Genomic complexity slows childhood disease research

By Mari Edlin

The trend toward personalized medicine for children is an evolutionary process, according to the authors of “Genomics, Personalized Medicine and Pediatrics,” published in Academic Pediatrics (January/February 2014). 

They attribute the slow pace to the complexity of genomics; uncertainty regarding the clinical benefits of new and often expensive applications; a myriad of health and social issues confronting patients; and the hesitation among some physicians to apply genomics to many pediatric settings.

However, experts are optimistic. Brian Crompton, M.D., a pediatric oncologist at  Dana-Farber/Boston Children’s Cancer and Blood Disorder Center, says he is positive about the progress of using genomics to sequence tumors and find mutations more easily and at a lower cost. He expects that those results will lead to a better understanding of what drives cancer and how to treat it,  and expand research to include children. 

He says that although it is more difficult to conduct large studies to uncover all the changes expressed by genes in children because of fewer existing mutations, the cells in children are less accumulated for mutations due to age and environment, making it easier to find real drivers and treatment for pediatric tumors. 

“My dream is to find a mutation and match it with treatment, providing a higher rate of cure with a less toxic regimen,” he says.

Legislation prompts more clinical trials in children

Although personalized medicine for children is not in revolutionary mode, it is gaining momentum. However, it does not yet match the research dollars devoted to adults. 

Since 1997, the rules of the game have changed, starting with a provision to provide marketing incentives to drug manufacturers to conduct studies of drugs in children-part of the Food and Drug Administration (FDA) Modernization Act. The law was reauthorized in 2002 and extended through 2007 as the Best Pharmaceuticals for Children Act (BPCA). Its exclusivity provision allows companies to qualify for an additional six months of marketing exclusivity in return for conducting studies as requested by the FDA. 

The Pediatric Rule, passed in 1998, requires pediatric studies to evaluate the safety and effectiveness of new drugs and biological products in pediatric patients. In 1999, additional legislation required manufacturers of certain new and marketed drugs and biological products to conduct studies to provide adequate labeling for the use of these products in children.

Under the 2003 Pediatric Research Equity Act (PREA), the FDA can require pediatric studies of a new drug application if the FDA decides that a product is likely to be used in a substantial number of children, or would provide a meaningful benefit compared with existing treatments for children. Both PREA and BPCA were reauthorized in 2012 and are part of the Food, Drug and Cosmetic Act.

The Pediatric Rule and exclusivity provision have resulted in label changes that provide guidance to physicians for use in children for more than 80 drugs. Prior to the passage of the BPCA and PREA, more than 80% of drugs approved for adults were being used in children; however, the safety and effectiveness of those drugs had not been confirmed for the younger population.

The FDA considers this to be one of the causes of the “pediatric knowledge gap,” a term used to describe the disparity in pediatric research and the resulting lack of child-specific drug development. 

Pediatric research barriers

The FDA has acknowledged that the study of drugs in children has been discouraged due to ethical issues, concerns about testing new drugs on a vulnerable population, increased liability, inefficiencies tied to testing clinical trial drugs on an insufficient population and lack of legislation requiring drug makers to conduct pediatric trials.

The result has been limited access to potentially life-saving drugs for children, and off-label prescribing for drugs with limited knowledge of how they could affect children. The attitude that “children are just small adults” is widespread, leading to smaller doses of adult medications for children.

The challenge often comes in translating results from clinical trials on adults to children when the same condition might be caused by entirely different factors. For example, atrial fibrillation in an adult might induce a blood clot, while it is rarely the cause of a clot in children.

Dan Housman, chief technology officer for ConvergeHEALTH, a business unit of Deloitte Consulting, says it’s more difficult to understand the reaction of drugs in children who are not yet fully developed. 

“Children might benefit from trial results for medications used by adults, but there is concern over the potential for harmful side effects,” he says.

Housman attributes the lack of research on children to drug manufacturers, who find it is economically not viable to invest in products for diseases affecting a small percentage of the population, not to mention getting consent from patients too young to make an informed decision.

Gregory Kearns, PharmD, associate chairman of the department of pediatrics and director of the pediatric pharmacology research unit at Children’s Mercy Hospitals and Clinics in Kansas City, Missouri, also notes that children are usually healthy and often experience acute situations and self-limiting conditions rather than chronic diseases. 

Cancer corners market 

Of all the diseases affecting children, cancer is the most researched. Children’s Mercy and Dana-Farber/Boston Children’s Cancer and Blood Disorders Center are two institutions taking the lead. 

Twenty years ago, Children’s Mercy decided to specialize in pharmacology and therapeutics and has developed a stand-alone clinic and a program on experimental therapeutics to explore medications for children through research and to support decision-making.

Dana-Farber developed a personalized medicine initiative called Profile that is analyzing 471 mutations in 41 genes for all types of cancer. The goal is to detect genetic alterations in tumors and potentially identify targeted therapies that are most likely to be effective in individual patients.

The institution has enrolled pediatric patients in its individualized cancer therapy (iCAT) to study tumors for specific genetic alterations that might allow doctors to identify a treatment targeted to their cancer. 

“Children are a more vulnerable population and more complex as they age, and personalizing medicine depends on their growth and development,” says Kathleen Neville, M.D., MS,  director of experimental therapeutics in the pediatric oncology program at Children’s Mercy.

She says that genomic testing for children focuses on whether a gene exists rather than on gene expression used in determining appropriate medications. 

“Once a gene is identified, can we use that information to find ways to treat a cancer?” Crompton says. He believes that personalized medicine today focuses on genetic profiling of tumors, not on patients. 

“Today, we are using genomic information to profile risk, efficiency and expectations of a given drug,” Kearns says. “We need to harness the expertise of physicians, researchers and pharmacology to choose the right medication and tailor the dose. The way of the future is not one-size-fits-all.”

Neville applauds the American Academy of Pediatrics (AAP) for supporting clinical research on children. Last year, the academy issued new guidance on genetic testing of children calling for mandatory testing on newborns but allowing parents or guardians to opt out once they are informed of benefits and risks. The AAP also recommends testing with parental consent for children at risk of childhood-onset conditions, and when feasible, with the child’s consent.

Erik Deurell, M.D., senior medical director for INC Research, a phase 1 to 4 clinical research organization in Raleigh, N.C., says, “Children are not small adults nor are infants small children, so there is a need to look at new ways of providing medications: liquid formations versus pills, dissolvable tablets, multi-dose inhalers, derma patches and potable water if a solution requires mixing.”  

Mari Edlin is a freelance writer based in Sonoma, Calif.