Fire up the rocket. This month I hope to stimulate debate in favor of an underrepresented group in clinical pharmacology research. Two decades ago women were underrepresented, including even female rats. We’ve made real progress. The same is true for the elderly and racial minorities, although that challenge continues, as reflected in the FDA declaring 2016 the Year of Diversity in Clinical Trials.
Children remain a group neglected by the pharmaceutical industry. They are a vulnerable and inconvenient population for medical research, especially outside the developed economies. This is a demographic which demands an individualized approach to therapy that is even more compelling than for adults.
Many children die of infectious diseases and malnutrition while others are permanently damaged. Others have inborn metabolic errors which respond well when caught early. Children, of course, contract cancer. Physicians often must guess on drug choice and dose, because there is limited supporting data and often no suitable formulation. Mixing portions of drugs with compatible (or not) “baby food” is common for parents and not well controlled. Adult formulations are often unsuitable for children in physical size, dose and excipients. Special pediatric formulations, such as liquids, require extensive regulatory review, including oral syringes for parents to use, which are then medical devices.
Self-administered protein-based drugs become more popular for adults, for example, using pumps. In children, this presents costly regulatory issues with labeling, instructions and compatibility with little hands and physical play.
There is opportunity, step-by-step, to now reduce the art and increase the science. Pharmacophenomic progress can be made today, without any speculative drug discovery. Most approved drugs compatible with pediatric disease are generic, but few have been thoroughly studied in children as N=1 individuals. The goal of individualized, data-based dosing for children also has implications for adults. The current government precision medicine initiative is largely genetics-focused and does not explicitly deal with the phenotypic reality of individuals. The likelihood of genomics solving many diagnostics challenges is very small. It is only one dimension of a multifactorial problem for which we have many new tools.
Why are children not the focus of clinical pharmacology?
- Children are not small adults. Their phenotype changes very rapidly from birth to their early 20s. This is inconvenient for scientists and statisticians alike.
- Children are generally healthy and thus represent a small market for new drugs. This is inconvenient for CFOs.
- The ethical challenges of clinical trials with children are daunting to some. Informed consent is for parents/guardians. We do not do drug trials on healthy children as we typically do for adults (Phase 1). On the other hand, adult trials will have been done first. Recruiting sufficient numbers of patients for statistical power is tough, but with better measurements you need fewer subjects.
- The rate of change in children confounds clinical trials of any length. For example, newborns vary biochemically month to month. Age is not a good metric for measured phenotype. The equivalent of a three-year trial for patients in their 40s is impossible in patients who will double in age over three years.
- While Congress and the FDA have provided incentives (extended market exclusivity) to pharmaceutical companies who add a pediatric component to trials for new drugs, the incentive is not often sufficiently compelling. There are many generic drugs that are useful in children, but most have not yet been studied in children using modern protocols before patents have expired.
- Young children are small. Neonates are tiny. This makes both physical and chemical measurements more difficult than for adults. Small blood volumes is one challenge. Children also do not have the mobility to get to a clinic on their own and most can’t describe their feelings with any precision to a caregiver as researcher.
- Because of the “tyranny of averages” from clinical trials and the significant variations in the rate of ontogeny person-to-person, children are especially subject to medical errors of drug choice and dose. Dosing in units of mg/kg of body weight is done because it is better than nothing, not because it optimizes a satisfactory result. It does not!
There are good things to say about pediatric research, though.
- The return on investment in children’s health promises to be much higher than the return on investment in the health of elderly professors like me. Preventive medicine means a lot.
- Children as a rule have avoided some of the bad habits that make studies in adults inconvenient (smoking, alcoholism, drug addiction, French fries…) and have not experienced the degenerative diseases of aging.
- Children are less subject to polypharmacy and thus have fewer drug-drug interactions or drug-induced enzymes.
To facilitate research, we are moving step by step from accumulated “art” to evidence-based medicine (decisions by averages from randomized trials) and on now to individualized medicine based on N=1 data. While physics plays a role, chemistry is more specific in healthcare research.
My own team has developed means of automatically sampling exquisitely small blood volumes in a preprogrammed, painless way that eliminates labor and reduces infection risk. This is especially important with respect to recruiting children for trials, where parental approval is crucial. Colleagues have further developed measurement technologies that are compatible with much smaller sample volumes than even a decade ago. These include several ambient ionization mass spectrometry schemes, among others. Today the required sample volumes and concentrations for quality measurements are both reduced by up to a millionfold compared to 1980.
Expertise in modeling and predicting, much of it developed from industrial engineering, is now coming into play. Healthcare is a process that is largely “out of control” because of inadequate process monitoring along the way. Proper decisions by healthcare providers are thus inhibited. Imagine operating a chemical, electronics or auto plant with such haphazard in-process monitoring.
Nutrition matters because food affects matter and the microbiome also impacts circulating drug concentrations. Today these are not adequately measured in children. Some data will improve decision-making; better, faster, cheaper data will improve decision-making more. A malnourished child in Africa will not react to a drug the way a plump, over-nourished child in Indiana will.
There are several networks of Children’s Hospitals, many of which have a research component. The NIH (through the Eunice Kennedy Shriver National Institute of Child Health and Human Development, or NICHD) has organized a pediatric trials network (PTN) and a neonatal research network (NRN) among children’s hospitals that share experiences and data.
As noted on the NICHD website: “Formed in 1986, the NICHD Neonatal Research Network (NRN) is a collaborative network of neonatal intensive care units across the United States. The NRN comprises 18 clinical centers ... The main objective of the PTN is to provide an environment and an appropriate infrastructure for conducting safe and effective pediatric clinical trials for the Best Pharmaceuticals for Children Act drug development program and for performing ancillary activities in support of these trials. The network will conduct pediatric clinical drug trials in a variety of therapeutic areas, including but not limited to cardiovascular diseases, cancer, infectious diseases, gastroenterology, respiratory diseases, neonatology, and medical devices.”
I encourage those working in drug discovery to consider pediatric applications early and often. Please also recall that many drugs used in this population were approved before the new tools became available. When you consider estate planning, consider pediatric pharmacology. After all, government contribution to R&D is far below traditions in percentage of the federal budget and as a percentage of GDP. The kids will be unaware of this until they are 30. Let’s lend them a hand now to reduce the cost of the downstream consequences of inadequate care.
[Note: On July 14, The Research to Accelerate Cures and Equity (RACE) for Children Act was introduced to Congress requiring compliance with the Pediatric Research Equity Act (PREA) of 2003. This no doubt will be debated for quite some time. Alert readers will note that the word compliance almost always implies longer R&D cycles, higher drug prices and less venture investing in research. Of course, RACE would not stimulate the optimization of generic drug use in children as described above.]
Peter T. Kissinger (who can be reached at firstname.lastname@example.org) is professor of chemistry at Purdue University, chairman emeritus of BASi and a director of Chembio Diagnostics, Phlebotics and Prosolia.