Increased pressure to conduct trials in children can be daunting when faced with practical, legal and clinical considerations found only in pediatric trials. Successfully implementing regulations and ethical standards into study conduct requires a comprehensive understanding of the unique concerns raised by ethics committees, investigators and parents.

William Kennedy, M.D., senior medical director at Genentech, answered a series of questions prepared by Marcus Evans in preparation for the 9th annual Pediatric Clinical Trials Conference, being held April 24-26 in Philadelphia. Kennedy, who has been conducting clinical trials in rheumatoid arthritis and lupus in early clinical development at Genentech for three years and previously worked in clinical pharmacology at Merck, shared his professional views on the challenges of conducting pediatric clinical trials. 

What is the top challenge faced when designing clinical trials for pediatrics?

I have been struck by the impact of medical associations in the field of rheumatology, the American College of Rheumatologists (ACR) and the European League Against Rheumatism (EULAR) in particular, to enjoin industry efforts to develop new medicines. This has led to the introduction and acceptance of new trial endpoints, ACR and DAS, in rheumatoid arthritis, the development of new endpoints in lupus, SLE Responder Index, efforts to develop instruments to measure changes in disease activity in lupus and changes in flare activity in lupus, in funding consortia to collect academic and industry placebo trial data to understand variable placebo responses across trials and to bring industry, academic and other interested parties together through annual meetings to discuss how to make advances in clinical trials generally. As the compliance rules for work between academic clinicians/scientists and pharmaceutical industry researchers become more regulated, the medical associations will become more important as independent bodies that can guide and protect the scientific exchange of ideas and global connections that are the lifeblood of scientific advances.

I believe a similar effort by the American Academy of Pediatrics would be invaluable for the work to develop new medicines for children beyond vaccines. For example, there are no recognized clinical trial endpoints for the evaluation of the benefits of pharmacotherapy in RSV trials; it is not much better for hospitalized adults with influenza. Pharmaceutical industry researchers may have some internal guidance and some external regulatory guidance for how they might develop a drug for RSV, but case-by-case programs will be limited and standardization of methodologies will be lacking. The AAP could be instrumental by advocating for appropriate drug development in children, through coordination of annual meetings to include American and European regulatory colleagues with interests in safety and pediatric medicines, and sponsorship of registries and initiatives that build medical epidemiological frameworks for pediatric diseases and drug development.

Given that there is much pressure to streamline drug development, what have you found successful when incorporating alternative endpoints into the study?

I anticipate the difficulty of success from the medical, regulatory and commercial sides early enough that when the results come out, others will be able to focus not on what the results mean, but on how they will effectively share that information for the new medicine as it moves forward in development. 

What have you found useful when standardizing how and when endpoints are measured in multi-site trials?

Intensive training of all investigators in clinical meaning of the endpoints, how the components are measured, how much the quality of the information impacts the outcome of the study, use of central, independent groups (laboratory, imaging readers, EEG interpretation, QT waveform analysis, etc.) with validated tools with known intra- and inter-observer or measurement variability.

Periodic  re-training, regional or selected site visits, sharing of interim safety data, weekly teleconferences, willingness to amend protocols based on investigator feedback on study outcome and detailed attention to the ongoing conduct of the trial are useful tools to consider.

How has the renewal of the Best Pharmaceuticals for Children Act (BCPA) and the Pediatric Research Equity Act (PREA) affected your programs at Genentech?

Broadly, the renewal of these acts is good for pediatric medicine and drug development. The neonatal development issues brought forward in the acts’ renewal is especially important.  Specifically, autoimmunity development programs at Genentech are currently not working in the arena of neonatology as part of pediatric development.  This could change in the future.