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The Willowbrook approach of using institutionalized children as
experimental subjects was not unprecedented. Other studies with
institutionalized children in Massachusetts during the 1950s exposed children
to radioactive compounds, in one case to study mineral absorption and in
another case to study the protective effect of nonradioactive iodine in
blocking radioactive iodine in the event of a nuclear explosion. Both studies
had federal funding, and the former study had additional funding from the
Quaker Oats Company because one of the study questions was to examine the
effect of cereal composition on mineral absorption.
36
In 1966 the Surgeon General of the United States, Dr. William H. Stewart,
issued a memo based on recommendations by his predecessor, Dr. Luther
Terry, and the NIH director, Dr. James Shannon, requiring institutions
accepting federal funds to certify to establish independent review of research
projects before they were started. In addition, institutions had to provide the
relevant federal funding agency assurance that procedures were in place for
consent and review.
In December 1966, the policy was expanded to include behavioral as well
as medical research.37 In 1967, the Public Health Service required that
intramural research, including that conducted at NIH, abide by similar
requirements.38 Even institutions with existing review committees had to
improve their procedures to comply with the new regulations.
Also in 1967, the U.K. Royal College of Physicians Committee on the
Supervision of the Ethics of Clinical Investigation in Institutions published a
first report recommending that every hospital or institution in which clinical
research was undertaken have a research committee that should satisfy itself
of the ethics of all proposed investigations. The proposed research
committees, with at least one lay member, should be established in every
region to review the ethics of proposed investigation, and by law they should
be responsible to the General Medical Council.39 In the same year, M. H.
Pappworth published Human Guinea Pigs, which detailed several hundred
reports of questionable ethics in human experimentation.
40,41
In 1973 in Great Britain, the chief medical officer of the Department of
Health and Social Security requested the Royal College of Physicians
Committee to again make a recommendation. The subsequent committee report
reflected a shift in attitude. It stated, “If advances in medical treatment are to
continue, so must clinical research investigation. It is in this light, therefore
that it is recommended that clinical research investigations of children or
mentally handicapped adults which is not of direct benefit to the patients
should be conducted, only when the procedures entail negligible risk or
discomfort and subject to the provisions of any common and statute law
prevailing at the time. The parent or guardian should be consulted and his
agreement recorded.” This revision appears to suggest that it is permissible to
conduct nontherapeutic research on children provided this is perceived to be
of negligible risk.42 In 1974, the U.S. Department of Health, Education, and
Welfare issued regulations requiring institutions that receive federal funds for
research to establish institutional review boards (IRBs) and described
procedures and criteria for informed consent.
43
Also in 1974, Congress passed the National Research Act. All federally
funded clinical research proposals as well as the adequacy of informed
consent had to be reviewed by an IRB with oversight and enforcement
dependent on the particular federal funding agency, meaning there was no
global oversight of federally funded research.
44
The National Research Act also established a National Commission for
the Protection of Human Subjects of Medical and Behavioral Research. The
National Commission had a mandate to develop ethical guidelines for the
conduct of research on human subjects, in particular children, and to make
recommendations to the secretary of Health, Education, and Welfare.
When the U.K. Department of Health and Social Security issued a circular
entitled “Supervision of the Ethics of Clinical Research Investigations and
Fetal Research” in 1975, it drew attention to this point, stating, “(one) ought
not to infer from this recommendation that the fact that consent has been given
by the parent or guardian and that the risk involved is considered negligible
will be sufficient to bring such clinical research investigation within the law
as it stands”.45 The British chief medical officer wrote in another publication
that it was not legitimate to perform an experiment on a child that was not in
the child’s interests.
The 1975 revision of the Declaration of Helsinki addresses this point by
stating, “the potential benefits, hazards and discomfort of a new method
should be weighed against the advantage of the best current diagnostic and
therapeutic methods.” It provides no clear guidance on the subject of
nontherapeutic research on children or any other potential subject deemed
legally incompetent. The final statement of the Declaration concerning
nontherapeutic research states, “In research on man, the interest of science and
society should never take precedence over considerations related to the wellbeing of the subject.”
46
The U.S. National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research established by the National Research
Act in 1974 and in 1977 published its report on research involving children.
To prepare the report, the National Commission, over the next several years,
held public hearings, commissioned papers and other reports, commissioned a
survey of the practice of more than 400 investigators engaged in pediatric
research, and convened a national conference to ensure that the views of
various constituencies were heard. The report contains an analysis of law as
it applies to research of children and considerable discussion of the ethical
bases of various viewpoints.
47
The conclusions were that research involving children was important for
the health of all children and that such research could be conducted ethically
within the general conditions outlined in documents such as the Helsinki
Declaration. The rationale for pediatric research was based on two factors:
(a) children are different than adults and animals in general and some diseases
only occur in children, and (b) the risk of harm from treatments and practices
is increased without research. Part of the mission was to develop guidelines.
These included a determination by an institutional ethical review board that
the proposed study is scientifically sound and significant; that appropriate
studies must be conducted first on animals, subsequently in adult humans, and
then on older children prior to involving infants; and that the risks must be
minimized by using the safest method consistent with sound research design
and by using procedures performed for diagnostic or treatment purposes
whenever feasible.
Parents must provide permission for children to participate in research
and the child, when feasible, should provide assent. Assent was considered
feasible for a normal child at 7 years of age. The Commission report, in an
innovative approach, categorized risk and made the following
recommendations:
1. Research not involving greater than minimal risk might be conducted on
children subject to permission obtained from parents.
2. Research greater than minimal risk might be conducted if it held out the
prospect of direct benefit to the subject.
3. Research not holding the prospect of benefit to the subject might be
conducted so long as the risk involved was no more than a minor
increase over minimal.
4. An additional category for research that was not included in the previous
categories is research that carries no prospect of direct benefit to the
subject but carries a risk greater than a small increase over minimal.
Such research could be carried out provided it was approved by a
national ethics advisory board and was open to public review and
comment.
The Commission also recommended that adolescents could have the
requirement for parental permission waived in specific circumstances. The
Commission published a report in 1978 on IRBs, and in 1979 the Belmont
Report (named after the donor of the conference room where the Commission
met) reviewed the Commission’s findings and outlined the ethical basis for
clinical research.
48,49
The Commission’s recommendations can be summarized
in three principles:
1. Respect for the personal dignity and autonomy of individuals, with
special protection for those with diminished autonomy
2. Beneficence to maximize benefit and minimize harm
3. Justice to distribute fairly and equitably the benefits and burdens of
research
The recommendations of the Commission were adopted in June 1983 as
federal regulations that apply to all federally funded research (45 CFR 46),
with only some minimal changes, for example, excluding the waivers for
parental permission for adolescents. Subpart A applies to all research
participants, Subpart B applies to research enrolling fetuses and pregnant
women, Subpart C applies to research with prisoners, and Subpart D applies
to research with children. Sections within Subpart D describe the risk
categories and are shown in Figure 1.2.
50
TABLE 1.1
Figure 1.2 Risk categories and applicable sections of Subpart D Title 45 CFR Part 46, the subpart of
the Common Rule of the Federal Regulations Governing Federally Funded Research that applies to
children.
Tyson and colleagues published a study in 1983 that evaluated the quality
of perinatal research. The object of the investigation was to determine the
quality of the studies because the treatment methods recommended were
widely and rapidly incorporated into clinical practice after publication in a
respected obstetric and pediatrics journal. They found that many of the studies
failed to meet the criteria for quality perinatal therapeutic research, as shown
in Table 1.1.
51
Summary of Re view of 88 Therapeutic Trials in Perinatal Research
HISTORIC LACK OF BENEFITS TO
CHILDREN OF PHARMACEUTICAL
RESEARCH
The U.S. federal government has been systematically supporting clinical trials
with children since the 1950s. Early studies on childhood leukemia were
sponsored by the National Cancer Institute; on rheumatic heart disease by the
National Heart, Blood and Lung Institute; on retrolental fibroplasia by the
National Institute of Neurological Diseases and Blindness; on diabetic
retinopathy by the National Eye Institute; on diabetes by the National Institute
of Arthritis and Metabolic Diseases; on extracranial to intracranial arterial
anastomosis (a clinical trial) by the National Institute of Neurological and
Communicative Disorders and Stroke; and on hereditary angioedema (a
clinical trial) by the National Institute of Allergy and Infectious Diseases.
52
An NIH institute dedicated to pediatric investigation was founded in 1960, the
National Institute of Child Health and Human Development (NICHD). The
first director was Dr. Robert Aldrich.
53
As noted earlier, in 1962, the Food, Drug and Cosmetic Act was amended
to include efficacy data in the FDA approval process and in the approved
product package insert. Despite the growing interest in pediatric research, the
majority of medications used in children were not studied in children. In 1968
Dr. Harry Shirkey coined the term “therapeutic orphan” to refer to the
situation in which sick children were deprived of access to medications
because the drugs had not been adequately tested in children.
54
In 1972, at the annual meeting of the AAP Dr. Charles Edwards, former
commissioner of the FDA, stated that a large percentage of the drugs used in
sick infants and children are prescribed on empirical grounds.55 In 1973, a
report from the National Academy of Sciences emphasized the different nature
of the response of an immature organ to pharmacologic agents and suggested
that innovative investigative programs were needed to supply information on
the use of pharmacologic agents in the pediatric population. Among the
reasons cited was that children are different from adults in the process of drug
disposition and receptor sensitivity. As an example: the plasma concentrations
of the drug theophylline change with the age of the patient.
In 1974, the AAP issued a report commissioned by the FDA: General
Guidelines for the Evaluation of Drugs to Be Approved for Use during
Pregnancy and, for the Treatment of Infants and Children.56 In the following
year, Dr. John Wilson found that 78% of prescription drugs had a statement in
the package insert that its use in infants and children had not been adequately
studied or there was no statement and the label was silent on the issue.
57
The FDA adapted the AAP report and in 1977 published it as a guidance
document entitled “General Considerations for the Clinical Evaluation of
Drugs in Infants and Children.” The major points were an emphasis on
anticipating and describing unexpected toxicities in the pediatric population,
an expectation that reasonable evidence for efficacy should exist prior to
study in infants and children, that only sick children should be enrolled in
studies, a preference for active or historical controls over placebo controls,
and a recommendation for studying patients in decreasing age order so that
experience is gained with older children first.58 Concurrently, the AAP issued
“Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric
Populations”.
59
In 1979, the FDA issued a regulation adding a Pediatric Use Subsection to
the Product Package Insert Precautions Section.60 The intent was to highlight
differences in adverse event profiles and to note whether any pediatric use
information existed.
Although not directed exclusively at pediatric patients, an important
regulatory change occurred in 1983 with the passage of the Orphan Drug
Act.61 The Act outlined criteria whereby rare diseases, many of them pediatric
and defined as having a prevalence of less than 200,000 in the United States,
could benefit from incentives to develop new therapeutics. The program is
administered by the FDA and provides both a longer period of marketing
exclusivity (7 years for an “orphan” indication compared to 5 years for the
first approved indication of a new molecular entity) and subsidies in the way
of grants and technical advice for clinical development. An orphan
designation is given to the combination of a rare disease and a product. This
allows the same disease to have multiple products qualify for orphan
designation and does not restrict a product to only being used to treat an
orphan disease. The Orphan Drug Act established the principle of government
incentives to promote product development in areas of public health need.
Despite the initiative to encourage pediatric data, in 1988 Dr. Franz Rosa,
an FDA epidemiologist, surveyed product labels for drugs that are used in
infants and found that only 50% had been formally evaluated. Of these, half
had been considered safe and effective and the other half had a caution or risk
statement in the product label. Of the 50% that had not been evaluated, 60%
had a disclaimer about not being indicated for use in children and 40% had no
information.62 An independent survey in 1991 found that, just as in 1975,
about 80% of product labels had either limited pediatric dosing information
or had a disclaimer for use in children.
63
FEDERAL PEDIATRIC INITIATIVES
To further encourage pediatric therapeutic development and the inclusion of
pediatric information in product package inserts (product labels), in 1994, the
FDA revised the Pediatric Use section of the regulations, adding a Subsection
(iv) permitting extrapolation of efficacy data if the disease course in adult and
pediatric patients was similar.
64
An FDA guidance document issued in 1996 on the Content and Format of
Pediatric Use Section noted that extrapolation should be considered, that the
effects of the drugs, both beneficial and adverse, in adult and pediatric
patients should be described, and that critical literature references should be
included. Compliance was voluntary and did not result in an increase in the
proportion of products with pediatric labeling.
65
Also in 1995, the AAP Committee on Drugs issued a revision of its
Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric
Populations with detailed discussion of IRBs, informed consent, risk and
benefit determination, investigator competence, scientific validity and special
cases of the dying patient, the newly dead patient, and patients with chronic
progressive and potentially fatal diseases.
66
The NICHD established the Pediatric Pharmacology Research Unit
Network in 1994 as the first national network for pediatric research, with
seven institutions. The network was expanded to 13 institutions in 2001 and
ran until 2010, when it was replaced by the Pediatric Trials Network. A
guiding principle was that children are not small adults.
67,68
As part of the 1997 Food and Drug Administration Modernization Act
(FDAMA), an incentive, similar in spirit to the Orphan Drug Act, was added
as an option for certain types of products for which pediatric data were
submitted to the FDA in response to a written request from the agency.
The incentive was a 6-month extension to existing marketing or patent
exclusivity for any product that had the active moiety that was studied in the
written request. To qualify for the incentive, a study report must be submitted
to the FDA that fairly responds to the terms of the written request. Written
requests can be initiated by a sponsor through submission of a proposal for
pediatric studies to the FDA or internally by the FDA when a perceived
public health need exists. Not all sponsors that received an FDA written
request accepted the opportunity. Some of the reasons sponsors declined were
because the product was a generic drug that lacks exclusivity, the requested
indication was for a hard to study small population for a rare condition,
reluctance to conduct studies in populations such as neonates or premature
infants, or a business decision that the exclusivity extension was not useful.
The results of the submitted studies must be interpretable and informative,
but do not need to demonstrate a positive outcome. A negative study can be
part of the submission and still contribute to the granting of pediatric
exclusivity because the intent is to provide appropriate pediatric information.
At the time, existing and newly approved products could qualify with the
exception of biologics, certain antibiotics, and devices.
69
In 1998, the FDA issued a Pediatric Rule that mandated pediatric studies
based on the proposed labeling claim. If the adult indication occurred in
children, the Pediatric Rule would apply. If the adult disease or condition did
not apply to children, a waiver from compliance could be granted. If the adult
indication did not apply to a pediatric subpopulation, for example, children
younger than 5 years, a partial waiver could be granted. In contrast, the
pediatric incentive program in the FDAMA could apply to any pediatric
disease independent of the adult indication.
One of two additional conditions had to be met before the Pediatric Rule
would apply. Either the product had to be a therapeutic advance or it likely
had to have widespread use defined as 50,000 or more children with the
relevant disease or condition. The Pediatric Rule did apply to biologics, but
products with Orphan Drug designation were exempted.
70
In October 2002, the Rule was invalidated in a court decision that ruled
that the FDA did not have authority to mandate studies in a population to
which a drug sponsor did not intend to market.71 In November 2003, the FDA
gained the statutory authority to mandate pediatric studies with the signing of
Public Law 108-155, the Pediatric Research Equity Act, into law. The
Pediatric Research Equity Act was an updated version of the Pediatric Rule
that continued as a principle that the linkage between an adult and pediatric
indication is flexible and may evolve over time as biologic, genetic, and
physiologic knowledge advances.
72