Rare Pediatric Disease Research Faces Market, Scientific Barriers

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WASHINGTON, DC—Over the last several years, federal agencies have made a concerted effort to direct research and funding to those rare diseases that might not get attention if left to the whim of market forces. For rare pediatric diseases, the challenge can be even greater.

FDA defines a rare disease as one that affects fewer than 200,000 Americans. According to NIH, there are 6,800 rare diseases affecting 25 to 30 million people. Most of these conditions have no treatment or cure, and companies are unlikely to undertake experimental and lengthy research to develop drugs with which they will never see a full return on their investment.

Pediatric disease research sees the same disincentives that apply to other rare disease research. Also, treating children creates unique issues due to their size, metabolic rate, and their growth.

Tackling Scientific and Market Hurdles

Congress has created incentives in recent years to coax researchers and drug companies to tackle these rare diseases. The Orphan Drug Act, passed in 1983, provides tax credits, grants for clinical testing expenses, and waivers of FDA application fees and annual product fees for companies developing drugs for rare diseases.

There have also been similar incentives for pediatric diseases. The Pediatric Research Equity Act gives FDA authority to require studies in children for certain medical products. The Best Pharmaceuticals for Children Act encourages manufacturers to conduct pediatric studies by extending exclusivity for drugs already on the market.

The goal of these bills has been to level the playing field and give rare diseases—pediatric and adult—a more even chance to find funding and support. At a Senate Health, Education, Labor, and Pensions Committee hearing last month, legislators and federal officials credited such efforts with leading to increases in rare disease research, but admitted that there are still barriers.

“We’ve worked tirelessly to pass the NIH reform act to end a funding structure that targeted specific disease in response to political rather than scientific reasons. [It] should be based on research and not popularity. If it was based on popularity, probably the Senate would put all the funding into prostate cancer,” quipped ranking Republican Sen Mike Enzi, R-WY. “If a rare disease is defined as one impacting less than 200,000 individuals, then we’re talking about a group that has significantly smaller lobbying force to request increases in funding, which is not a fair or scientific process for determining funding allocations.”

Even if given huge influxes of cash and an army of researchers, answers might still be a long time in coming. “There’s really two big barriers to getting products,” explained Jesse Goodman, MD, FDA’s chief scientist. “The first is market incentives are not always clear, as we’ve heard about. But second, is that there are some serious scientific challenges to translating basic science and getting enough basic science to translate ideas and concepts into products.”

He cited well-researched diseases such as malaria, TB, and HIV. Despite considerable efforts to understand and combat these diseases, there are still considerable knowledge gaps. “We still don’t have a lot of clear answers,” Goodman admitted. What makes these diseases so good at infecting people is also what makes them so hard to develop vaccines and drugs against.”

He noted that Congress’s efforts have helped considerably. There are many more studies being done on pediatric diseases now that there is legislation firmly in place promoting it. “Before this legislation, 80% of products had no information about pediatric uses, forcing clinicians to essentially [do] their best and guess,” Goodman explained. “Today we still have a lot of work to do, but pediatric information is now routinely included in product labeling.”

Working with Industry

“Children are not just small adults,” Goodman declared. “We need a lot of data about their diseases.”

He could not stress enough the FDA’s willingness to work with industry to help gather that data and help bring new treatments to market. The conception of FDA being a barrier to approval rather than a facilitator needs to be done away with, he told the committee. “If a product is promising, FDA wants to work with product developers to make sure it succeeds in the product development process. The problem here is that there simply aren’t enough effective products being developed.”

FDA sponsors a significant amount of outreach and training when it comes to how to develop products for rare diseases and developing clinical trials. One course recently held online had 1,500 participants, Goodman said.

The agency is also committed to being as flexible as possible when it comes to developing these products. That includes accepting data from relatively small clinical trials, and often from only one trial on a product. FDA is also anxious to discover more surrogate biomarkers that can allow scientists to predict a drug’s effectiveness more quickly and not have them waiting for the culmination of lengthy clinical trials.

“That doesn’t mean that we’ll accept every proposal that a sponsor makes, but we want [to be] open to those proposals,” Goodman said. “These initiatives are very labor intensive for FDA, but the more we can work with sponsors early on to identify and solve problems, the higher chance we have of success.”

Targeting Research

“One of my former patients, Kevin Hartman, is now a young adult with Marfan syndrome‚Äîan inherited rare disorder that impacts the body’s connective tissue,” Alan Guttmacher, acting director of the National Institute of Child Health and Human Development, told legislators. “The most serious manifestation of the diseases is that the aorta can become distended and stretched so thin that it tears, requiring emergency surgery, or even resulting in sudden death.”

Individuals with Marfan syndrome are counseled to avoid stress to their heart, including any sort of physical activity, Guttmacher stated. When Kevin was still a young child, the only drug that was known to combat this effect were beta-blockers, which were not very successful.

In 2008, a small study using the drug losartan showed promising results in slowing the rate of aortic enlargement in children with Marfan syndrome. On the basis of those findings, the National Heart, Lung, and Blood Institute has initiated a larger, multisite trial. “The availability of medication to inhibit aortic tearing and slow its growth would have tremendous impact on Kevin and the other children with Marfan syndrome,” Guttmacher declared. “Kevin hopes that this kind of approach will enable him to avoid the serious surgical complications that his father had from the same condition.”

Similar examples of NIH taking the lead in research on rare pediatric diseases can be found across the agency. In 2009, NIH funded nearly $3 billion in pediatric research, including $86 million in grants in the orphan drug category.

“Developing and testing drugs in children has always represented a particular challenge because of children’s vulnerabilities, [Congress has authorized NIH] to identify pediatric research gaps and help fill them,” Guttmacher noted.  

Some of the greatest leaps forward have not been in any one particular disease but in the culture surrounding basic science research. He cited the Human Genome Project as an example. Every 24 hours, the research data developed from the project was made publically available online. “This changes the culture that says data that is derived from biomedical research that’s funded by the federal government does not belong to the principal investigator, but it belongs to society,” Guttmacher stated. “This is particularly important when we talk about rare diseases, where there will be a relatively small number of researchers involved. It’s particularly important that they work collaboratively to tackle this. I think it also has caused NIH to think of new and creative ways to work across the silos that are the NIH institutes.”

Rare pediatric diseases are rarely contained within the purview of a single NIH institute. In the case where a condition requires institutes to work together, NIH researchers form a trans-NIH working group. Such was the case of research being conducted into Fragile X Syndrome, the most common inherited cause of intellectual and developmental disabilities. Nine participating NIH institutes meet regularly to discuss the implementation of the Research Plan on Fragile X and Associated Disorders, which the group developed and published in 2008.

Each goal outlined in the plan is being addressed by grants funded by member institutes. One example is a Phase I trial of a novel drug that may effectively compensate for the missing protein in individuals with the disease. If results suggest the medication is safe and tolerable, a Phase II clinical study of dosage and efficacy in adults will be planned. Should the results from these adult trials prove promising, the compound will be assessed for pediatric safety and clinical trials in children.

Another program targeting such diseases is the Therapeutics for Rare and Neglected Diseases Initiative (TRND), which was launched in 2009. NIH researchers begin with a chemical compound, testing its effectiveness on a rare disease in the hopes that it will be successful. The compound would then progress to become a candidate compound for a new drug application. Often the candidate compound will be licensed to pharmaceutical companies for clinical testing, permitting the TRND program to remain focused on the more scientifically challenging stages of preclinical development.

The goal, according to Guttmacher, is to “de-risk” development of new drugs for less common diseases and make them more attractive to private companies, while at the same time advancing the entire research enterprise by allowing open dissemination of information during initial testing phases.

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