Research disclosure and drug safety monitoring requirements raise new challenges


The Food and Drug Administration Amendments Act (FDAAA) enacted in September 2007 requires new initiatives to expand information on the risks and benefits of prescription drugs. One goal established in FDAAA is the modernization of FDA’s system for detecting adverse drug events (ADEs); therefore, the current system is being reviewed so limitations and capabilities can be identified.

The Food and Drug Administration Amendments Act (FDAAA) enacted in September 2007 requires new initiatives to expand information on the risks and benefits of prescription drugs. One goal established in FDAAA is the modernization of FDA’s system for detecting adverse drug events (ADEs); therefore, the current system is being reviewed so limitations and capabilities can be identified.

Another important component of FDAAA calls for federal agencies to devise a system that will expand public access to data from clinical trials. The policy reflects demands from policy makers, researchers, and drug safety advocates for better information on safe and effective treatments, as research transparency concerns continue to surface.

A long delay in releasing results from studies on ezetimibe/simvastatin has caused controversy and ignited concerns about the “wastebasket effect,” the effect of not publishing negative study results. An article recently published in the New England Journal of Medicine (2008;358:252–260) focused on trials of antidepressants and the publication rates for positive and negative data.

In an effort to reduce and/or eliminate the ability of drug research sponsors to hide unfavorable data, a group of leading medical journals established a policy 4 years ago to reject all articles discussing results from clinical trials not registered in a public database. The policy also aimed to rebuild public trust in the biomedical research system and to provide reassurance to patients that “their altruism would see the light of day,” according to Christine Laine, MD, MPH, senior deputy editor, Annals of Internal Medicine, at a January 2008 conference in Washington, DC, sponsored by ExL Pharma, New York, NY.

Expanded registration
To further these efforts to increase drug and trial information, FDAAA requires research sponsors to register most clinical trials on the website, which is operated by the US National Library of Medicine (NLM)/the National Institutes of Health (NIH). Prior to FDAAA’s implementation, the only trials that required FDA registration were those including drugs to treat serious or life-threatening conditions; clinical trials of medical devices did not require registration. Now, more products are covered and more detailed information is required as part of the registration requirements. Phase 1 studies are still exempted from FDA registration requirements,  although World Health Organization (WHO) regulations require these trials to be registered. This inconsistency is just one of many that exist worldwide.

Implementing the registration requirement has been an enormous task. According to information presented during the ExL-sponsored conference, new trial registrations doubled from approximately 250 to nearly 500 a week in the last weeks of 2007,  in part because of the December 26, 2007, registration deadline. Approximately 12,000 registered studies had to be modified to include additional data related to primary and secondary outcomes, patient recruitment criteria, study sites, and contacts.

Expanding information
Of particular interest to formulary managers is the FDAAA requirement to link trial registration to resulting safety and efficacy data. Some pharmaceutical companies have posted trial results, although on a voluntary basis.

The first step, which already is in effect, links registrations to public information about drugs. This includes the posting of FDA’s drug approval package, documents discussed by advisory committees, public health advisories, NLM Medline citations of published articles, and the product’s approved label in the NLM’s DailyMed database.

By September 2008, the database must include “basic results” from clinical trials that support product approval. These basic results include baseline characteristics of study participants, primary and secondary outcomes, point of contact for scientific queries, and information on sponsor agreements with investigators that could restrict their ability to discuss or publish trial results. This disclosure must be made within 12 months of trial completion, which occurs when patients stop taking the trial drug.

Another step is the establishment of a process to include ADE reports in the results database. FDA is required to have this process in place by March 2009. The final step is to have trial sponsors provide summary information on study results. By September 2010, FDA has to define how technical and “plain language” (nontechnical) summaries should be constructed so as not to mislead the public or appear promotional.

Pharmaceutical companies have raised concerns that posting such summaries could easily violate rules against promoting unapproved uses of drugs and that the release of data out of context could cause unnecessary public alarms. Disclosure advocates believe that access to prior research data and negative results will help patients and healthcare professionals make treatment decisions while also opening the door to more and better meta-analysis.

Assessing adverse events
FDAAA’s drug safety provisions also support efforts to expand and improve FDA’s Adverse Event Reporting System (AERS). This adverse event database contains approximately 4 million case reports and approximately 300,000 new reports are added each year as patients and healthcare professionals inform manufacturers and regulatory authorities of problems related to medical products.

The AERS is considered effective at detecting signs of rare, unexpected drug safety events, including new drug interactions and confusion over product names and labeling. But there are concerns among experts that reports are often incomplete and that the system is not particularly useful in addressing safety issues that could stem from existing medical conditions, such as cardiac problems related to cyclooxygenase-2 (COX2) inhibitors or diabetes drugs.

FDA is assessing the value of the AERS, including the time it takes for the system to identify safety problems, and to what extent spontaneous reports from patients and health professionals actually lead to regulatory action. FDA and Congress are considering expanding the oversight of drug safety by building an active AE detection program linked to health-system and government healthcare databases; however, the assessment of the current system must first be competed.

At an FDA public workshop in January to examine the current AE reporting system, Solomon Iyasu, MD, MPH of CDER’s Office of Safety and Epidemiology (OSE), explained that the AERS is valuable because it covers all FDA-regulated products and reaches a large real-world patient population, including those patients using drugs off-label. However, officials at the meeting said that the AERS fails to detect many safety problems, and many of the reports are incomplete and uninformative. The massive volume of reports in the AERS “varies from utter nonsense to real gold,” said Ralph Edwards, MB Chb (Bachelor of Medicine), MRCP, of the WHO. Despite the system’s weaknesses, there was a strong consensus among workshop participants that spontaneous AE reporting should be retained and strengthened, and that a new active safety detection system should be complementary to what already exists.

An analysis by OSE researchers demonstrated that safety issues occur throughout a drug’s life cycle, with many serious issues emerging after some drugs are on the market for more than 13 years. These issues will be examined in depth in a report on the current AE reporting system and how alternative approaches may improve drug safety oversight.

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