FDA Issues Warnings to Makers of Topical Ibuprofen Products

The Food and Drug Administration issued warning letters to eight companies marketing unlawful over-the-counter topical drug products containing the pain reliever ibuprofen. The products, which contain ibuprofen in combination with a variety of other active ingredients and are marketed for pain relief, are unapproved new drugs that require an approved new drug application in order to be legally marketed.

Orally administered ibuprofen has been approved as a safe and effective treatment for pain and inflammation. There are no approved applications for topical ibuprofen products. Although the FDA has proposed to add orally administered ibuprofen to the applicable OTC monograph, it has never proposed that topical ibuprofen be added to any OTC monograph. Topical ibuprofen is often promoted as a “safer” alternative that can be used in place of oral ibuprofen because of certain side effects such as stomach ulcers and cardiovascular effects that are associated with prolonged use of oral ibuprofen. However, these safety claims for topical ibuprofen have not been reviewed by the FDA, nor has the agency evaluated what side effects might be associated with such products.

The names of the products and manufacturers that received warning letters are: Emuprofen, BioEntopic 15% Ibuprofen Crème, Ibunex Topical Ibuprofen, LoPain AF 15% Ibuprofen Crème, IB-RELIEF, Profen HP, IbuPRO-10 Plus, IBU-RELIEF 12. The FDA warning letters advise the companies that they may not continue to market their products without FDA approval. The FDA is requesting a written response from the companies within 15 business days of receipt of the warning letters stating how they will correct these violations and prevent similar violations in the future.

Accelerated Approval Given to Hib Booster

Last month, the Food and Drug Administration approved Hiberix, a Haemophilus influenzae Type b (Hib) vaccine, as a booster dose for children 15 months through 4 years old. Hiberix is manufactured by GlaxoSmithKline, with US headquarters in Research Triangle Park, NC, and Philadelphia.

A nationwide shortage of Hib vaccine began in December 2007 due to a voluntary recall by the manufacturer and subsequent production suspension of PedvaxHIB and COMVAX, two of four vaccines licensed in the United States for primary and booster immunization against invasive disease due to Hib. Both PedvaxHIB and COMVAX vaccines are manufactured by Merck & Co. Inc. (Whitehouse Station, NJ).

This shortage resulted in a recommendation by the Centers for Disease Control and Prevention to temporarily defer the Hib vaccine booster dose for children who were not at high risk for infection, until the vaccine supply could be restored. This deferral was in effect from December 18, 2007, through June 25, 2009.

According to FDA, the current vaccine supply is sufficient to reinstate the booster dose and begin catch-up vaccination, but is not yet ample enough to support mass vaccination of all children whose boosters were deferred. Before the availability of Hib vaccines, Hib disease was the leading cause of bacterial meningitis among children under 5 years old in the United States. Hib disease can also cause pneumonia, severe swelling in the throat, infections of the blood, joints, bones, and tissue covering of the heart, as well as death. Hib disease is spread through the air by coughing and sneezing.

Hiberix is used in nearly 100 countries. The FDA based its conclusion that Hiberix is safe and effective for use as a booster dose in certain children in the United States on data from seven clinical studies conducted in Europe, Latin America, and Canada that involved more than 1,000 children. As part of the approval, the manufacturer, GlaxoSmithKline, will conduct a post-market study in the United States to evaluate the safety and immunogenicity of primary and booster vaccination with Hiberix compared to a Hib vaccine already licensed in the United States. The study is intended to confirm the clinical benefit of booster immunization with Hiberix in accordance with the accelerated approval regulations, and to provide additional data on Hiberix for young infants.

Baby Boomers Continuing Drug Use Into Later Years

Many baby boomers (Americans born between 1946 and 1964) are continuing to use illicit drugs as they grow older, causing the rate of illicit drug use to go up within the 50-to 59-year-old age segment of the population. According to a new analytical publication produced by the Substance Abuse and Mental Health Services Administration, those aged 50 to 59 reporting use of illicit drugs within the past year has nearly doubled from 5.1% in 2002 to 9.4% in 2007, while rates among all other age groups are statistically staying the same or decreasing.

An Examination of Trends in Illicit Drug Use among Adults Aged 50 to 59 in the United States is the first in a series of new scientific reports being published periodically by SAMHSA’s Office of Applied Studies that will provided detailed analyses on important substance abuse and mental health issues challenging the nation.

The report analyzes many aspects of this phenomenon, including the types of illicit substances involved, different demographic and behavioral factors associated with higher rates of use, and other issues. The data used in the analysis comes from a wide range of sources including 16,656 respondents aged 50 to 59 participating in the 2002 through 2007 National Surveys on Drug Use and Health—the nation’s premier national public health survey of its kind. The full report is available on the web at http://oas.samhsa.gov.

Researchers Sequence Exomes of Twelve People

In a pioneering effort that generated massive amounts of DNA sequence data from 12 people, a team supported by the National Institutes of Health has demonstrated the feasibility and value of a new strategy for identifying relatively rare genetic variants that may cause or contribute to disease. The proof-of-concept findings were published online last month in the journal Nature.

The new strategy involves isolating and sequencing all exons which are the parts of the human genome that contain the information needed to produce proteins, the building blocks of the body. The complete set of exons—referred to as the “exome” —makes up only 1% of the human genome. By selecting only the exome to sequence, the important information about an individual can be obtained at a much lower cost than sequencing a person’s entire genome. Assessment of the results of exome sequencing is based on knowledge of the genetic code and allows for a more informative interpretation of genetic variants. Using the exome strategy, like other methods of direct DNA sequencing, investigators also can detect rare variants that typically provide a stronger indication of disease susceptibility.

The research, conducted by scientists from the University of Washington in Seattle and Agilent Technologies in Santa Clara, CA, was funded by the National Heart, Lung, and Blood Institute, the National Human Genome Research Institute, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. It was carried out as part of The Exome Project, a program jointly managed by the NHLBI and the NHGRI that was established to develop, validate, and begin to apply a cost-effective, high-throughput approach for exome sequencing that can be deployed in large, well-phenotyped human populations.

To demonstrate the utility of their approach, researchers focused on the exomes of eight people (four Yoruba, two East Asians, two European-Americans), whose DNA had previously been characterized by the International HapMap Project. The HapMap Project was an effort that produced a comprehensive catalog of common human genetic variation across the human genome. In addition, the study included four unrelated people with Freeman-Sheldon syndrome, a rare inherited disorder caused by mutations in the MYH3 gene, to see if exome sequencing had the power to detect the MYH3 mutations known to exist in their DNA. The researchers began by shearing the 12 samples of genomic DNA into fragments and then using special probes to capture only those fragments that contained exons. The resulting 12 collections of exomes were then sequenced and analyzed. Altogether, the project determined 300 million bases of DNA sequence—the largest data set reported so far of human coding sequence produced by more advanced second-generation sequencing technologies.

Comparison of the exome sequences to the publicly available human genome sequence highlighted the sensitivity of this technique for detecting genetic variations, both common and rare. The investigators were able to identify a range of these DNA misspellings such as rare and common single letter variations known as single nucleotide polymorphisms, or SNPs, and insertions and deletions of sequences within genes.

From the DNA of the four people with Freeman-Sheldon syndrome, the researchers were able to pinpoint the causal genetic variant by applying a multi-step systematic strategy to filter out common variants and variants that were specific to each individual. The findings demonstrate that sequencing the exomes of a small number of unrelated individuals with a disorder that is due to a single gene can serve as a genome-wide scan for the causative gene. Within large population studies, the researchers suggest that exome sequencing could be used to uncover genes that contribute to the risk for more common, multigenic diseases such as diabetes or cancer.

Gene Therapy Patients Maintain Visual Improvement One Year Later

Three young adults who received gene therapy for a blinding eye condition remained healthy and maintained previous visual gains 1 year later, according to an August online report in Human Gene Therapy. One patient also noticed a visual improvement that helped her perform daily tasks, which scientists describe in an Aug 13 letter to the editor in the New England Journal of Medicine.

These findings emerged from a phase I clinical trial supported by the National Eye Institute and conducted by researchers at the University of Pennsylvania, Philadelphia, and the University of Florida, Gainesville. This is the first study that reports the 1-year safety and effectiveness of successful gene therapy for a form of Leber congenital amaurosis (LCA), a currently untreatable hereditary condition that causes severe vision loss and blindness in infants and children.

The three patients in the study—aged 22, 24, and 25—have been legally blind since birth due to a specific form of LCA caused by mutations in the RPE65 gene. The protein made by this gene is a crucial component of the visual cycle. The RPE65 protein is necessary for the production of a retina-specific form of vitamin A that is required for the light-sensitive photoreceptor cells to function. Mutations in the RPE65 gene prevent this production, which halts the visual cycle and blocks vision. The RPE65 disease offers an opportunity for treatment in that it leaves some photoreceptors intact. In this study, researchers pinpointed an area of intact photoreceptors in the retina of each patient. They injected healthy copies of the RPE65 gene under the retina in this area in an attempt to repair the visual cycle.

One year after the procedure, the therapy had not provoked an immune response in the eye or in the body. Though the patients’ visual acu

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