FDA action on pediatric antidepressant use occurred amid existing concerns that the FDA had insufficient authority and resources to fulfill its mission to protect the public's health. This prompts the question of whether a more robust regulatory environment could have provided the FDA with earlier and more complete information on benefits and risks of antidepressants in treating children.
Historically, one important tool available to the FDA has been a pediatric exclusivity provision, which extends patent protection for drugs to encourage clinical trials on medication effects in child populations. Enacted by Congress in 1997, this provision grants manufacturers an extra six months of patent protection for performing FDA-requested pediatric clinical trials. Relevant to this case, the FDA's meta-analysis assessing the risks of suicidality included several clinical trials conducted under the pediatric exclusivity provision. This provision has substantially increased the available evidence on medication use in children,23
and has been reauthorized twice by Congress in 2002 and 2007. Benjamin and colleagues found, however, that pediatric study results were often not widely disseminated to clinicians through peer-review; only 36 percent of studies where results were unfavorable were published in peer-reviewed journals.24
This provision had been important because the FDA has been limited in its ability to compel firms to comply with requests to complete post-market studies. Between 1991 and 2003, only 24 percent of post marketing studies agreed to during the drug approval phase were completed.25
In 2007, Congress took steps to strengthen the FDA's regulatory authority with passage of the Food and Drug Administration Amendments Act (FDAAA). The FDAAA included many of the recommendations of the Institute of Medicine's 2007 report, The Future of Drug Safety: Promoting and Protecting the Health of the Public
The agency now can require additional studies be performed either at the time of drug approval, or if new safety concerns come to light, post approval. Importantly, the agency was given significant tools to enforce this provision. Also, changes were enacted to improve the usefulness of the FDA's Adverse Event Reporting System (AERS), the voluntary post market surveillance system for providers to report of adverse drug reactions. Another important provision of the FDAAA requires the FDA establish a post-market risk identification and analysis surveillance system in collaboration with public, academic, and private entities to identify risks associated with products already on the market. The Sentinel Initiative, scheduled to be operational in 2010, will use large datasets to identify risks associated with products already on the market. In May 2008, the FDA announced efforts to include data from the Medicare prescription drug benefit in this initiative. Several other recent initiatives, including newly funded centers in the Center for Education and Research on Therapeutics (CERTs) program, have been aimed at increasing the amount of post marketing observational data available regarding prescription drugs. The post-market phase is crucial to identify safety concerns because, as noted above, clinical trials are powered to identify clinical efficacy but may be under powered to detect risks.
Evidence suggests that post-market surveillance systems in other countries have been informative in signaling and assessing potential safety concerns. A study from Finland illustrates the advantages of such systems to study rare events. Linking several national data sources, Tiihonen and colleagues found that current use of an antidepressant (in both adults and children) is associated with both an increased risk of attempted
suicide, and a decreased risk of completed
suicide and mortality.27
If a post marketing surveillance system had been in place in the U.S., such information may have been available to the FDA.
The FDAAA also enacted policy changes aimed at improving the availability of information to providers and patients on prescription drug safety and efficacy. One provision requires that the results from clinical trials be made available publicly in the National Library of Medicine clinical trials database. In the case of pediatric antidepressant use, if data from negative or inconclusive trials had been disclosed, clinicians may have had earlier access to information on the comparative efficacy of antidepressants in treating children. Also important, Congress gave the FDA new regulatory authority under the FDAAA to require a pharmaceutical manufacturer develop a plan to manage known risks associated with a medications use. Risk Evaluation and Mitigation Strategies (REMS) may require the inclusion of risk information in a package insert, a communications plan to inform providers about safety concerns associated with a drug, provisions that can restrict prescribing to certain types of providers or health care settings, as well as other strategies. A REMS plan can be required by the FDA before drug approval or post approval if new safety information is discovered. Since this provision is newly enacted, it is not yet known the extent to which REMS will be effective in improving the overall risk-benefit profile for drugs with safety issues.