Pediatric trials for AD systemic treatments

See above: A girl with severe atopic dermatitis.  The disease ranks among the top skin conditions for impact on disease-adjusted life-years (DALY).

The expanding pipeline of drugs for the treatment of atopic dermatitis (AD) is creating excitement among dermatologists as they anticipate effective new therapies akin to the recent breakthroughs that have occurred for management of moderate-to-severe plaque psoriasis. At the same time, however, pediatric dermatology experts have been concerned about the exclusion of children from the drug development process.

See above: Eczema herpeticum incognito 

Now, after a recent meeting of the Food and Drug Administration (FDA) Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC), there is good reason to believe that the unmet medical need will be addressed regarding systemic treatments approved specifically for children with severe AD.

Elaine C. Siegfried, M.D., Dermatology Times editorial advisor and professor of pediatrics and dermatology, Saint Louis University Health Sciences Center, St. Louis, Mo., served as a temporary DODAC member for the March 2015 meeting.  She tells Dermatology Times, “Prior to the meeting, we anticipated differing opinions about the importance of including children in clinical trials. But at the end of the day there was unanimous agreement that benefits of including children outweighed the risks, and that even young children should be considered eligible to participate in trials.”

See above: AD antecubital

Dr. Siegfried also paid tribute to current leaders at the FDA whose enlightened thinking and collaborative spirit are paving the way to a better future for children with severe skin disease.

She says, “I can’t over emphasize how thrilled the pediatric dermatology community is to have leaders at the FDA like Dr. Kendall Marcus (Director, Division of Dermatology and Dental Products, DDDP) and Dr. Jill Lindstrom (Clinical Team Leader, DDDP) who recognize that children with skin disease have been therapeutic orphans and who are interested in moving forward to correct that omission.”

Dr. Siegfried observes that, historically, the FDA has always served as a strong guardian of children’s safety. More recently, however, there has been a sea-change in concepts about how best to carry out that responsibility.

She notes that a presentation at the DODAC meeting by Michelle Roth-Cline, M.D., Ph.D., Pediatric Ethicist in the FDA Office of Pediatric Therapeutics, included a slide that eloquently summarized the issue, stating, “We have evolved from a view that we must protect children from research to a view that we must protect children through research.”

Dr. Siegfried adds, “There has also been a misperception that many parents would not consent on behalf of their children to participate in trials of investigational agents because they don’t want them to be guinea pigs. However, without the quality of data on the safety and efficacy of medications possible only through prospective, multicenter clinical trials, all children treated off-label are guinea pigs.”

A productive afternoon

The open session DODAC meeting was sponsored by the DDDP. It featured several formal presentations delivered by FDA officials and industry representatives, as well as testimony from dermatologists, researchers with expertise in basic science, representatives from the National Eczema Association, parents and pediatric patients suffering with severe AD, and a series of discussions designed to address various issues relating to the conduct of future clinical trials of novel systemic products for children with AD that is inadequately responsive to topical therapy. Questions explored during the discussions include:

• How much evidence of treatment effect and safety should be obtained in adults prior to conducting studies in children?

• How much uncertainty about the potential risks and benefits is tolerable when initiating a pediatric trial?

• What are the features of the appropriate pediatric population in whom to study systemic treatments so that risks and potential benefits of investigational agents can be compared to the population receiving currently available alternate treatments?

• Should older pediatric subpopulations be studied prior to or concurrently with younger pediatric subpopulations?

Lawrence Eichenfield, M.D., chief of Pediatric and Adolescent Dermatology, Rady Children’s Hospital, San Diego, Calif., spoke as a representative for Regeneron-Sanofi, but prior to the meeting he also obtained unanimous support for including children in AD clinical drug trials from non-industry stakeholders. Those groups included the American Academy of Dermatology, Society for Pediatric Dermatology, the International Society of Atopic Dermatitis, and the National Eczema Association.

Heartfelt testimony from young patients with severe AD was particularly compelling in bringing forth the impact of the disease on affected children and their families.

READ: Developments in management for atopic dermatitis

“Considering 15 skin conditions using disability-adjusted life years to measure burden, the 2010 Global Burden of Disease Study found ‘dermatitis including eczema’ ranked number one. Yet, until recently, there has been relatively little interest in drug development for this common, often debilitating disease,” says Dr. Siegfried.

“Although interest is growing, the fact remains that AD affects many more children than adults. With that in mind, pediatric dermatologists have been concerned about exclusion of children from investigational research of new drugs that have the potential to better control their disease. We have been struggling for generations to make the best treatment recommendations for children with severe AD.  Finally, we have hope for the chance to offer them better options in the foreseeable future.” 

NEXT: The path forward

The path forward

Seven years ago, as chairman of the Environment and Drugs Committee of the American Academy of Dermatology, Dr. Siegfried began to explore mechanisms to facilitate inclusion of children in the new drug development process.  At that time, she became aware of the FDA Code of Federal Regulations on Good Guidance Practices¹ (GGP's), including the FDA’s policies and procedures for developing, issuing, and using guidance documents.  Article 10.115 of the Federal Register² defines a guidance document as a tool “prepared for FDA staff, applicants/sponsors, and the public that describe the agency’s interpretation of or policy on a regulatory issue. Guidance documents include, but are not limited to, documents that relate to: the design, production, labeling, promotion, manufacturing, and testing of regulated products...”

READ: Latest advice on managing atopic dermatitis

Dr. Siegfried initiated her efforts in the early days of new drug development for psoriasis, after recognizing a general reluctance to include children in trials, as well as suboptimal design and lack of standardization among the few studies that were enrolling children. 

“Over the years, we have implemented several action items to further the process of developing a guidance document that could be adopted by the FDA and used by industry as a framework for pediatric drug trial planning. The recent DODAC meeting has been the most positive step towards acknowledging our efforts, and we are looking forward to working together for the benefit of children with severe AD."

With funding and administrative support from the National Eczema Association and the Pediatric Dermatology Research Alliance, and encouragement from the FDA, Dr. Siegfried and colleagues are hoping to organize a group of individuals with wide-ranging expertise in clinical trial design relevant to investigation of medications for AD in children. Although it may be ambitious, she hopes a draft that can be submitted to the FDA for review and that revision will be completed within a year.

“The FDA has final say on the content of its guidance documents, so FDA review and acceptance are required,” says Dr. Siegfried. “However, we are very pleased that the FDA DDDP leadership is receptive to extramural input. Working together in a positive and cooperative way will ultimately lead to development of the best products.”

In the meantime, Dr. Siegfried expects there will be an ongoing dialogue about the issues of pediatric AD drug development and that companies involved in this area of research will be approaching pediatric study plans with increased interest and effort. 

NEXT: References

Disclosures:

Dr. Siegfried serves as a consultant for Valeant, Promius, Pierre-Fabre, Boeringer-Ingelheim and Celgene, and as a principle investigator for Pierre-Fabre, Anacor and Amgen.

References:
1. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=10.115 draft
2. http://www.gpo.gov/fdsys/pkg/FR-2000-09-19/pdf/00-23887.pdf