The still-unfolding story of the antidepressant drug Paxil (paroxetine) is a commonly cited cautionary tale about a less salubrious side of the pharmaceutical industry. But the story of Paxil also illustrates the power of somewhat obscure laws that have saved children’s lives by changing the way drugmakers test their products.

Paxil—which increases extracellular levels of the neurotransmitter serotonin by inhibiting its reuptake into presynaptic cells—was approved by the US Food and Drug Administration in 1992, and by 2000 it was making the drug company GlaxoSmithKline (GSK) $2 billion per year. But around this time, problems with Paxil began to surface. Adult and adolescent patients were anecdotally reporting side effects, including sexual dysfunction, weight gain, high blood pressure, and increased suicidality—an uptick in thoughts of suicide or self-inflicted injury in some severely depressed patients. These reports of increased suicidality particularly worried pediatricians.

In 1999 the FDA sent GSK...

GSK eventually agreed to conduct the requested studies and submitted the results to the FDA sometime in early 2002, after FDAMA had expired and been replaced by the Best Pharmaceuticals for Children Act (BPCA) of 2002. Though GSK’s own reports on preliminary studies of Paxil in adolescents indicated that it was safe and more effective than a placebo—a heavily disputed interpretation contained in the article reporting the results of the now infamous study 329[1. M.B. Keller et al., “Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial,” J Am Acad Child Adolesc Psych, 40:762-72, 2001.]—the FDA’s analyses of Paxil studies found that suicidal thoughts, suicide attempts, and episodes of self-harm were almost twice as high in young patients with major depressive disorder taking the drug than among those taking a placebo. To boot, the agency found that the drug was no more effective than placebo in treating major depression in children and adolescents.

Infographic: How the Laws Work View full size JPG | PDF
Infographic: How the Laws Work
View full size JPG | PDF

In 2003, the FDA issued a warning that Paxil should not be used in people under age 18. Then, in 2004, the agency issued a stronger black-box warning on Paxil drug-information inserts and on those of other selective serotonin-reuptake inhibitors, stating the potential risk of patients experiencing an increase in suicidal thoughts.

Though the details of GSK’s conduct and misreporting of Paxil studies are still being sorted out, the fact remains that FDAMA and BPCA played a key role in urging the drugmaker to conduct thorough studies in pediatric patients. The resulting warnings concerning Paxil may have saved numerous lives.

The BPCA and the Pediatric Research Equity Act (PREA) of 2003, which also addresses the paucity of clinical data for drugs commonly prescribed to children, are due to expire on October 1, 2012. The case of Paxil is just one example of how these laws help to bring crucial pediatric safety, efficacy, and dosing information to light.

Prior to the enactment of BPCA and of PREA, which mandates drug company-sponsored pediatric drug trials of new compounds indicated for adult conditions that also exist in kids, about 70 percent of the drugs prescribed to American children had never before been tested in patients of the appropriate ages. According to the FDA, that number is now closer to 50 percent.

The laws have also helped counter some of the pharmaceutical industry’s reluctance to conduct clinical trials in children and have worked to curb the practice of prescribing children adult medications that haven’t been subjected to pediatric testing, according to the FDA’s senior pediatric ethicist Robert Nelson. “Historically—in the 1980s and early 1990s—there was a concern that children needed to be protected from research,” he says. “We ought to protect children through research. One needs to take a careful look at the consequences of off-label prescription that lacks evidence in support of that practice.”

University of Pennsylvania emergency doctor Jill Baren articulates the importance of testing drugs in pediatric patients even more plainly: “How society treats our young is often a reflection of our core values.”

And according to Anne Zajicek, chief of the obstetric and pediatric pharmacology branch of the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, society is still not doing a stellar job. “Children are pharmaceutical orphans,” she says, paraphrasing the title—“Therapeutic Orphans”—of a 1968 Journal of Pediatrics paper on the lack drug studies in children.[2. H. Shirkey, “Therapeutic orphans,” J Pediatr, 72:119-20, 1968.] “It’s still an ongoing battle to get children involved in the drug development process.”

BPCA and PREA were last reauthorized in 2007 as part of the FDA Amendments Act (FDAAA). Though few experts dispute the positive impacts of the laws on the health of children in the 15 years since they existed in early forms, some feel that there is room for improvement as the US Congress prepares to hash out their reauthorization.

Establishing the need for pediatric testing

Prior to the 1997 enactment of FDAMA, pediatric drug testing was a rarity. According to a 1989 report published by the FDA’s Center for Drug Evaluation and Research, 80 percent of the new molecular entities approved by the agency from 1984 through 1989 had no labeling for children.[3. Offices of Drug Evaluation Statistical Report. Center for Drug Evaluation and Research, Food and Drug Administration, Public Health Service, 1989. Rockville, MD: US Department of Health and Human Services publication 89-233530.] Most of these compounds lacked such labeling information because they had never been tested in children.

Children are pharmaceutical orphans. It’s still an ongoing battle to get children involved in the drug development process.—Anne Zajicek, National Institute of Child
Health & Human Development

But just because a drug has never been tested in children does not mean that a sick child is prohibited from legally receiving it. Due to off-label prescribing, in which physicians can engage but drug companies are not allowed to promote, medications developed and indicated for adult conditions were and are administered to children with similar conditions. “[Drug companies] had no incentive to do [clinical trials in children] before because [doctors] could and still can prescribe drugs to children off-label,” says Norm Fost, a pediatrician and bioethicist at the University of Wisconsin.

This can pose serious problems. A drug’s pharmacokinetic, pharmacodynamic, and toxic properties can vary widely between adults and children for a variety of physiological reasons. (See “Child-Proofing Drugs”) Without adequate safety, dosing, or efficacy data on a particular drug for younger age groups, prescribing that drug to children becomes potentially dangerous guesswork.

The American Academy of Pediatrics voiced the urgency of these concerns as early as the 1970s. “It is not only ethical but also imperative that new drugs to be used in children be studied in children under controlled circumstances so the benefits of therapeutic advances will become available to all who may need them,” the AAP’s Committee on Drugs wrote in 1977.[4. American Academy of Pediatrics, Committee on Drugs, “Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations,” Pediatrics, 60:91-101, 1977.] By 1995, the AAP had upgraded the importance of testing drugs in children to a “moral imperative.”[5. American Academy of Pediatrics, Committee on Drugs, “Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations,” Pediatrics, 95:286-94, 1995.]

But still, drug companies by and large resisted running clinical trials in children as long as they could get a product approved by the FDA without doing them. The reasons for this reluctance are manifold. Certainly, pediatric clinical trials can be ethically tricky; for example, informed consent becomes problematic when a child may not be able to fully understand the risks and benefits of participating in a trial. Historically, such ethical quandaries dissuaded many researchers from conducting needed studies.

But Fost claims that in modern times it is not the ethics, but the expense of conducting additional trials in children, that has kept drugmakers from doing pediatric studies. The ethical considerations are complicated, but not insurmountable, he says. “There’s no inherent ethical barrier to doing needed, well-designed, important clinical trials in children. It’s just more expensive, and the expense is not a sufficient reason for not doing them.”

Lori Reilly, vice president for policy and research at the drug industry’s largest trade association, the Pharmaceutical Research and Manufacturers of America (PhRMA), agrees that the primary sticking point for drug companies leery of conducting pediatric clinical trials has indeed been cost. Reilly emphasizes that conducting sound clinical trials in children requires even more time and money than adult trials because of the physiological differences among children and adolescents.

Prior to the financial incentives in BPCA, laying out those additional funds did not make economic sense for pharmaceutical firms. “A company may engage for 6 years in pediatric research to get an indication for a particular use in children, and it affects such a small percent of children that the return on investment is too small,” Reilly says. “What’s certainly clear is that [BPCA’s] economic incentives work,” adds the FDA’s Nelson.

The physiological differences between children of various ages and adults make it all the more critical to ensure that data exist to better inform the treatment of children, says Baren. “Medications just simply adjusted for size and weight may still not behave exactly the same way in a child’s body,” she notes. “There may be unique characteristics of children that should force us to reexamine how drugs perform in a pediatric population.”

“Children are not small adults, and the smaller the child the less like an adult they are,” Fost concurs. “There’ve been too many examples of drugs being unsafe and ineffective or even lethal in children.”

But BPCA and PREA seem to be turning that around. Since the laws were reauthorized in 2007, drug companies have conducted more than 360 pediatric studies involving more than 166,000 patients, and the labeling information on more than 180 products has been changed, according to the FDA. As of December 2011, the agency has granted about 185 marketing exclusivity extensions under BPCA and its predecessor FDAMA.

Some experts maintain, however, that even given all the positive changes encouraged by BPCA and PREA, there are still ways that the laws can be improved.

Can BPCA and PREA do more?

“There are some gaps in populations that are not well served by the existing legislation,” admits Nelson, who is a neonatologist by training. For example, he says, a lot of the drugs used in neonatal intensive care units are generic and carry very little clinical data from tests conducted in appropriately aged populations. But because the marketing exclusivity extensions promised by BPCA do not apply to off-patent drugs or biologics, and because the FDA can only require pediatric studies of new drugs under PREA, it’s exceedingly difficult to entice drug companies to sponsor new trials of generics. Without the prospect of the marketing exclusivity incentive, BPCA becomes rather toothless. “How do you get studies in the off-patent space?” Nelson asks.

The FDA can refer written requests that are declined by the sponsors of off-patent drugs to the National Institutes of Health for funding, but between the 2007 reauthorization of BPCA and June 30, 2010, that only occurred twice, and the perennially cash-strapped NIH has only initiated funding for the study of one of those two products.

There are also specific drug classes and disease areas to which the laws’ impacts have not yet extended. For example, researchers reported last year that antipsychotic drugs, which are used to treat schizophrenia, severe autism, and other psychiatric disorders sometimes experienced by very young children, may cause brain-tissue loss over time.[6. B.C. Ho et al., “Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia,” Arch Gen Psychiatry, 68:128-37, 2011.] That finding, combined with 2010 data indicating that antipsychotic drug treatment of children aged 2 to 5 approximately doubled between 1999–2001 and 2007,[7. M. Olfson et al., “Trends in antipsychotic drug use by very young, privately insured children,” J Am Acad Child Adolesc Psych, 49:13-23, 2010.] and the fact that very little clinical data exists for this class of drugs in pediatric patients, constitutes a worrisome state of affairs.

Negotiating the reauthorization

Even with their shortcomings, PREA and BPCA have been steps in the right direction. But some outside the pharmaceutical industry are critical of the 6-month marketing extension that BPCA uses as a carrot for drug companies. Marcia Angell, former editor-in-chief of the New England Journal of Medicine and a medical ethicist at Harvard University, considers the provisions of the BPCA little more than legal bribery. “What in fact this law does is extend the exclusive marketing rights for another 6 months, and already they are quite long marketing rights,” she says. “These companies are among the most profitable in the world, and they don’t need any more bribes.” Angell suggests instead that the stick represented by a law like PREA, with its requirement for pediatric testing of any new drug that could be indicated for children or adolescents, come to the fore. “Just as we shouldn’t approve drugs that haven’t been tested in women,” she says, “we shouldn’t approve drugs that haven’t been tested in children.”

Fost considers the cost to the public of BPCA’s 6-month marketing exclusivity incentive to be higher than if the government simply funded necessary pediatric studies with tax revenue. “It sure seems as if the taxpayers and citizens are paying a lot more by virtue of this patent extension,” he says. “It seems like a cumbersome way to get clinical trials done.”

As October 1 approaches, US legislators will have to decide whether or not to reauthorize BPCA and PREA, and if so, how the laws might be changed to exert an even greater impact on children’s health than they already have. The pharmaceutical industry would like to see Congress make the provisions of BPCA and PREA permanent, as Europe has done with similar laws, according to PhRMA’s Reilly. “I think that [in Europe] there has been a strong value and immense return for pediatric patients in having these laws made permanent,” she says. Doing the same with BPCA and PREA would “provide greater certainties, which we believe would allow our companies to further grow their pediatric programs.”

Others, like Baren and Fost, would like to see more federal money folded into the laws, and into BPCA in particular, so that more trials could be done, especially when sponsors decline the FDA’s requests to do so. Baren says that devoting more funding to the NIH’s National Institute of Child Health and Human Development could bolster that agency’s Pediatric Trial Network, which is currently conducting studies on psychiatric drugs, pediatric cancer medications, and neonatal treatments, among others. “Having additional resources in that regard would probably be very, very helpful,” she says.

Fost agrees, but also says he knows that the regulatory climate in Washington, DC, these days is not what it was in 2007, the last time BPCA and PREA came up for reauthorization. “It’s a more discouraging time than it was 5 years ago, just because there is such a bizarrely antigovernment sentiment in the land at the moment,” he says. “I have great fears whether that attitude will damage the thinking on Capitol Hill about the FDA reauthorization.”

At least one big pharma firm, GSK, has parlayed a somewhat negative experience with the FDA’s pediatric drug testing laws into positive growth for the company. “Globally, GSK has developed indications for use in at least one pediatric age group for at least 70 percent of potentially relevant products, covering disease areas such as asthma, HIV/AIDS, cancer, infectious diseases, epilepsy, and eczema,” writes GSK spokesperson Sarah Alspach in an e-mail. “There are many different factors that are considered before deciding to conduct clinical trials in pediatrics,” she continues. “Nevertheless, BPCA and PREA provide an important framework to encourage research to better understand the appropriate use of medicines in children.”

Update (Feb 29) – After this article went to press the Institute of Medicine issued a report stating that BPCA, PREA, and similar laws are successfully enticing drug makers to conduct pediatric clinical trials, but that the trend could be improved further by making trials higher quality, requiring more robust ethical justifications for the work, encouraging more long-term studies, and requesting more trials in neonates.

Update (Feb 29) – After this article went to press the Institute of Medicine issued a report stating that BPCA, PREA, and similar laws are successfully enticing drug makers to conduct pediatric clinical trials, but that the trend could be improved further by making trials higher quality, requiring more robust ethical justifications for the work, encouraging more long-term studies, and requesting more trials in neonates.

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