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perception of children evolved from one of being the property of adults to
individuals worthy of special protections, the role children played in the
history of research is complex and, prior to the mid-20th century, often
unfavorable to the individual.
BRIEF HISTORY OF RESEARCH INVOLVING
CHILDREN
Children have been utilized to test new therapies for thousands of years, but
the first documented prospective structured clinical investigations to test
scientific hypotheses were a development of the 18th century during the
period known in Europe as the Age of Enlightenment. While living in
Constantinople in 1718, Lady Mary Montague, daughter of the Duke of
Kinston, observed the Turkish procedure of inoculation against smallpox and
had her 6-year-old son inoculated. Upon her return to London, she requested a
surgeon to inoculate her 5-year-old daughter. The surgeon used a thread
soaked in pustular secretions bound to the skin. This technique was replaced
by scarring with a lance tip dipped in pus. The resulting plaque was then
covered until it healed, and experimental research in pediatric preventive
medicine began in Europe.
1
The American clergyman Cotton Mather also became interested in the
procedure after hearing from the slave Onesimus about the practice of using
fluid from a patient with mild smallpox to inoculate uninfected people in
Africa. Subsequently, he read about the European experience in his
correspondence with members of the Royal Society of London. An outbreak
of smallpox in Boston in 1721, despite efforts at quarantining the index case,
provided an opportunity to experiment. Mather persuaded Boston physician
Zabdiel Boylston to proceed with what may have been the first clinical trial in
North America. Boylston inoculated his 6-year-old son by lancing the skin
and applying to it 9- to 14-day-old pustular material from a smallpox patient,
then wrapped the skin in a cabbage leaf. Subsequently, he inoculated 280
people, including 65 children. Unfortunately, six of the adults, although none
of the children, subsequently died, with a case fatality rate of approximately
2%. Despite the fact that the smallpox fatality rate for the general population
in Boston was 14%, a great controversy about the value of inoculation
followed, including the hurling of a bomb into Rev. Mather’s home.
Fortunately, the explosive did not detonate, but the practice of inoculation did
not become public policy.
2
Experimental immunotherapy evolved further with the work of Edward
Jenner in England. In 1796 Jenner injected James Phipps, an 8-year-old boy,
with extract from pustules from the hand of Sarah Nelmes, a milkmaid. Jenner
had been told by milkmaids that cowpox protected them against smallpox. The
word “vaccination” is derived from the Latin word for cow—vacca. Jenner
examined his patient every day and then 2 weeks after the cowpox injection;
Jenner applied a challenge of smallpox extract and found that the boy was
protected. He expanded his study from the initial child to “a number” of others
ranging in age from 11 months to 8 years. None of the children became ill.
Over the course of the next 50 years, vaccination became compulsory in some
areas of England.
3
During the 19th century children’s hospitals were established in Europe
and the United States in cities including Paris, Vienna, London, Philadelphia,
Boston, and New York. Concurrently, pediatrics became an academic
specialty, and textbooks were published. Ludwig Friedrich Meissner of
Leipzig, Germany, published a survey of texts and monographs pertaining to
pediatric medicine in 1826 noting that prior to 1775 there were 200
publications, and subsequently there were at least almost 7,000.
1
In 1828 Charles-Michel Billard of the Hospice des Infants-Trouvés in
Paris published a revolutionary treatise classifying pediatric diseases on the
basis of tissue pathology rather than patient symptoms. In addition, he
included a catalogue of height, weight, and vital signs.4 This was followed by
surveys by Quetelet in Belgium and Chadwick in England on growth rates of
children showing that lower socioeconomic class was associated with less
growth, most probably due to nutritional deficiencies.
5,6
Comparative
pharmacology began in about the middle of the 19th century.
In 1834 the first periodical devoted entirely to the care of children,
Aizalekteiz iiber Kinderkrankheiten (Annals of Diseases of Children), was
published in Stuttgart; it ceased publication in 1837 after publishing 12
volumes. Over the course of the following decades, many journals appeared
in several countries as academic societies and publishing houses developed
interest in the field of pediatric research.
In 1847 John Snow began to administer anesthesia with ether to children
aged 4 through 16 years. He also experimented with chloroform and, by 1857,
had successfully anesthetized hundreds of children, including 186 infants
under the age of 1 year. He first described differences in metabolism between
adults and children, noting that the effects of chloroform were more quickly
produced and also subsided more quickly in children, explaining the
observation in terms of the quicker breathing and circulation in pediatric
patients.
1
Frederik Theodor Berg was appointed the first European professor of
pediatrics at the Karolinska Institute in Stockholm, Sweden, in 1845. In 1858,
he resigned the post to become director of the Central Bureau of Statistics. In
that capacity, he expanded the bureau’s data banks to include not only
population, but also welfare, agricultural, and industrial data. He founded a
statistical journal in 1869, and in the same year, utilizing parish records, he
published a paper analyzing infant mortality rates in Sweden.
7
The first course in the United States at an academic institution devoted to
pediatrics was offered at the Yale College of Medicine in 1813 by Eli Ives.
8
In 1860, Abraham Jacobi, an émigré from Germany, was appointed as
professor of infantile pathology and therapeutics at the New York Medical
College, which may have been the first full academic pediatric appointment in
America. A pediatric clinic with the first use of bedside teaching was founded
in 1862.
9,10
The first institution for sick children in the United States was founded in
1855 in Philadelphia. Boston and New York followed in 1869 and the District
of Columbia in 1871. By 1880, Jacobi had been instrumental in the
establishment of several hospitals for children in the United States—Chicago,
San Francisco, St. Louis, and Cincinnati—so that by 1895 there were 26
children’s hospitals in this country. In 1868, Jacobi wrote an article on croup
in the first issue of the American Journal of Obstetrics and Diseases of
Women and Children, published by the American Medical Association
(AMA). The first American journal dedicated totally to pediatric research,
Archives of Pediatrics, began publication in 1884.
In 1880, Jacobi organized the pediatric section of the AMA and in 1885
he became president of the New York Academy of Medicine. In 1888, he
became a founding member of the American Pediatric Society, which limited
membership to 110. The society published its Transactions, which, for the
first third of the 20th century, was the major American journal devoted to
pediatric research. Jacobi was among the first to recognize the potential of
using government resources to advance clinical science. He is credited with
persuading the U.S. Congress to appropriate funds for the first printing of
Index Medicus, compiled by his friend John Shaw Billings.
TRANSITION INTO THE 20TH CENTURY AND
THE BEGINNING OF RESEARCH
REGULATION
Claude Bernard wrote in 1865, “It is our duty and our right to perform
experiments on man whenever it can save his life, cure him or give him some
personal benefit”.11 This statement has been subsequently interpreted that on
an ethical basis only studies that provide direct benefit to the participants
should be undertaken, but the principle had no legal authority. The question of
prior permission to participate was not addressed.
The last decades of the 19th century saw further experimentation in
immunotherapy for the treatment of infectious diseases, with many of the
major advances resulting from studies on children. In 1885, Pasteur injected
9-year-old Joseph Meister of Alsace, who had been bitten by a rabid dog,
with extract of rabbit spinal cord from a rabbit that had died of rabies 2
weeks before. Thirteen inoculations were given daily, with the last an extract
from a rabid dog. The boy recovered, and a second shepherd boy was
similarly cured.
12
In 1892, an immunologic approach to reduce transmission of venereal
disease was attempted in a study by Albert Neisser, Professor of Dermatology
and Syphilis in Breslau and discoverer of the organism responsible for
gonorrhea. He subcutaneously and intravenously injected eight women and
girls, the youngest being 10 years old, with cell-free extract of syphilis in an
attempt to stimulate an immune response. Subsequently, four of the women
became infected, leading to the speculation that the cause of their illness could
have been Neisser and his experiment, and a subsequent public scandal
followed.
13
The debate continued primarily in the press for several years until
December 19, 1900, when the Prussian Ministry of Education and Medicine
issued a policy statement about human experimentation. The proclamation
stated that research may not be performed without the permission of the
patient and that research on children was forbidden. It further stated that
research should have as its goal the diagnosis, treatment, or prevention of
disease.
This was probably the first government edict about human research, and
although a potent statement had been made, enforcement powers did not
follow.
14,15
The rise of the chemical industry, particularly in Germany, fed the
hope of targeting diseases through the administration of manufactured
compounds. As an example, the recognition of genital infections as a source of
infant morbidity led Karl Sigmund Franz Crede in 1884 to use silver nitrate
solution to prevent gonorrhea infections of the eyes of the newborn.
16,17
There was a rush to examine the medical (and potential commercial)
activity of many newly synthesized products, spurred by Paul Ehrlich’s vision
of a “magic bullet” and a permissive social climate. In 1902 the psychiatrist
Albert Moll published a monograph, Aertzliche Ethik,
18,19
in which he
catalogued some 600 publications of medical experiments where, he argued,
there was no possible benefit to the subject. Moll criticized not only the
dangers of the experiments, but also the lack of advantage to the research
participant. Despite the Prussian edict and Moll’s book, however, there would
be no translation of research participant protection into public policy for
another third of a century.
EVOLUTION OF ETHICAL PRINCIPLES AND
THEIR APPLICATION TO RESEARCH
Health crises involving children have played a major role in the evolution of
food and drug law in the United States. The first major domestic controls
occurred early in the 20th century, following more than 100 attempts in the
19th century to pass federal legislation regulating the manufacture and sale of
foods and drugs. In the autumn of 1901 in St. Louis, more than a dozen
children died of tetanus after receiving diphtheria antitoxin that had been
recovered from a tetanus-infected horse. Subsequently, another 100 cases of
tetanus were reported, including the deaths of 9 more children. This led to the
passage of the Biologics Control Act of 1902, which called for the licensing,
labeling, and supervision of biologic products intended for humans.
20
In the autumn of 1905, Collier’s Weekly published an expose of fraud in
the manufacture and sale of patent medicines, citing cases of infants who died
following administration of syrup that contained morphine that was intended
to treat colic. Although concern was widespread, public documentation of
specific cases of death or morbidity due to commercial drugs was lacking due
to contract clauses on publications by drug manufacturers threatening to
cancel advertisements if legislation regulating drug marketing was passed.
Nevertheless, through the efforts of a coalition of chemists, women’s clubs,
state officials, civic organizations, and writers, in June 1906, President
Theodore Roosevelt signed the first Pure Food and Drug Act into law. The
Act established the need for product labels, prohibited interstate commerce in
adulterated or misbranded drugs, and established the need to maintain
standards.
20,21
There was, however, a provision in the Act that permitted
deviation from the standards if they were stated on the label. Enforcement was
to be by the courts.
This led to the case of US v Johnson in 1911, in which a majority of the
Supreme Court ruled in favor of the defendant, the manufacturer of Dr.
Johnson’s Mild Combination Treatment for Cancer, that claimed as its
ingredients a mixture of substances with names like Cancerine tablets,
Antiseptic tablets, Blood purifier, Special No. 4, Cancerine No. 17, and
Cancerine No. 1. The Court stated that prosecution was to be limited to false
and misleading statements about the ingredients or the identity of a product
and was not intended to extend to false therapeutic claims.22 In an effort to
address the gap, the 1912 Sherley Amendment to the Pure Food and Drug Act
stated that false therapeutic claims could be prosecuted, but only if intent to
defraud could be proven in court.23 The rising political prominence of
pediatrics led to the first White House Conference on the Care of Dependent
Children in 1909. Based on a recommendation from the Conference, the
United States Children’s Bureau was established by Congress in 1912 to
coordinate health care policy.
24
World War I had multiple aftereffects, including recognition of the poor
physical condition of many of the young men recruited to serve in the armed
forces. A political response was the Sheppard-Towner Bill in 1921 to
provide funding for the health care of poor mothers and infants and extend
health supervision from infancy to preschool children (Reference Sheppard
Towner Bill, Public Law 67–97: Statutes at Large: 42 Stat. 224, Chap 135:
November 23, 1921). The question of the role of government and how much
support it should provide for health care and children’s issues was debated
for much of the 20th century, primarily on philosophical and political grounds.
The next major change in regulations occurred in 1927 when the Federal
Caustic Poisons Act was passed in an effort to protect children from lye and
other dangerous chemicals by requiring labeling with warnings and antidotes
(Reference United States Code: Federal Caustic Poison Act, 15 U.S.C. §§
401-411 [Suppl. 1 1925]).
The AMA was not sheltered from the discussion of pediatric safety, and at
the 1928 meeting there was plan for a society that would be open to any
physician trained in pediatrics. Two years later, a schism occurred within the
AMA on the issue of government support for clinics to treat infants and
children with the goal of reducing mortality. A group of pediatricians
withdrew and formed a new organization, the American Academy of
Pediatrics (AAP).
25
In 1930, the U.S. Congress established the National Institutes of Health
(NIH) by renaming the U.S. Hygiene Laboratory in Washington, DC.26 In
addition, the Food, Drug and Insecticide Administration was established as an
enforcement agency.20 The name was shortened in 1930 to the Food and Drug
Administration (FDA). Legislation to revise the 1906 Food and Drug Act was
proposed in 1933 but became mired in Congress.
20
In 1931 the German Ministry of the Interior issued the first guidelines
published for the conduct of research on children. These were part of general
guidelines for the conduct of clinical research that were issued in response to
allegations by the press and members of the national legislature of
questionable and even unethical conduct by physicians. The guidelines were
the initial governmental statement of requirements for the ethical conduct of
clinical research, which are found in subsequent statements such as the
Helsinki Declaration.
The general principles were the primary obligation and duty of the
experimenter to protect the subject, the need for informed consent in all
circumstances, the principle of preclinical testing in animals prior to human
use, and the principle of accurate publication of findings. An experimental
compound was defined as any intervention that did not contribute directly to
the treatment of an individual patient. No mention is made of peer review in
either the experimental or the publication process, although the Berlin
Medical Board, which earlier in the century had issued its own
recommendations on protection of research subjects, had proposed a
regulatory oversight body. This proposal was not incorporated into the final
guidelines.
The German guidelines contained two sentences specifically about
children: “Application of the new treatment must be considered particularly
carefully if it involves infants or adolescents of less than 18 years” and
“Experimentation on infants or persons of less than 18 years is forbidden even
if it will only expose them to a very slight danger”.
27
In September 1937, the Samuel E. Massengill Pharmaceutical Company in
St. Louis marketed the newly discovered antibiotic sulfanilamide as a 10%
solution, substituting 72% diethylene glycol for the usual solute of ethanol and
sweetening it with sugar and raspberry syrup. The resulting elixir killed more
than 100 people including many children, due to glycol-induced renal failure,
and resulted in the suicide of the chemist who made it. The product was only
labeled as an elixir, which implied ethyl alcohol and did not state the full list
of ingredients, and thus the company was charged with misbranding. The
absence of an applicable law meant that there was no culpability for the
deaths.
This tragedy led to the passage of the Food, Drug and Cosmetic Act,
which was signed into law by President Franklin Roosevelt in June 1938. The
Act gave authority to the FDA to require that safety is established prior to
marketing, required disclosure of all active ingredients, required directions
for use and warnings about misuse unless the product was sold by
prescription, allowed federal inspections of manufacturing facilities,
established procedures for the formal review of applications for marketing,
explicitly prohibited false claims, and extended the scope of the regulation to
cosmetics and devices. There were no provisions for premarketing review,
and only those products that were to be sold for interstate commerce were
covered. All applications were automatically approved if the FDA did not act
within 60 days. The regulation of advertising of therapeutics was assigned to
the Federal Trade Commission.
28
International recognition of the need to protect participants in clinical
experiments surfaced during the Nuremberg Military Tribunals in 1946.
Evidence was given that up to 200 German doctors had performed
experiments with prisoners of war and civilians that had no protections for the
participants and caused harm without any prospect of benefit. The subsequent
court proceedings led to the development of the Nuremberg Code, which
established international standards for the treatment of one human by another.
The guiding principle was that “The voluntary consent of the human subject is
absolutely essential.” This statement has been widely interpreted as
precluding research on children, although the Nuremberg Code is silent on the
specific subject of pediatric research.
29
In 1962, the tragedy of the births of malformed children, primarily in
Europe and Canada due to thalidomide taken as a sedative by their mothers
while pregnant, resulted in part in Congress passing the Kefauver–Harris
amendment to the Food, Drug and Cosmetic Act.
30
This amendment added an important new facet—the requirement that a
product demonstrate efficacy prior to approval of a marketing claim.
Additional provisions in the amendment were the need to establish good
manufacturing practice (GMP) and maintain production records, the
requirement to file an application with the FDA prior to clinical testing
(Investigational New Drug application, or IND), an increase in the time for
FDA marketing authorization review from 60 to 180 days, the transferal of
regulatory authority for drug advertising to the FDA, and withdrawal of
approval if new evidence indicated lack of safety or effectiveness.31 The
addition of an efficacy requirement prompted a retrospective study by the
National Academy of Sciences of FDA approvals between 1938 and 1962
that showed that 40% of the approved products lacked evidence that they
were effective.32 The new aspect in analysis of product use by adding an
efficacy requirement was that benefit and risk could be assessed and
acceptable ratios of risk to benefit determined for the intended use at the
prescribed dose.
To summarize, the three principles of drug regulation—labeling, safety,
and efficacy—were formalized during the first two-thirds of the 20th century.
Formal guidelines for the protection of participants in research, and children
in particular, are a product of the last third of the 20th century.
As a point of reference, protection for animals goes back to the 19th
century. For example, in the United Kingdom, the Cruelty to Animals Act
became law in 1876.31 In 1960, Louis G. Welt, of the Department of Medicine
at Yale University, sent a questionnaire regarding practices for clinical
research to university departments of medicine. Sixty-six replied, of which 24
(36%) either already had or were in favor of establishing a committee to
review studies involving human experimentation.32 In 1962, the Medical
Research Council of the United Kingdom made a statement in its annual report
that drew a distinction between research interventions intended to be of direct
benefit to the subject of the research and those that are not so intended. These
two categories of research were referred to as “therapeutic” and
“nontherapeutic”, respectively. The report went on to state that “In the strict
view of the law, parents and guardians of minors cannot give consent on their
behalf to any procedures which are of no particular benefit to them and which
may carry some risk of harm.” This statement has regularly been interpreted
as placing a complete embargo on nontherapeutic research on children. A
follow-up report in 1963 addressed some of the perceived legal and ethical
problems in clinical research.
33
The World Medical Association adopted in 1964 the Declaration of
Helsinki: Recommendations Guiding Medical Doctors in Biomedical
Research Involving Human Subjects. The document made a distinction
between therapeutic and nontherapeutic research and stated that protocols,
independent review of the proposed research, and informed consent should be
part of the protection of participants in research. Third-party consent for a
participant unable to give consent was described, thus offering an approach to
pediatric research.
34
Henry Beecher, Professor of Anesthesia at Harvard Medical School,
published an article entitled “Ethics and clinical research” in the New
England Journal of Medicine in 1966.35 He drew attention to 22 reports that
contained clinical research with a variety of ethical problems, most of which
put patients at considerable risk. One of these was the Willowbrook study in
New York, which exposed institutionalized children to serum infected with
hepatitis. The study was performed with institutional approval, and parents
gave permission. The rationale was that hepatitis was so prevalent that the
children were likely to become infected and that it was scientifically
important to study the early phases of the infectious process.