Drug Regulations and the Paediatric Promise
The introduction of the sulphonamide antibiotics to clinical practice
also indirectly had a major impact on drug regulation. While drugs have
been regulated in the UK since 1540 – initially under the Apothecaries
Wares, Drugs and Stuffs Act – the primary focus of concern, as was the
case drug regulatory agencies in most countries up to the early
20th century, related to identifying commercial
preparations for the purpose of securingpatent and proprietary rights.
Early regulatory frameworks paid little attention to the efficacy or
safety of approved medications, notably with respect to use in children.
A classic case study of this disregard is the approval of a product
known as Dr. James Soothing Syrup Cordial, advertised as a cure for
cholera infantum or infectious diarrhoea and suggested for use for colic
and teething pain (11). The active ingredient in Dr. James Soothing
Syrup Cordial was heroin – which the company claimed was not habit
forming. Other examples include cocaine drops marketed for teething pain
and marijuana cigarettes, listed on the US Pharmacopeia for headache.
Following the introduction of the first sulphonamide preparations on the
market, it became clear that the very large commercially available
tablets were difficult for children to take, especially children under
the age of six. To address this problem, a chemist at S.E. Massengill
dissolved sulfanilamide in diethylene glycol, an effective solvent and,
unfortunately, a potent nephrotoxin. With the addition of pleasantly
flavored raspberry syrup, the liquid sulphonamidewas then marketed as
Elixir of Sulfanilamide in September of 1937. Although the toxicity of
diethylene glycol was known –and had been documented – since 1930,
this had not been appreciated by the development team at Massengill. In
addition, prior to commercializing the product or obtaining approval to
market, no animal testing was performed and no rigorous safety appraisal
was completed, as neither were required for such testing at the time–
and Sadly, very shortly after Elixir of Sulfanilamide became available,
a number of patients – mostly children – sustained significant renal
injury and more than 100 died (11, 12). The public outrage following
this event lead to the development and passage of the 1938 Food, Drug
and Cosmetic Act, the legislation that was fundamentally responsible for
the structure of the US Food and Drug Administration (“FDA”) as it
exists today. This legislative framework– which established that
Federal drug regulatory agencies have a fiduciary duty to ensure that
marketed drugs are safe – has been adopted by national drug regulatory
agencies worldwide.
Changes in drug policy and regulation driven by tragedies in childhood
unfortunately did not end with the Elixir of Sulfonamide disaster.
Despite the preliminary protections provided by the early versions of
the Food, Drug and Cosmetic Act, paediatric patients remained a uniquely
vulnerable population with respect to marketed drug products. As new
therapies for a variety of conditions became available, paediatricians
and other child health care providers rapidly adopted them into
practice. This use was primarily based on literature from adult
populations, as the need for paediatric testing was not required, and
was rarely available. . For example, after the discovery of the
antimicrobial efficacy of chloramphenicol in 1947, the drug was widely
used, including for the therapy of presumptive sepsis in neonates. When
used for this indication – without efficacy or safety data in children
- a number of babies developed cardiorespiratory collapse, termed the
Chloramphenicol Grey Baby Syndrome (13, 14). It has subsequently been
recognized that this was due to the developmental immaturity of drug
metabolizing systems, specifically glucuronidation, paired with a
developmentally driven reduced renal clearance of the parent drug in the
neonate resulting in accumulation of toxic concentrations of
chloramphenicol (15). This, in turn, produced mitochondrial dysfunction
and cellular toxicity, impairing cardiac function resulting in the
Chloramphenicol Grey Baby Syndrome. This tragedy was key in driving
foundational research in developmental pharmacology, manifesting the
truth of Abraham Jacobi’s quote 1889 that “pediatrics does not deal
with miniatures men and women, with reduced doses and the same class of
diseases in smaller bodies, but it has its own independent range and
horizon and gives as much to general medicine as it receives from it”
(16).
A further tragedy – and one with equally monumental consequences for
pharmacotherapy for children – occurred when the German pharmaceutical
company Chemie Grünenthal marketed thalidomide as a sedative-hypnotic in
1957 (17). The product launch was very successful; it was marketed in a
number of other European countries including the UK, and was used by
more than a million women in Germany alone (18). Four years after the
product launch, William McBride, an Australian obstetrician, described
an association between in utero exposure to thalidomide and
congenital limb malformations, more specifically phocomelia,
preferential shortening of the upper limb segments which has a natural
incidence of between 1 and 4 per 100,000 live births but was seen in up
to 20% of women taking thalidomide over the time of embryogenesis (19).
This was subsequently confirmed by Lenz, with approximately 8,000
children effected worldwide, mostly in West Germany, the UK and Japan
(1, 20). While there were some cases in North America, there were
relatively few, as thalidomide was only approved in Canada in April
1961, and subsequently withdrawn in 1962. Thalidomide was never approved
in the United States due to the concerns of Dr. Francis Kelsey, a
reviewer at the FDA who was troubled by reports of embryopathy from
Australia and Europe. Of note, Dr. Kelsey’s graduate work at the
University of Chicago had included studies with Gelling exploring the
toxicity of sulfanilamide.
Despite the fact that thalidomide had never been approved in the United
States, knowing that thousands of children worldwide had been harmed by
drug therapy during pregnancy lent urgency to critically important
drug-related legislative changes proposed by Estes Kefauver, a Senator
from Tennessee, and Oren Harris, a Representative from Arkansas. This
important legislation – known as the Kefauver-Harris Amendment – was
passed in October 1962, and served to strengthen the Food, Drug and
Cosmetic Act in the United States. These changes made the approval of
the Food and Drug Administration mandatory prior to the release of a
drug to market, and granted powers to the FDA enabling them to require
manufactures to demonstrate the effectiveness of their products and
report serious adverse events following market authorization. These
changes also transformed quality of clinical trials to be used for the
purpose of drug approval, set controls for the marketing of generic
products and established good manufacturing practices for industry
clearly delineated the requirement that drugs must be shown to be both
safe and effective in the populations for which they were indicated
before they could be approved for marketing and regulated the sale and
marketing of generic drugs as well as the conduct of clinical trials
(21). This amendments had an immediate and profound effect on the drug
approval process notably on the quality of new drug submissions, and are
credited with transforming the landscape of drug development and
approval.
Unfortunately, this landmark Amendment also had an equally profound and
quite unintended effect on pediatric pharmacotherapy. With an aim to
secure the safety of marketed pharmaceuticals, the Act stipulated that
there must be substantial evidence of efficacy pursuant to the
conditions of use as outlined in the product monograph. Adverse effects
of the drug also needed to be studied during drug development and had to
be stated in detail in the product monograph.. The unique circumstances
of conducting research in children at the time created a number of
pragmatic problems that made this difficult including a relative lack of
clinical trial data in children, small population sizes in most centres
mandating multi-centre and network studies, lack of validated end-points
for clinical trials, the ethics of appropriate informed consent and cost
of conducting studies. In many cases, it was determined that if the
product indication did not include children there was no legislative or
regulatory requirement to conduct studies in children. This frequently
led to strategic decisions during drug development to not include
children in clinical studies of new therapeutic agents. Therefore, as
most new drugs were not studied in children prior to market
authorization, to ensure compliance with the regulations, product
monographs often contained exclusionary language that recommended
against use of the drug in children.
This paradoxical situation where legislation intended to enhance safety
testing in children produced a decrease in drug research in children,
resulting in the majority of drugs used in the care of children being
used “off label”, that is to say without guidance from the product
monograph – and often without evidence to guide clinicians as to dose
or safety, a problem for children most eloquently described by Harry
Shirkey in 1968 as children being “therapeutic orphans” (22).
Thus, an important amendment intended to protect all citizens from harm
by strengthening the authorities of the FDA, and enforcing regulations
designed to increase the safety and efficacy of prescribed medications,
resulted in children being excluded from the new regulatory protections.
For many years following the passage of the Kefauver-Harris Drug Control
Act, there was neither incentive nor regulatory imperative to include
paediatric data in new drug submissions unless the drug was specifically
indicated for children.
This issue persisted for decades, despite calls by professional
societies and pharmacologists for change (23-26), and despite clear and
compelling evidence that there was “off label” use was becoming an
unacceptable norm for paediatric practice (23, 40, 41). Coupled with the
barriers identified with respect to the conduct of clinical trials in
children, there has been a persistent and incorrect belief that
“children rarely require prescription medication”. This, however, is
simply not the case. Children are frequently prescribed medications, and
for a wide range of indications (27-39). Having studied a cohort of
nearly a million children in Canada for a year, researchers found that,
on average, children received 4 prescriptions per year (27, 28).
American studies have demonstrated similar numbers; in one study, 27%
of all children studied had received a prescription in the past 30 days
(33, 36). For inpatient care, a multinational study of drug utilization
demonstrated that 96% of children admitted to hospital in the UK
received at least one prescription medication (34).
In addition to a large number of medications being prescribed, there are
large range of medication classes used (27-36). While antimicrobials
were found to be the most commonly prescribed drugs for children, up to
1200 other drugs from a wide range of classes were used (27-36).
Although the use of drugs for children is to some extent variable from
country to country, probably reflecting national differences in child
care practices and drug availability, one trend that has emerged as well
was that over time fewer antimicrobials were used and more psychoactive
drugs are being prescribed (34, 36). To add complexity, over the past
decade, the number of biological agents prescribed to children has
increased almost logarithmically (37-39).
An additional consideration is that the use of pharmacotherapy for
children is not uniformly distributed across the population. For many
children, pharmacotherapy is indeed infrequent and largely confined to
antimicrobials and respiratory medications. However for children with
serious and/or chronic disease, therapy is not only frequent but also
frequently involved polypharmacy (27, 28). As an example, it has been
demonstrated that for children with epilepsy they were treated with up
to seven different drugs over the first year after diagnosis (28).