Paediatric Prescribing: Questionable Science and Ethics
On the cold night of 23rd February 1994 Karlee, from Rouleau, Canada, ventured out of her home in search of her dad. Karlee, just two at the time was found frozen in the morning. She had spent an estimated five hours in temperatures thought to be around -22 °C. Her mother tried unsuccessfully to resuscitate her.
In February 2001, thirteen month-old Erika Nordby was discovered in the snow outside her home in Edmontion. When found, her feet were frozen together and she had no pulse. Arriving at hospital, she was pronounced clinically dead.
Both children recovered because children’s body temperature decreases quicker than adults’, as does their metabolism.
These are just two differences, though significant, between children and adults; so why does the FDA state: “Most drugs prescribed for children have not been tested on children… doctors have routinely given drugs to children ‘off-label’…” meaning the drug hasn’t been approved for children based on safety and efficacy as demonstrated in randomised clinical trials.
The FDA website gives some reasons – or excuses – for the lack of scientific testing of paediatric drugs. Primarily, drug companies, we are told, view children “as a market that would bring only small financial benefits.”
Without any science for paediatric prescribing, “We take our best guess based on what’s been done before,” admits Dr Jeffrey Blumer, chief of pediatric pharmacology at Case Western Reserve University in Cleveland.
The tendency has been to give half the adult dose, the FDA continues, but “… this trial-and-error approach has also resulted in tragedy, indicating that adult experiences with a drug aren’t always a reliable predictor of how children will react.” With the huge revelation, Dr Ralph Kauffman (director of medical research at Children’s Mercy Hospital) is quoted as saying: “… We need to study drugs in children because they aren’t small adults.” “It’s not just about smaller weight,” he’s further quoted, saying, “There are dynamics of growth and maturation of organs, changes in metabolism throughout infancy and childhood, changes in body proportion, and other developmental changes that affect how drugs are metabolized.”
To facilitate research, the FDA took a two-pronged approach; facilitating research and demanding certain standards. The facilitation was initiated with the Food and Drug Administration Modernization Act of 1997 (FDAMA) which was reauthorised in 2002 and extended through 2007 as the Best Pharmaceuticals for Children Act (BPCA) provided a voluntary exclusivity provision allowing companies to qualify for an extra six months of marketing exclusivity if they do the studies in children as requested by the FDA.
The demanding side of the deal is the Pediatric Research Equity Act (PREA), which allows the FDA to require paediatric studies.
The FDA, however, has been very generous in interpreting the BPCA. Not only is the drug studied in the paediatric population to receive this extra exclusivity, but so too are any of the drug company’s formulations, dosage forms and indications that contain the same active part of a molecule.
The FDA can issue a “Written Request” regarding studies: requirements, goals and age groups. Again, “no matter how studies are initiated, if the data submitted fairly respond to the Written Request, then the company gets its six month paediatric exclusivity.
The FDA article quotes Dr Kauffman as saying: “the exclusivity is proof that economics plays a large role in the lack of pediatric studies.”
The FDA tells us it implemented voluntary measures in the’90s to encourage paediatric studies which were largely a failure. The rule was re-written in 1997, finalised in 1998 and the first studies were expected in 2000. Unsurprisingly, the pharmaceutical industry opposed the rules:
The rule, however, had its critics. In December 2000, the Association of American Physicians and Surgeons, the Competitive Enterprise Institute, and Consumer Alert filed a lawsuit against the pediatric rule, challenging the FDA’s legal authority to require pediatric studies. And in October 2002, a federal district court concluded the FDA did not have that authority and the rule could not be enforced.
Former HHS Secretary Tommy G. Thompson responded in mid-December 2002 by announcing that his department would push for rapid passage of legislation that would give the FDA authority to require pharmaceutical manufacturers to conduct appropriate pediatric clinical trials on drugs.
The European experience has been similar though late in the history of medicine to demand a bit of science from drug manufacturers. It was only on 7th September 2005 that the European parliament approved new rules – as opposed to laws – that would oblige drug companies to design and test drugs for children, rather than just giving them a reduced adult dose.
The 2016 updated version of the FDA website puts a more positive spin on the improvements in paediatric prescribing yet a paediatric nurse reacted with: “so why are we weighing children?” Exactly! Children continue to be erroneously and dangerously treated as small versions of adults.
The important question is: have these improvements disseminated into the practice of medicine and dentistry? An effort has been made – in spite of the drug companies rather than with them – but only a small percentage of medicines are licensed for children and when the FDA article still confesses: “Most children receive their cancer therapy as part of a clinical trial,” it neither inspires confidence nor does it sound much like hard science, does it?
1. FDA, “Drug Research and Children”, https://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143565.htm
2. Articles on the licensing of children’s medicines seem to say more by what they don’t say! (link)
Photo credits: Wikimedia: https://commons.wikimedia.org/wiki/File:Three_Card_Monte.jpg