FDA Lawyers Blog

The Pediatric Committee ("PDCO") of the European Medicines Agency ("EMA") is tasked with identifying the needs for children in a variety of therapeutic areas and aims to encourage the research and development of pediatric medicinal products. The first Inventory, which is now open for discussion and public consultation, covers medicines for cardiovascular diseases. The EMA points out that it will be releasing similar lists for other therapeutic areas for public consultation during 2012 and 2013.

According to the EMA, the Inventory aims to enable:

• Companies to identify opportunities for business development;

• The PDCO to judge the need for medicines and studies when assessing draft pediatric investigation plans, waivers and deferrals; and

• Healthcare professionals and patients to have an information source available to support their decisions as to which medicines.

Written by Howard E. Rosenberg, Ph.D.

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The Inventory is based on a report on the survey of all pediatric uses of medicinal products in Europe completed by the PDCO in December 2010.

There has been an increased effort to increase pediatric testing for adult medications, due to the expense of pediatric clinical trials and parent concerns about participation. For example, an alarming 70 percent of medications prescribed for children have never been tested on them, the National Institute of Health ("NIH") estimates.

In an effort to address the issue, on July 9, 2012, President Barack Obama reauthorized the "Best Pharmaceuticals for Children Act" and "Pediatric Research Equity Act" providing drug companies with a six month period of "pediatric exclusivity" if they perform studies approved by the FDA. This approval is a main proponent in easing parents' minds when allowing their own children to participate in clinical trials. In addition, such initiatives have helped incentivize sponsors to conduct more pediatric research with NIH funding for pediatric research rising by 18% "from $2.77 billion in 2008 to $3.28 billion in 2011.

Written by Brian Malkin

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Still, while improvements are on the horizon, there is much to be done to fully address the lack of pediatric clinical trials. A July 23 study in Pediatrics found a scarcity in pediatric drug trials as well. Dr. Florence T. Bourgeois, lead researcher on the new study, expressed concern that doctors have long been known to "extrapolate" findings from adult studies to then apply them to children. Bourgeois said that "children are not small adults." Due to children's developing bodies, they metabolize drugs differently than adults do. In fact, children encounter disease just as frequently, or more so, than adults, according to Bourgeois, yet "[c]hildren continue to be underrepresented in clinical trials compared with their burden of disease." Overall, just 12 percent of all clinical trials focused on children and teenagers. Yet children accounted for 60 percent of those suffering the conditions studied. Bourgeois said that more may need to be done to encourage not only drug company trials, but studies funded by non-commercial sources as well.

"One of FDA's top priorities is giving pediatricians and parents the same level of tested and researched information on drugs used to treat children that is required for drugs used to treat adults," FDA spokesperson Sandy Walsh reportedly said. "Congress has helped increase studies for children by passing legislation that gives companies financial incentives to conduct pediatric studies and to require them to study a product they are developing for adults if the disease also occurs in children," Walsh added.

The impact and influence of the Best Pharmaceuticals for Children Act and Pediatric Research Equity Act will be discussed by FDA's Pediatric Advisory Committee this upcoming September. The meeting agenda includes the discussion of pediatric-focused safety reviews as mandated by both of the recently authorized Acts.

As of 2009, 46 percent of the drug products listed in the electronic Physician's Desk Reference ("ePDR") contained information for pediatric use. While this is a substantial increase from the mere 22 percent of labels that included this information in the 1970's, more than half of all drug labels still lack pediatric-use information. This scarcity of pediatric data in drug labels was recognized at least as early as 1968, when Dr. Harry Shirkey coined the term "therapeutic orphans."

In 1975, Dr. John Wilson performed a research study on the availability of medicines for children (and pregnant or breast-feeding women). Dr. Wilson studied the labeling of approximately 2000 drugs found in the 1973 print Physician's Desk Reference ("PDR") and found that only 22 percent of these drugs included adequate pediatric labeling. For the labeling to be deemed adequate, it had to contain effectiveness and safety data in children as well as dosage information for all pediatric age groups. Regarding the 78 percent of labels that were inadequate, 16 percent contained a disclaimer for the drug's use in children (a contraindication, a "use with caution" or a "use restricted by age"), while 62 percent either did not list a pediatric dose, or only included a dose for a single age group.

Written by Julie E. Kurzrok

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Dr. Wilson published an update in 1999 which demonstrated the continuous presence of the therapeutic orphan dilemma. Between 1973 and 1991, little had changed with the PDR -- while 22 percent of drugs in the 1973 PDR had adequate pediatric labeling, the 1991 PDR had only 19 percent (most having age disclaimers). As further validation for the dilemma, Dr. Wilson presented an analysis of off-label use of various drugs that had pediatric age restrictions. Drugs such as Albuterol, Ampicillin, Zoloft, and Prozac were frequently prescribed off-label to children despite the age-disclaimer present in the label.

by Howard Rosenberg

The MHRA announced yesterday in a press release that the first ever children's medicine to hold a Paediatric Use Marketing Authorization (PUMA) had been granted by the European Commission.

For many years it has been recognized that medicines are generally developed and designed for adults with their use in children coming as an after thought. In an effort to get around this problem incentives have been developed in many countries for new medicines to be tested for acceptability in children either at the time of submission for regulatory approval or within certain time scales. The incentives generally increased the new product's patent life and/or added a data exclusivity period to slow down generic entry. However, for old medicines with no intellectual property cover there was a need to find some way to encourage the research and development of formulations acceptable to children and to incentivize companies to make these products available.

The MHRA has been pushing for an increase in the availability of specific children's only medicines for several years, particularly as in general many adult medicines are offered to children only as cut-down doses.

by Erin A. Lawrence

On November 10, FDA released 36 proposed warning labels. The images are designed to cover half of the surface area of the front and back of packs and cartons of cigarettes and to cover a fifth of cigarette advertisements. The labels contain graphic pictures and text that says, for example, "Smoking can kill you" or "Cigarettes are addictive." FDA Commissioner, Margaret Hamburg, said, "We need to make sure that anyone who is considering smoking fully appreciates the consequences of cigarette use." According to the proposed rule, cigarette manufacturers will no longer be allowed to distribute cigarettes without the graphic warnings as of October 22, 2012.

Smoking is a grave concern with striking statistics. There are about 46 million smokers in the United States--20.6 percent of adults and 19.5 percent of high school students. Approximately 443,000 people die every year from smoking-related health problems. About 49,000 people die each year because of second hand smoke. It is estimated that 30 percent of all cancer deaths are related to tobacco use. Tobacco use is the leading cause of premature and preventable death nationwide. Smoking is also a fiscal burden on the United States. According to the Center for Disease Control, the United States spends around $193 billion a year on healthcare expenses and decreased productivity and an additional $10 billion on healthcare expenses related to second-hand smoke.

Canada, Europe, and other countries already require graphic warning labels on cigarette packs and cartons. Studies suggest that graphic warnings make smokers more likely to quit and adolescents less likely to start. In Canada, graphic warnings contributed to a five percent drop in the smoking population. Smokers now account for only 13 percent of the Canadian population--down from 18 percent of the population.

FDA hired a company to survey 18,000 smokers to determine which labels would be most effective. The 36 proposed labels will be narrowed to nine by June. The tobacco companies will not be allowed to pick their preferred label--they will be required to allocate all nine warnings evenly among products.

Some cigarette companies argue that the warning label requirement infringes the companies' Constitutional rights to free speech and due process. This issue was litigated and decided on January 4, 2010 in the Western District of Kentucky in a case called Commonwealth Brands, Inc. v. United States. The court held that a blanket ban on color and graphics in tobacco labeling and advertising was overly broad and that prohibiting tobacco companies from labeling products as FDA regulated was unconstitutional. However, the court also held that Congress and FDA could constitutionally ban tobacco companies from sponsoring events, require more conspicuous labeling, ban introduction of modified-risk tobacco products without FDA approval, and ban outdoor advertising, free samples, and gifts with purchases. The case is being appealed to the Sixth Circuit.

by Brian Malkin

On August 4, Senator Sherrod Brown introduced legislation to provide additional "priority review voucher" incentives to develop innovative treatments for tropical and rare pediatric diseases. The bill, S. 3697, entitled the "Creating Hope Act of 2010" amends the Federal Food, Drug, and Cosmetic Act under section 524 (21 U.S.C. § 360n) and builds upon a similar measure added in the Food and Drug Administration Amendments Act of 2007 that only included priority review vouchers for tropical diseases and described in this guidance. The bill has been currently referred to the Committee on Health, Education, Labor, and Pensions.

Priority review vouchers entitle manufacturers to receive expedited review of another drug produced by the same manufacturer. A manufacturer, therefore, could speed FDA review of a "blockbuster" new drug, which provides a strong incentive for the development of treatments for tropical and rare pediatric diseases, including pediatric cancer. Moreover, there is no limit on the number of times a priority review may be transferred to another manufacturer before the voucher is used.

The bill defines "rare" similarly as in the Orphan Drug Act, i.e., affects less than 200,000 people or the cost of development would exceed revenue. Chagas disease was specifically added to the list of neglected tropical diseases. Whereas the 2007 measure only designated a product as qualifying for a voucher at the time of FDA approval, the new bill's process would permit sponsors to seek a designation for eligibility for the voucher prior to submitting a new drug application. Companies must submit a statement of good faith intent to market the eligible drug and a report that outlines the demand and distribution of the product. Companies, however, cannot receive a voucher for tropical disease products that they already market in other countries.