Saturday, May 08, 2004

The Long, Strange Trip
What Happened to Pediatric Drug Safety Testing?

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?


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.