Link:  http://content.nejm.org/cgi/content/full/NEJMp0910479?query=TOC

NEJM Published at www.nejm.org November 2, 2009

Debra Birnkrant, M.D., and Edward Cox, M.D., M.P.H.

On October 23, 2009, Food and Drug Administration (FDA) Commissioner Margaret Hamburg issued an Emergency Use Authorization (EUA) for peramivir for intravenous injection (BioCryst Pharmaceuticals). Peramivir is an unapproved investigational neuraminidase inhibitor that may be effective in treating certain hospitalized adult and pediatric patients with suspected or confirmed cases of 2009 H1N1 influenza. The EUA allows health care providers to use peramivir, subject to specified conditions. This is the first EUA that has been issued for an unapproved drug.

The legal standard for the authorization of an EUA during a declared public health emergency requires a finding that it is “reasonable to believe” that the product “may be effective,” as well as a finding that its known and potential benefits outweigh its known and potential risks.¹ There must also be no other adequate, approved, and available treatment alternatives for the specific indication. This is a lower evidentiary standard than that used for marketing approval, which requires a finding of “substantial evidence” of efficacy for the proposed use based on adequate and well-controlled trials, as well as a robust safety evaluation (see table).

The FDA’s authority to issue an EUA was granted by Congress in the Project Bioshield Act of 2004. An EUA can be issued only after the secretary of health and human services has declared a public health emergency. In the case of the 2009 H1N1 influenza pandemic, such a declaration was made on April 26, 2009. An EUA for a medical product has a term of 1 year, but it can be renewed, depending on the circumstances of the emergency. It is important that product development continue to focus on the goal of approval (there are ongoing clinical trials evaluating the efficacy of intravenous peramivir in treating influenza), because the EUA is only a temporary means for making a product available during an emergency.

The FDA conducted an expedited review of the available data on peramivir, including data in preliminary or summary reports of clinical trials completed to date. Four efficacy trials evaluating the intravenous administration of peramivir have been completed; the details of these trials and information about the use of peramivir are summarized in the “Peramivir Fact Sheet for Health Care Providers” that was issued with the EUA.² A treatment benefit — alleviation of symptoms approximately 1 day sooner than with placebo — was observed after the administration of single intravenous doses of 300 mg or 600 mg of peramivir in patients with acute, uncomplicated seasonal influenza. This treatment effect is similar to that seen with currently approved oral neuraminidase inhibitors. Two other trials of peramivir were conducted using oral oseltamivir as an active control (with no placebo group). No conclusions about efficacy can be drawn from the results of these trials because they did not demonstrate that peramivir was superior to oseltamivir and a clinically meaningful noninferiority margin for such a comparison has not been established. A fourth small trial revealed no significant differences in efficacy between two different doses of peramivir or between single and multiple doses. There are very limited data available regarding the use of peramivir in seriously ill hospitalized patients. Because the 2009 H1N1 virus is a novel influenza virus, trials of peramivir have not been conducted in patients with this infection. Overall, our determination that intravenous peramivir may be effective in treating hospitalized patients with 2009 H1N1 influenza was based on the drug’s demonstrated activity as a neuraminidase inhibitor and the treatment benefit observed in patients with acute, uncomplicated influenza.

Under the EUA, the usual adult dose for peramivir is 600 mg administered intravenously once daily for 5 to 10 days. This dose was selected on the basis of findings of a treatment benefit at doses of 300 mg or 600 mg in acute, uncomplicated influenza; the expected proportionally greater exposure at 600 mg than at lower doses; and the consideration that patients with more severe disease may need a higher dose. The treatment duration was selected on the basis of the expected need for a longer duration in hospitalized patients and is consistent with the design of ongoing phase 3 trials in hospitalized patients. The available safety data, including data from the limited number of patients who received 600 mg daily for 5 or more days, supported the selection of this dose and duration under the EUA.

Only 1891 clinical trial subjects have received peramivir at any dose, in any formulation (intravenous or intramuscular), or for any duration, including 478 who received a single dose of 600 mg intravenously and 33 who received 600 mg (or more) intravenously once daily for 5 or more days. No pediatric patients have received peramivir in clinical trials. The most commonly reported adverse effects in clinical trials were diarrhea, nausea, vomiting, and neutropenia. A limited number of pediatric and adult patients have also received peramivir under Emergency Investigational New Drug (EIND) procedures.

The FDA determined that despite the limited data on efficacy and safety, the criteria for an EUA for peramivir had been met for the treatment of certain patients hospitalized with known or suspected 2009 H1N1 influenza. Specifically, it is reasonable to believe that peramivir may be effective in patients with the pandemic virus on the basis of the limited results available from trials in patients with seasonal influenza. Furthermore, the serious, and potentially fatal, nature of the disease observed to date in patients who have been hospitalized because of 2009 H1N1 influenza infection and the lack of alternative treatment options (i.e., an intravenous antiviral agent with activity against influenza) for many of these patients led to issuance of the EUA for peramivir.

The Centers for Disease Control and Prevention (CDC) is responsible for managing the drug’s distribution and has established an electronic system through which health care providers can request peramivir under the EUA (www.cdc.gov/h1n1flu/EUA/peramivir_recommendations.htm). Currently, approximately 1200 treatment courses (if all given once daily for 5 days, or 600 treatment courses, if all given once daily for 10 days) of intravenous peramivir are available for distribution; more are expected to become available over time. The CDC will distribute peramivir directly to a hospital after verification of the request from a licensed clinician.

Health care providers and patients considering using peramivir under the EUA must carefully read the “Peramivir Fact Sheet for Health Care Providers” and the “Peramivir Fact Sheet for Patients and Parents/Caregivers” to assess the limited and preliminary nature of the available safety and efficacy data.^2,3 Alternatives should be considered in making treatment decisions for individual patients who are hospitalized with 2009 H1N1 influenza.

Prescribing under the EUA is different from prescribing FDA-approved drugs (see table). Health care providers need to recognize that peramivir is an unapproved drug authorized for use only because of and during the 2009 H1N1 public health emergency. Although review by an institutional review board is not required, health care providers who prescribe the drug must fulfill certain requirements. These requirements are detailed in the “Peramivir Fact Sheet for Health Care Providers”² and include documentation in the medical record that the patient and caregivers have been given the “Peramivir Fact Sheet for Patients and Parents/Caregivers,” informed of alternatives to receiving peramivir, and told that peramivir is an unapproved drug to be used only under the EUA. Providers must also report all medication errors and selected adverse events to the FDA’s MedWatch program (www.fda.gov/medwatch/report.htm), after which the FDA may contact the provider for additional information.

Because of the severity of illness in some patients hospitalized with 2009 H1N1 influenza, it is expected that some patients may not survive, whether or not they are treated with peramivir. Furthermore, it is expected that the evaluation of adverse events will be complicated by patients’ underlying medical conditions, coexisting conditions, and use of concomitant medications. Interpretation of the safety data will be challenging and complex. The FDA will carefully assess all available data on an ongoing basis and will update clinicians and the public as we learn more about this drug’s safety.

Financial and other disclosures provided by the authors are available at NEJM.org.
Source Information

From the Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD.

This article (10.1056/NEJMp0910479) was published on November 2, 2009, at NEJM.org.

References

1. Emergency Use Authorization of medical products: guidance — Emergency Use Authorization of medical products. Silver Spring, MD: Food and Drug Administration, 2009. (Accessed November 2, 2009, at http://www.fda.gov/RegulatoryInformation/Guidances/ucm125127.htm.)
2. Emergency Use Authorization of peramivir: fact sheet for health care providers. Silver Spring, MD: Food and Drug Administration, 2009. (Accessed November 2, 2009, at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM187811.pdf.)
3. Emergency Use Authorization of peramivir: fact sheet for patients and parents/caregivers. Silver Spring, MD: Food and Drug Administration, 2009. (Accessed November 2, 2009, at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM187799.pdf.)

Link:  http://www.hhs.gov/news/press/2009pres/11/20091102a.html

News Release

Initial Results Show Pregnant Women Mount Strong Immune Response to One Dose of 2009 H1N1 Flu Vaccine

Healthy pregnant women mount a robust immune response following just one dose of 2009 H1N1 influenza vaccine, according to initial results from an ongoing clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health.

“For pregnant women, who are among the most vulnerable to serious health problems from 2009 H1N1 infection, these initial results are very reassuring,” says NIAID Director Anthony S. Fauci, M.D.  “The immune responses seen in these healthy pregnant women are comparable to those seen in healthy adults at the same time point after a single vaccination, and the vaccine has been well tolerated.”

According to the Centers for Disease Control and Prevention, since the outbreak began last spring, at least 100 pregnant women have been hospitalized in intensive care units in the United States and at the last official count, 28 pregnant women have died.

A preliminary analysis of blood samples taken 21 days post-vaccination from a subgroup of 50 pregnant women participating in the trial shows the following:

• In 25 women who received a single 15-microgram dose of the vaccine, the H1N1 flu vaccine elicited an immune response likely to be protective in 92 percent, or 23 of 25, of these women. 
• In 25 women who received a single 30-microgram dose of the vaccine, the H1N1 flu vaccine elicited an immune response likely to be protective in 96 percent, or 24 of 25, of these women. 

The trial began on Sept. 9 and reached its target enrollment of 120 volunteers in mid-October.  All participants are between 18 to 39 years old and began the study in their second or third trimester (14 to 34 weeks) of pregnancy.

At entry into the study, the participants were divided at random into two groups:  half are receiving two doses of a 15-microgram vaccine and the other half are receiving two doses of a 30-microgram vaccine.  The two injections of vaccine are spaced three weeks apart.  

Safety is being monitored closely in the trial, by the study investigators and by an independent panel of experts known as a safety monitoring committee.  To date, the vaccine appears to be well-tolerated, and no safety concerns related to the vaccine have arisen.  

The vaccine used in this clinical trial was manufactured by Sanofi Pasteur in its plant in Swiftwater, Pa., in the same manner as the company’s injectable seasonal influenza vaccine.  Like the seasonal flu vaccine, the 2009 H1N1 flu vaccine contains a purified portion of the killed virus and therefore cannot cause infection.  The vaccine does not contain the preservative thimerosal or an immune boosting substance known as an adjuvant.

NIAID is conducting this trial through five clinical sites affiliated with its longstanding clinical trials network known as the Vaccine and Treatment Evaluation Units.  For additional information about the NIAID trial in healthy pregnant women, see the Sept. 9 NIAID news release  http://www3.niaid.nih.gov/news/newsreleases/2009/H1N1pregnanttrials.htm  and related Q&A http://www3.niaid.nih.gov/news/QA/H1N1pregnanttrials.htm .

For more information on influenza, including pandemic influenza and avian influenza, visit www.flu.gov.  Also see NIAID’s influenza Web portal at http://www3.niaid.nih.gov/topics/Flu/ .

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH)—The Nation’s Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

###

When the smog lifts in Los Angeles, U.C.L.A.

But I digress…….

According to the latest research, exposure to whooping cough will provide immunity for an average of three decades.

http://omniphysicians.com/2009/11/02/whooping-cough-immunity/

This lengthy article discusses the pros and cons about teaching alternative medicine in medical and nursing schools.  The government has spent more than $22 million to help medical and nursing schools start teaching about the topic.  Whether you buy into alternative medicine or not, a significant part of the American populace use it and the healthcare professional should have some acquaintance with the good and the bad of it.

http://omniphysicians.com/2009/11/02/teaching-alternative-medicine-in-medical-schools/

The Nebraska supreme court has decided that a physician’s disciplinary history can be used in a malpractice case even though it has o direct bearing on the case.  Can supeme courts be sued for malpractice?

http://omniphysicians.com/2009/11/02/and-the-hits-keep-on-coming/

This is a FAQ about a recent CDC study on the numbers of ill in America associated with H1N1.  Through July 2009, a total of 43,677 laboratory-confirmed cases of 2009 H1N1 were reported in the United States, which is likely a substantial underestimate of the true number. Researchers in this study estimate there may have been between 1.8 million and 5.7 million cases during this time period, including 9,000-21,000 hospitalizations.  The study ended in July.  Wait until the stats come out for this fall and winter.

http://omniphysicians.com/2009/11/01/research-estimates-of-the-prevalence-of-pandemic-h1n1-2009-united-states-april-july-2009/

Paul R

The AP (11/2, Marchione) reports, “The government has spent more than $22 million to help medical and nursing schools start teaching about alternative medicine.” According to the government, “doctors need to know about popular remedies so they can discuss them nonjudgmentally and give competent advice…and many universities and medical groups agree.” But, critics contend that “students are being asked to close their eyes to science principles that guide the rest of their training in order to keep an open mind about pseudoscience.” Dr. Joseph Jacobs, former head of the federal Office of Alternative Medicine, noted, however, that “the real issue is not whether alternative medicine should be taught, but how.” The creation of the National Center for Complementary and Alternative Medicine 10 years ago is seen as having boosted the field by making “merging alternative and mainstream medicine ‘a central and overarching goal.’”

Link:  http://www.washingtonpost.com/wp-dyn/content/article/2009/11/01/AR2009110100980.html

The Associated Press
Monday, November 2, 2009; 12:00 AM

Bloomberg News (10/30, Olmos, Waters) reported, “Amylin Pharmaceuticals Inc. and Eli Lilly & Co. said safety warnings were strengthened for their diabetes drug Byetta [exenatide] relating to the risks of pancreatitis and the medicine’s use by patients with severe kidney disease.” Amylin and Lilly said patients with “severe kidney problems” should not take Byetta and the drug should be “used with caution” for those with a kidney transplant. “Six patients taking Byetta died in August 2008 from pancreatitis,” and the FDA issued a safety alert at the time. The “revised language reflects the concerns raised by the FDA a year ago,” according to Ken Wilhelm, Amylin’s medical director.

Link:  http://healthday.com/Article.asp?AID=632508

FRIDAY, Oct. 30 (HealthDay News) — Exposure to whooping cough will provide immunity for an average of three decades, new research suggests.

Doctors had previously thought that immunity lasted for much less time. But the new study, by researchers based at the University of Michigan and the University of New Mexico, rebuts that assumption.

Whooping cough, also known as pertussis, has become more common in the United States and elsewhere since the 1980s. Some health experts have thought that immunity is wearing off for people who’d been vaccinated or had been infected by the disease.

For the study, researchers used medical data from England and Wales from before a vaccine was available (1945-1957) as well as later (1958-1972). They created a mathematical model to determine how long immunity lasted after people were exposed naturally to the disease.

They found that immunity after natural infection lasts for at least three decades, on average, and maybe even as long as 70 years. The study suggests that people who lose some of their immunity might still have some protection and even gain more immunity when they’re exposed again to whooping cough.

“This is surprising because clinical epidemiologists currently believe the duration of pertussis immunity is somewhere between four and 20 years,” study co-author Pejman Rohani, of the University of Georgia, said in a news release from the publisher of PLoS Pathogens. The findings are published online Oct. 30 in the journal.

But there are caveats. “It’s worth pointing out that in the past 20 years or so, the nature of the vaccines that have been used has changed quite fundamentally,” Rohani said. “The data we’re using are from a time when a whole-cell vaccine was in use. Now an acellular vaccine, which stimulates a different part of the immune system, is typically used, especially in North America.”

Link:  http://www.washingtonpost.com/wp-dyn/content/article/2009/10/30/AR2009103003784.html

  By Lyndsey LaytonWashington Post Staff Writer
Saturday, October 31, 2009

 The 10 tomatoes sitting in a Tupperware tub at the Food and Drug Administration seem to be doing nothing more than rotting, slowly. But an invisible battle is raging on the surface of the fruit, with provocative implications for food safety and the war that humans have been waging against bacteria for a century.

American Medical News (11/2, Sorrel) reports that the Nebraska Supreme Court ruled that even though “a physician’s disciplinary history may have no direct link to a medical liability lawsuit…plaintiffs can still delve into such discipline to develop their cases.”

Nebraska “state law generally protects underlying complaints, incident reports, and materials generated during disciplinary investigations from disclosure, unless they are revealed as part of a contested hearing.” But, the court ruled that even though “the law does not specify whom the privilege was meant to protect, it does ’show the Legislature intended to balance the public’s need to know about disciplinary actions against healthcare professionals with the state’s need to encourage the reporting of unprofessional conduct.’”

Pediatric Burn Injuries Treated in US Emergency Departments Between 1990
and 2006
Anjali L. D’Souza, Nicolas G. Nelson, and Lara B. McKenzie
Pediatrics 2009;124 1424-1430
http://pediatrics.aappublications.org/cgi/content/abstract/124/5/1424?etoc

OBJECTIVE: The goal was to examine comprehensively the patterns and trends of burn-related injuries in children, adolescents, and young adults treated in US emergency departments between 1990 and 2006.

METHODS: Through use of the National Electronic Injury Surveillance System database, cases of nonfatal burn-related injuries were selected by using diagnosis codes for burns (scalds, thermal, chemical, radiation, electrical, and not specified). Sample weights were used to calculate national estimates. US Census Bureau data were used to calculate injury rates per 10000 individuals ^<20 years of age. Computation of relative risks with 95% confidence intervals was performed.

RESULTS: An estimated 2054563 patients <20 years of age were treated in US emergency departments for burn-related injuries, with an average of 120856 cases per year. Boys constituted 58.6% of case subjects. Children <6 years of age sustained the majority of injuries (57.7%), and more than one half of all injuries (59.5%) resulted from thermal burns. The body parts injured most frequently were the hand/finger (36.0%), followed by the head/face (21.1%). Of the 1542913 cases for which locale was recorded, 91.7% occurred at home. The rate of burn-related injuries per 10000 children decreased 31% over the 17-year time period.

CONCLUSIONS: Burn-related injuries are a serious problem for individuals <20 years of age and are potentially preventable. Children <6 years of age consistently sustained a disproportionately large number of injuries during the study period. Increased efforts are needed to improve burn-prevention strategies that target households with young children.

Serum 25-Hydroxyvitamin D Levels Among US Children Aged 1 to 11 Years: Do
Children Need More Vitamin D?
Jonathan M. Mansbach, Adit A. Ginde, and Carlos A. Camargo, Jr
Pediatrics 2009;124 1404-1410
http://pediatrics.aappublications.org/cgi/content/abstract/124/5/1404?etoc

OBJECTIVE: Single-center studies have suggested that hypovitaminosis D is widespread. Our objective was to determine the serum levels of 25-hydroxyvitamin D (25[OH]D) in a nationally representative sample of US children aged 1 to 11 years.

METHODS: Data were obtained from the 2001–2006 National Health and Nutrition Examination Survey. Serum 25(OH)D levels were determined by radioimmunoassay and categorized as <25, <50, and <75 nmol/L. National estimates were obtained by using assigned patient visit weights and reported with 95% confidence intervals (CIs).

RESULTS: During the 2001–2006 time period, the mean serum 25(OH)D level for US children aged 1 to 11 years was 68 nmol/L (95% CI: 66–70). Children aged 6 to 11 years had lower mean levels of 25(OH)D (66 nmol/L [95% CI: 64–68]) compared with children aged 1 to 5 years (70 nmol/L [95% CI: 68–73]). Overall, the prevalence of levels at <25 nmol/L was 1% (95% CI: 0.7–1.4), <50 nmol/L was 18% (95% CI: 16–21), and <75 nmol/L was 69% (95% CI: 65–73). The prevalence of serum 25(OH)D levels of <75 nmol/L was higher among children aged 6 to 11 years (73%) compared with children aged 1 to 5 years (63%); girls (71%) compared with boys (67%); and non-Hispanic black (92%) and Hispanic (80%) children compared with non-Hispanic white children (59%).

CONCLUSIONS: On the basis of a nationally representative sample of US children aged 1 to 11 years, millions of children may have suboptimal levels of 25(OH)D, especially non-Hispanic black and Hispanic children. More data in children are needed not only to understand better the health implications of specific serum levels of 25(OH)D but also to determine the appropriate vitamin D supplement requirements for children.

Multistate Outbreak of Salmonella Infections Associated With Small Turtle
Exposure, 2007-2008
Julie R. Harris, David Bergmire-Sweat, Julie H. Schlegel, Kim A.
Winpisinger, Rachel F. Klos, Christopher Perry, Robert V. Tauxe, and Mark
J. Sotir
Pediatrics 2009;124 1388-1394
http://pediatrics.aappublications.org/cgi/content/abstract/124/5/1388?etoc

OBJECTIVE: Turtle-associated salmonellosis was increasingly recognized in the United States during the 1960s, leading to a federal ban in 1975 on the sale of turtles <4 inches in carapace length (small turtles). Although sporadic reports of turtle-associated Salmonella are frequent, outbreaks are rare. In September 2007, several patients with Salmonella enterica serotype Paratyphi B var Java infections reported recent turtle exposure. We conducted an investigation to determine the source and extent of the infections.

PATIENTS AND METHODS: Patients with Salmonella Paratyphi B var Java infections with a specific pulsed-field gel electrophoresis pattern (outbreak strain) and illness onset between May 2007 and January 2008, were compared with healthy controls. Reptile exposure and awareness of a Salmonella-reptile link were assessed. Turtle size and purchase information were collected.

RESULTS: We identified 107 patients with outbreak-strain infections. The median patient age was 7 years; 33% were hospitalized. Forty-seven (60%) of 78 patients interviewed reported exposure to turtles during the week before illness; 41 (87%) were small turtles, and 16 (34%) were purchased in a retail pet store. In the case-control study, 72% of 25 patients reported turtle exposure during the week before illness compared with 4% of 45 controls (matched odds ratio [mOR]: 40.9 [95% confidence interval (CI): 6.9–unbounded]). Seven (32%) of 22 patients versus 11 (28%) of 39 controls reported knowledge of a link between reptile exposure and Salmonella infection (mOR: 1.3 [95% CI: 0.4–4.6]).

CONCLUSIONS: We observed a strong association between turtle exposure and Salmonella infections in this outbreak. Small turtles continue to be sold and pose a health risk, especially to children; many people remain unaware of the link between Salmonella infection and reptile contact.

Acute Heart Failure Syndromes in the Pediatric Emergency Department
Scott M. Macicek, Charles G. Macias, John L. Jefferies, Jeffrey J. Kim, and
Jack F. Price
Pediatrics 2009;124 e898-e904
http://pediatrics.aappublications.org/cgi/content/abstract/124/5/e898?etoc

OBJECTIVE: The objectives of this study were to (1) describe the clinical presentation of acute heart failure syndromes (AHFS) in the pediatric emergency department (ED) and (2) determine the physician treatment regimens and outcomes in the same population.

METHODS: This was a cross-sectional study of patients who presented with AHFS to the ED at our institution from January 2003 to October 2006. We defined AHFS as “the gradual or rapid deterioration in heart failure signs and symptoms resulting in a need for urgent therapy.” Patients were included when they had documented signs or symptoms of HF attributable to ventricular dysfunction. Patients were excluded when they were older than 21 years or had HF symptoms that were attributable to left-to-right intracardiac shunting or left-sided obstructive lesions. All eligible ED patient visits were adjudicated by a pediatric HF specialist.

RESULTS: Fifty-seven patient visits to the ED met inclusion criteria. There was a significant difference in time from arrival to treatment with a diuretic when the therapy was started in the ED rather than in the inpatient units. Median time to initiation of a vasoactive agent was significantly less for patients whose infusions were started in the ED compared with the ICU. Two patients died in the ED, and overall mortality or need for mechanical circulatory support for hospitalized patients was 18% (n = 10).

CONCLUSIONS: These data yield important insight into the clinical features and initial treatment of children who present with AHFS in the ED and may allow for improved recognition and treatment of this clinical syndrome.