The article presents some information about the history of
FDA
regulations related to the testing of drugs for safety and
effectiveness in children. This is pertinent for two reasons:
there still is an active controversy about the use of prescription
medications in general, and psychotropic medication in particular, in
children; and, I am sick and tired of the whole Abu Ghraib thing.
In December 2003, the UK's National Health Service issued an alert about
antidepressant medication. The alert mentioned two things. First, they
were not satisfied with the evidence for the effectiveness of antidepressant
medication, when used in children. Second, they were concerned about
the possibility that such medications could cause suicidal thinking or
suicidal behaviors. There were no actual suicides recorded in
the studies. However, in placebo-controlled studies in children, there
were more instances of suicidal or self-injurious thinking in those
on the active medicaiton compared to the placebo groups.
The UK NHS alert took many people off guard, especially since it is assumed
commonly that the US FDA keeps close track of safety and effectiveness data.
Shortly after the UK alert, the US FDA issued a similar alert.
In order to understand how these alerts could come as such a surprise, it
is necessary to understand the history of the FDA.
What this article shows is that there is a long an convoluted history
to the efforts of the federal government to regulate the pharmaceutical
industry. Up until the 1990's, though, the process was relatively
free of pernicious political and financial influences. In the new
millennium, something changed. I invite us all to wonder about
what changed and why.
In 1862, President Lincoln appointed a chemist, Charles M. Wetherill,
to serve in the new Department of Agriculture. This was the beginning
of the Bureau of Chemistry, the predecessor of the Food and Drug
Administration. In 1906, Congress passed the Food and Drugs Act
to establish the Food Drug, and Insecticide Administration.
In 1938, prompted in part by the deaths of 107 persons from a patent
medication containing diethylene glycol, Congress passed the Federal
Food, Drugs, and Cosmetics Act. This required that drugs be
tested for safety in adults before being put on the market. Note
that, although many
of the diethylene glycol deaths occurred in children, the 1938
legislation did not
require safety testing for children. The legislation in 1938 did
not actually require testing for effectiveness; only testing for safety
was mandated.
The first formal protocol for testing drugs (Guidance To Industry) was
published by the FDA in 1949. In 1950, a court ruled that a
company marketing a drug must declare the purpose of the drug.
Apparently, they had realized that you cannot test a drug properly for
safety unless you first declare what it is for. This appears to
have been the first adequate recognition of the need for the
scientific
method (first, formulate an hypothesis...). You can't
formulate an hypothesis about safety until you first answer the
question: "safe for what?" The safety of a medication is assessed
in relative terms. Risks that might be acceptable for a cancer
drug might not be acceptable for a drug used to treat acne.
Personally, I found it startling that the FDA did not formalize the use
of the scientific method until 1950. That was not very long ago,
but at least it happened before I was born. Remember, though,
that the FDA was not founded as a scientific agency. In Lincoln's
time, it was an agency that regulated agriculture. Even in 1950,
there was no requirement for testing a drug for effectiveness. In
1962, Congress passed the Kefauver-Harris Drug Amendments. This
was the first mandate to test a drug for effectiveness as well as
safety. It was not until 1966 that the FDA assigned the National
Academy of Sciences to evaluate the effectiveness of drugs already on
the market. In 1968, the FDA began implementation of
effectiveness testing recommended by NAS.
In 1988, the Food and
Drug Administration Act was passed, thus forming the FDA as we now know
it. I was already in medical school by then. Even then,
there was no requirement for pediatric testing. In 1992, the FDA
ruled that drug labeling should include specific information, if
available, regarding the use of the drug in children. The
National Institutes of Health established pediatric pharmacology
research units. In 1997, the
FDA
Modernization Act was passed. This still did not
require pediatric testing,
but it offered drug companies six extra months of patent protection for
any drug that a pharmaceutical company tested in children on a
voluntary basis. This led to the issuance of the Pediatric Rule,
in 1998, which formalized the FDA's position on pediatric
testing. By 1999, only about two dozen drugs had been tested
specifically in children by the PPRU's.
Pediatrics 1999;104:644-5.
A paid subscription is required for full text; see links
1
(free access) and
2
(free access with registration) for more information.
In October 2000, the
Children's
Health Act of 2000 was passed. This created the
Pediatric Research Initiative. In January, 2002, the
Best
Pharmaceuticals for Children Act was passed. This
enabled the the Secretary of Health and Human Services to issue
requests for specific drugs to be tested in children.
That's it for the background information. What this tells us is
that it took the FDA a long time to require proper scientific
methodology for drug testing, and even longer to consider the issue of
pediatric testing; but that by the late 1990's, they were starting to
pay attention to the specific issue of testing drugs for safety and
effectiveness in the pediatric population. Even thought they got
off to a slow start, they were building momentum in the early part of
this decade.
Given the news and
blogbuzz
we have seen about the problems with
antidepressant use in children, no one would be surprised to see a news
article like this one come out in early 2004. The questions are:
Who are the "political figures" involved, and what was the date?
POLITICAL
FIGURE X LAUNCHES NEW
PUBLIC-PRIVATE
EFFORT TO IMPROVE THE DIAGNOSIS AND TREATMENT OF CHILDREN
WITH
EMOTIONAL AND BEHAVIORAL CONDITIONS
DATE MM-DD-YYYY
Today,
Political Figure X, together with Secretary Y and
representatives of parents and a broad range of health
professionals, launched an unprecedented public-private effort to
ensure that children with emotional and behavioral conditions are
appropriately diagnosed, treated, monitored, and managed by qualified
health care professionals, parents, and educators. Federal actions she
will outline include: (1) the release of a new, easy to understand fact
sheet about treatment of children with emotional and behavioral
conditions for parents; (2) a new $5 million funding commitment by the
National Institute of Mental Health (NIMH) to conduct additional
research on the impact of psychotropic medication on children under the
age of seven; (3) the initiation of a process at the Food and Drug
Administration (FDA) to improve pediatric labeling information for
young children; and (4) a national conference on Treatment of Children
with Behavioral and Mental Disorders to take place this fall. Political
Figure X will also highlight actions taken by the private sector
to ensure
appropriate diagnosis and effective treatment of these children. All of
these actions build on the landmark work resulting from the first ever
White House Conference on Mental Health and the release of the
unprecedented Surgeon General's Report on Mental Health last year, both
of which were spearheaded by Political Figure Z, the President's Mental
Health
Advisor.
Answers: X=Hillary Rodham Clinton, Y=Secretary of Health and Human
Services Donna Shalala, and Z=Tipper Gore. The date was 3-20-2000
(link).
Next question, regarding the question of the safety and effectiveness
of drugs used in children: If the federal government was on the case in
2000, why
were we surprised in late 2003 when the
news (183 KB PDF) about equivocal efficacy of antidepressants used
in children, and a question about a
possible safety issue, were revealed? If Ms. Clinton et. al.
launched an effort to improve research in this area in 2000, why did it
take so long for the news to come out? And, more vexingly, why
was it the UK, and not the US, that broke the news? The following
news excerpts tell the story.
HUFFINGTON: Drugging
Our Children The Legal Way
By Arianna Huffington, AlterNet
October 31, 2002
Chalk up another profitable
victory for those promoting the legal drugging of America's children,
also known as the good folks of the pharmaceutical industry. Earlier
this month, a federal judge struck down a Food and Drug Administration
regulation that required drug makers to test medicines routinely given
to children.
As a result, America's legal drug
pushers are once again free to offer their potent concoctions for our
kids' consumption without having to prove that they are safe or
effective for pediatric use.
This is no small matter, given the
skyrocketing number of children being prescribed heaping helpings of
powerful mood-altering drugs. For instance, 1.5 million kids are
currently taking Prozac and its equivalents even though the FDA hasn't
approved these drugs for use by anyone under 18.
In making his ruling, U.S.
District Judge Henry Kennedy, Jr. made it clear that the problem wasn't
the FDA's attempt to protect our kids, but Congress' failure to
authorize them to do so. He pointed out that earlier this year Congress
considered but passed on the chance to require drug companies to make
sure that products designed for grown-ups but regularly given to kids
are, in fact, safe for children to take.
Ignore the polemical tome in the article; also ignore the error about
Prozac. (Prozac was approved for use in children in 2000.)
The point is, that the Pediatric Rule was struck down in 2002.
See
this
link for more on the court decision overturning the Pediatric
Rule. The opposition to the Pediatric Rule was led by the
Competitive Enterprise Institute (
about) and the
Association of American Physicians and Surgeons (
about). See
this link for a
summary of the CEI's position. Note that the implementation
of the Pediatric Rule had been
voluntarily
delayed (also see
this link) by the FDA in
March 2002, pending the court decision. The Pediatric Rule
had been supported by most physicians and other health care providers,
but some
individuals
and
advocacy
groups claimed that it was a scheme to generate more profits
for the pharmaceutical industry.
By 2003, efforts were underway to correct the legal deficiency that had
caused the Pediatric Rule to be overturned. SInce the Rule was
overturned based on the argument that the FDA did not have the proper
legal authority, Congress acted to provide that authority.
October
20, 2003
U.S. Senators
Mike DeWine (R-OH), Hillary Rodham Clinton (D-NY), and Christopher Dodd
(D-CT) have renewed their call for drugs that are widely used by
children to be studied, tested and labeled for safety and efficacy. One
year ago last week, on October 17, 2002, the Pediatric Rule was struck
down by the District Court in Washington DC. In July of this year, the
Senate passed legislation by Senators DeWine, Clinton and Dodd to
restore the Rule.
The Pediatric Research Equity
Act would give the FDA authority to
secure pediatric studies and labeling of drugs that are widely used for
children.
"Restoring the Pediatric Rule
would give parents the peace of mind they
deserve," said Senator DeWine. "It is time to stop playing guessing
games when it comes to our children's health. The Pediatric Research
Equity Act would provide children with the same safety assurances that
are afforded to adults. We need to make sure the FDA continues to have
every tool available to them to ensure that drugs are tested and
labeled for children."
"When a United States
District Court judge blocked the Pediatric Rule
last year, I joined my colleagues Senators DeWine and Dodd in
reiterating our pledge to provide clear Congressional authority to
reinstate enforcement of the Pediatric Rule, without which many
children will be under- or over- dosed, or even denied important
medications that are not labeled or formulated for their use," Senator
Clinton said. "In the 12 months since the Rule has been struck, over
100 medicines important to children have been approved by the FDA for
adults without assurance that children will ever have safe appropriate
access to these drugs. The consequences of this lapse, even for just
one year, are dire. A 2002 study found that over 200 children under the
age of 2 alone die from the failure to properly label and study drugs
for their use. That is why we took action in the Senate this July to
pass the Rule with the unanimous support of our colleagues. I look
forward to swift action to make sure that this bill passes because
every day this bill is delayed, is another day children's health is
left at risk."
After DeWine, Dodd, and Clinton proposed the Pediatric
Research Equity Act of 2003, it
passed quickly,
and was signed into law by President Bush on December 3, 2003. On
December 5, 2003, the Alliance for Human Research Protection (
about)
issued a press release that was highly critical of the new Legislation,
claiming that in would be unethical to test drugs in children. On
December 10, 2003, the UK National Health Service recommended that 10
popular antidepressant drugs be withheld from children because of
questions about safety and effectiveness.
My interpretation of this history is as follows: in the 1800's the
forerunner of the FDA was a small, inconspicuous bureaucratic entity
that was able to do its business without too much hassle. In the
early to mid-1900's, improved public health monitoring enabled the
government to learn of major problems with drug safety, and they
engaged in a fairly straightforward process to solve those
problems. There was not a formal implementation of the scientific
method, but that was not critical to the limited mission of the
agency. The earliest major drug discoveries: penicillin, polio
vaccine, etc., had such obvious effectiveness that rigorous testing for
effectiveness may have seemed superfluous. Health insurance was
not widespread then, so the massive amounts of money that change hands
today were not a corrupting influence.
During World War II, wages were controlled strictly. Therefore,
employees bargained for improved benefits instead of higher
wages. Health insurance became a common benefit. Medicine,
and the pharmaceutical industry, suddenly became much more
profitable. Along with profit comes widespread fraud. This
led to the need for expanding the mission of the FDA. It became
necessary to mandate testing for effectiveness as well as safety.
In that era, children did not have the status that they have
today. After all, it was illegal to beat your dog before it
became illegal to beat your kids. The elevation of concern for
the safety of children is a complex issue, but for various reasons it
became a prominent social issue by the 1970's. I cannot explain
the lapse in time from the 70's to the 90's, before the FDA began to
consider the issue of drug safety testing in the pediatric
population.
By the 1980's, the pharmaceutical industry had become one of the most
profitable industries on the planet. This was due to the
widespread availability of health insurance, coupled with advances in
the biomedical sciences. The rising expenditure on prescription
drugs was one factor that led to the phenomenon popularly known as
managed care, but more accurately referred to as rule-based care.
This posed the first serious threat to the profitability of the
pharmaceutical industry. Also, the cost of developing a new drug
had risen considerably, and huge lawsuits were becoming more
common. These developments led to a difficult situation for the
pharmaceutical corporations. Although the potential for profit
was still enormous, the risks associated with development became much
more significant.
The issue of risk became even greater in the new millennium. The
economic recession caused all companies to become much more wary of
risk. The potential for stock market shenanigans also became
significant. For a corporate executive with stock options, a
single unfavorable news story could lead to a loss of several million
dollars. Likewise, an artificially good news story could lead to
a windfall.
As a result of these various factors, the pharmaceutical industry was
transformed. Early on, the industry had a reasonably secure
probability of a solid return on their R&D investments. They
did not have to resort to artificial means to influence the
market. As the economic pressures and risks increased, it became
increasingly tempting to engage in a political process to shelter those
risks and increase the likelihood of a good return on investment.
Also, there was increasing pressure to stifle the dissemination of
potentially unfavorable research results.
As this was happening, the health care industry became much
broader. Not only were there profits to be made by physicians,
but insurance companies, hospitals, and many other groups developed a
financial stake in the vicissitudes of the pharmaceutical
companies. There were many more competing interests, all with
their own agendas. Even groups that were not directly tied to the
health care industry -- such as the The Competitive Enterprise
Institute -- started to get into the act. The Pediatric Rule,
which was fairly obscure in 1998, became a focal point for all these
competing interests. What had appeared to be a fairly
straightforward and uncontroversial topic became an issue on which
fortunes could be made or lost, and a focal point for political
ideology. As a result, the important issue of pediatric safety
testing became a political football.
It has been a long, strange trip. The strange part has developed
only recently. My impression is that the Pediatric Research
Equity Act of 2003 is a good piece of legislation, and that the matter
now is more or less settled. There is an apparatus in place for
appropriate pediatric drug safety studies to be done. Reform of
corporate finance is underway. There are still competing
interests, and there still is a need for public vigilance. There
is a need for reform in the way research is done and reported.
Greater transparency would help.
There is a way to defuse some of the political and financial issues
that led to this mess. Even though the mess is getting
straightened out, it would be well for us all to think about ways to
keep important legislation such as the Pediatric Research Equity Act of
2003 in place, and to prevent excessive politicization
of important safety issues. We could either drop the notion of
health insurance completely, or work toward universal health
coverage. The former is not an attractive option. The
latter is not attractive either, but would offer some advantages.
It probably is no accident that the revelations about pediatric use of
antidepressants first occurred in the UK. With a national health
plan, all citizens have an interest in the efficient operation of the
health care system. In such a system, if a class of drugs is
being used inappropriately, everyone suffers. This has the effect
of getting everyone on the same team, at least partially nullifying the
competing interests. Likewise, everyone benefits if the only
pharmaceuticals that are used are those that are safe and effective.
Link skipping from 
article is
about the complications at NIH. I conclude with some comments of
my own. 
Yesterday, I wrote some background material on
fMRI. After I did that, I ran across a site, whimsically named 
:
Joseph j7uy5
