub-Saharan Africa, a new study suggests that for-profit clinics may be more likely than large public hospitals to prescribe expensive treatments instead.

Children younger than 5 years are at risk of death from diarrheal illnesses, which claim about 700 000 young lives each year. Most of the deaths result from dehydration and can be prevented by providing a solution of glucose and electrolytes. This simple and inexpensive intervention, which can cost less than 50 cents, is referred to as oral rehydration therapy (ORT). Unfortunately, this lifesaving tool is underused in sub-Saharan Africa.

To better understand why some children aren’t receiving ORT, Neeraj Sood, PhD, of the University of Southern California, and Zachary Wagner, of the University of California,Berkeley, analyzed survey data on 19 059 children from 29 countries in sub-Saharan Africa collected between 2003 and 2011. When they compared the care children with diarrhea received from for-profit vs public health providers, they found that for-profit providers were 15 percentage points less likely to provide ORT and about 12 percentage points more likely to provide treatments like antibiotics that may not be necessary and may cost more.

The for-profit facilities tended to be single-practitioner clinics or pharmacies compared with large public hospitals. The researchers found that pharmacies “were particularly likely to provide poor care.” Although wealthy parents were more likely to visit for-profit providers, underprivileged children from rural areas were disproportionately likely to receive poor care at for-profit facilities.

These findings are particularly concerning because for-profit facilities are becoming more common in sub-Saharan Africa as public health systems struggle to meet demand for care. Alan Magill, MD, president of the American Society of Tropical Medicine and Hygiene, said in a statement that the data suggest better coordination with the emerging private care sector in this region is needed to ensure the dissemination of evidence-based care.

“Given the important role that private health care providers are playing in Africa, this research shows that we need to be employing engagement strategies that we know have been successful in helping combat other diseases like HIV and malaria,” Magill said. “It is an illustration of the hand-in-hand relationship that research plays with clinical care.”

Author Insights: Published Studies Often Conflict With Results Reported to ClinicalTrials.gov

Joseph S. Ross, MD, MHS, of Yale University School of Medicine and his colleagues found discrepencies between the reporting of results in journals and ClinicalTrials.gov. Image: Yale University

Joseph S. Ross, MD, MHS, of Yale University School of Medicine and his colleagues found discrepencies between the reporting of results in journals and ClinicalTrials.gov. Image: Yale University

Study results published in major medical journals often conflict with the data its authors have submitted to ClinicalTrials.gov, according to an analysis published in JAMA today.

The ClinicalTrials.gov registry, maintained by the National Library of Medicine, was created to help improve transparency in the medical literature by ensuring that all results of clinical trials, whether published or not, are archived in a single repository. A 2007 law mandated that researchers post results of studies on all products regulated by the US Food and Drug Administration (FDA) within 12 months. Many journals have also pledged to require their authors to report their findings in the registry. But numerous problems with the registry have been documented since its creation, including a failure of many researchers to report their results and sloppy data entry by investigators.

A new analysis by Joseph S. Ross, MD, MHS, an assistant professor of medicine at Yale University School of Medicine, and his colleagues raise questions about the accuracy of what is reported in the registry and in the medical literature. The team compared the results of 96 trials published in top-tier medical journals, including JAMA, the New England Journal of Medicine, and the Lancet, with the results of those trials reported in ClinicalTrials.gov. They found at least 1 discrepency in the results reported for 93 of the trials. Results matched in both the registry and journal article in only about half the cases.

Ross discussed the findings with news@JAMA.

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

Dr Ross: Our research group is interested in thinking of ways to improve the quality of clinical research. When the Food and Drug Administration amendments were passed requiring results reporting [to the ClinicalTrials.gov registry], we were interested in how that would play out. There have been studies about how compliant researchers are with this requirement. We wanted to look at how accurate the reported findings are. By comparing the reported results to published trials, we wanted to see how well it was working. What we found was a surprise.

news@JAMA: Why were the results surprising?

Dr Ross: We found important discrepancies between the results reported in ClinicalTrials.gov and the published results. We don’t know which is right. There were lots of end points reported in 1 source that weren’t reported in the other.

news@JAMA: Can you give an example?

Dr Ross: We started by looking at the primary end points published in high-impact journals and what end points were reported in ClinicalTrials.gov. Of 90-some-odd trials, there were 150 to 160 primary end points; 85% were described in both sources, 9% only in ClinicalTrials.gov and 6% only in the publications.

For the more than 2000 secondary end points, 20% were reported only in ClinicalTrials.gov and 50% only in publications. Only 30% were described in both sources.

You see that only part of the information is available in 1 source. We need to make the sources as complete as possible. The publications need to link back to ClinicalTrials.gov because they often don’t include all the end points.

news@JAMA:Why might there be such a difference?

Dr Ross: There are a lot of potential explanations.

More end points were reported in the published papers than in ClinicalTrials.gov. This suggests authors are reporting end points in the paper that make the results look better that weren’t predetermined. That can skew the literature.

news@JAMA: Could edits made by the journals, such as requests for more information or new analyses, or typographical errors account for some discrepancies?

Dr Ross: It could be editing. An authorship team submits the results and these are publications that have strong editorial staffs. There could be slightly different approaches in analysis submitted to the 2 sources.

Some are typographical errors. For example, 1 study reported a hazard ratio of 4 in ClinicalTrials.gov instead of the hazard ratio of 2 in the study [the hazard ratio and standard deviation were transposed]. That perverts the study result.

news@JAMA: What can be done to improve the accuracy results in reporting?

Dr Ross: These results are increasingly being used by researchers and in meta-analyses; we want them to be accurate. The journals pay a large staff of full-time editors to make sure these studies don’t have errors, but ClinicalTrials.gov has a relatively small staff. We may need a larger endeavor than what the National Library of Medicine originally envisioned.

A third of the discordant results led to a different interpretation of the trial. This a problem we need to be attending to. We studied the highest-tier journals, so this is likely the best-case scenario. These are likely the highest-achieving researchers. Who knows what’s happening with lower-tier journals?

Author Insights: Limited Quality Improvement But No Cost Reduction in Medical Home Pilot

Mark Friedberg, MD, MPP, of RAND, and colleagues found limited quality improvement and no cost reduction in a large pilot of medical homes. Image: RAND

Mark Friedberg, MD, MPP, of RAND, and colleagues found limited quality improvement and no cost reduction in a large pilot of medical homes. Image: RAND

There’s been great hope that the patient-centered medical home model could help alleviate rising health care costs and improve the quality of care. But results from a large pilot study published in JAMA today found no cost savings and only a modest improvement in quality.

The concept of the patient-centered medical home model is that it redesigns care around the patient’s needs. It offers patients one-stop shopping, with a primary care clinician and interdisciplinary physicians, specialists, nurses, and care managers working together all in one place. For patients with complex or chronic diseases, this may decrease the need for multiple visits to various clinicians, improve coordination of care between clinicians, and give such patients a regular point of contact, such as a care manager who can help them navigate the day-to-day challenges of their condition. To encourage physicians to adopt the model, payers have offered financial incentives.

Numerous pilot studies of the patient-centered medical home model are under way. So far, the data suggest only modest quality improvement over usual care and offer little evidence that this model reigns in costs. Mark Friedberg, MD, MPP, a researcher at RAND, and his colleagues analyzed data from a large multipayer pilot of primary care practices in southeastern Pennsylvania featuring a medical home based on standards set by the National Committee for Quality Assurance. The analysis included 64 243 patients in the pilot practices and 55 959 control patients. The researchers found a modest  improvement in the quality of care for only 1 of 11 measures, and no reductions in care utilization or costs.

Dr Friedberg discussed his findings with news@JAMA.

news@JAMA: What do you think is driving the enthusiasm behind medical homes?

Dr Friedberg: Two things have been big drivers of the enthusiasm: a large body of evidence over decades that having a strong primary care system leads to lower costs and higher-quality care, and some hope that medical care homes would help revitalize the field of primary care by attracting students and improving care.

news@JAMA: Prior to your study, had the research backed that up?

Dr Friedberg: It’s too early to tell. The research is very limited and not much is known about how to best implement the model. There is a theoretical model, but taking a real-life practice and transforming it into a medical home hasn’t been well studied.

A few studies of small and medium pilots have been consistent with our results. But some early studies of the medical home model didn’t include things like the National Committee for Quality Assurance criteria. Some, including the ones in large systems, did show some improvement in quality and cost of care.

news@JAMA: What does your study add?

Dr Friedberg: The main addition is that we evaluated a pilot that was larger, ran longer, and had more payers and greater financial incentives than most pilots before it. We found improvement on 1 quality measure [kidney disease screening for patients with diabetes], and a [not statistically significant] trend toward improvement on diabetes care. But we didn’t see overall improvements on screening, utilization, or costs of care. This was despite the practices hiring nonphysician staff to manage patients with chronic conditions.

news@JAMA: What do you think explains the lack of quality improvement or cost reduction?

Dr Friedberg: It’s really hard to say. I don’t think this study can answer that. These pilots are really complex interventions. To pinpoint 1 or a number of things, you would need a large number of studies that change 1 or 2 things. There are dozens of medical home trials under way. Hopefully, in a couple of years we will be in a position to say x, y, or z are necessary for a successful medical home.

news@JAMA: In light of these disappointing results for the medical home model, what do you think are the next steps for research in this area?

Dr Friedberg: We need continued experimentation, to try different combinations of medical home ingredients and to evaluate them. Then we will be in a position to refine this model and improve its success rate. I think it would be a mistake to say, based on this study, that the model can’t work.

Author Insights: Quality of Evidence Supporting FDA Approval Varies

Not all US Food and Drug Administration approvals are created equally, said Nicholas S. Downing, a medical student at Yale University, who along with Joseph S. Ross, MD, MHS and colleagues found wide variations in the quality of evidence supporting drugs approved by the agency. Image: Nicholas S Downing

Not all US Food and Drug Administration approvals are created equally, said Nicholas S. Downing, a medical student at Yale University, who along with Joseph S. Ross, MD, MHS and colleagues found wide variations in the quality of evidence supporting drugs approved by the agency. Image: Nicholas S Downing

Physicians and patients often rely on US Food and Drug Administration (FDA) approval of a drug as a sign that the medication has been thoroughly vetted for safety and efficacy. But the evidence base backing drugs that the agency approves varies considerably, according to an analysis published in JAMA today.

The authors’ analysis found that some drugs gain FDA approval based on the evidence of multiple controlled studies, while others, particularly cancer drugs, may be approved based on a single study without being compared with a placebo or another drug. One reason for the variation is that in certain circumstances, the FDA exercises more flexible drug approval pathways. For example, it may use an accelerated approval pathway for drugs to treat life-threatening diseases, or when the drug would be the first for a particular condition. But the public may not realize that not all FDA-approved drugs are evaluated based on the highest standards.

In the new work, Nicholas S. Downing, a medical student at Yale University; Joseph S. Ross, MD, MHS, an assistant professor of medicine and public health at Yale; and other colleagues analyzed data on FDA approvals for 188 drugs between 2005 and 2012 to assess the quality of evidence backing approvals. They found that on average, drugs are approved on the basis of 2 clinical trials, but there were wide variations in the number of trials supporting drugs. In addition, nearly half the drugs (45.3%) were approved on the basis of trials that used surrogate end points, clinical markers such as blood pressure, without evidence on whether the drug had a beneficial effect on actual clinical outcomes, such as preventing a stroke or reducing the likelihood of death during a specified time span.

Nicholas Downing discussed the team’s findings with news@JAMA.

news@JAMA: What do your findings say about the evidence behind FDA approvals?

Nicholas Downing: The principal finding is that there is tremendous variability. Many drugs are approved on the basis of multiple randomized controlled trials that provide very meaningful information for patients and physicians. Many were based on a single trial or on the basis of a surrogate end point, which may be less useful.

news@JAMA: Were you surprised that so many were supported by a single trial?

Nicholas Downing: One-third of drug approvals were based on a single trial. It has been traditionally understood that having multiple trials is the standard for FDA approval. Replication is one of the basic principles of science; if a study’s findings are replicated, we would feel more certain about the effectiveness of a drug. This variability isn’t always clear to physicians and patients.

news@JAMA: What does your study say about the differences in therapeutic categories?

Nicholas Downing: Some variability should be expected, given that some diseases are more serious and may need therapeutics more urgently. We would hope regulators would be flexible in speeding drugs to those patients. Some of the trials for cancer drugs tended to be single arms [not compared with a placebo or another drug] and have surrogate end points. This type of data would be considered more preliminary than data from randomized control studies used to support other drugs or drugs for other indications.

news@JAMA: Using surrogate end points rather than clinical outcomes for studies has been criticized. What does your study tell us about this practice?

Nicholas Downing: We found that just under half of drugs approved in our 8-year cross section of approvals involve trials that involve surrogate end points. There’s a real debate about surrogate end points.

news@JAMA: What do you think patients or physicians need to know about your findings?

Nicholas Downing: The principal message is that not all FDA approvals are created equally. Some new drugs have been well studied and we can be reasonably confident that the risks and benefits seen in the clinical trials will predict the risks and benefits down the road in practice. But many drugs are approved based on smaller trials that provide only preliminary evidence.

news@JAMA: What can the FDA do to facilitate better understanding of approval data?

Nicholas Downing: Our study is based on a review of documents from the FDA. These come in the form of a long document that can run hundreds of pages. It’s not a good source of information for the public. It’s difficult for physicians and patients to find. Future initiatives should seek to make the information more available. The FDA is considering creating a drug fact box, with a goal of concisely summarizing the data on the risks and benefits of a new drug. It is going to take 3 to 5 years to do this, so in the short-term it will remain quite difficult for patients and physicians to get their hands on this information.

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.