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Leveraging Post-Marketing Safety Data in 505(b)(2) Drug Development Programs

A significant part of the FDA’s charge is ensuring the safety of drugs available to the public. While a substantial part of the FDA’s efforts in guaranteeing public safety go into the safety assessment process during drug development, the process does not end with NDA approval. Post-marketing assessments such as pharmacovigilance programs play a critical role in assuring the public has the most up-to-date safety information about approved products. Additionally, the data generated from these evaluations can assist in the development of future products.

Adverse Event Reporting

The assessment of drug safety is an ongoing process. Even if a product passes the critical hurdles of clinical trials, the Agency recognizes that these studies cannot account for all possible adverse events. For example, a rare, but serious adverse event may not be observed in a clinical study if it has a prevalence of 1:5000. To ensure the safety of a product in a large population, surveillance programs provide a repository for adverse event reporting for the public. The two largest databases of reported adverse events are the World Health Organization’s Vigibase® and the FDA’s Adverse Event Reporting System (FAERS).

Both Vigibase® and FAERS receive adverse event reports from consumers and healthcare providers. Both databases are comprised of records that are reported voluntarily. Over 80 countries participate in Vigibase®, and as of 2014, 10 million adverse events had been reported to the system. For FAERS, the number of reports submitted per year has been steadily increasing, and amounted to 1.2 million reports in 2014 alone.

The Adverse Event Reporting Process

In the United States, when an adverse event occurs, consumers or healthcare providers report these events to the FDA or to the drug manufacturer. If submitted to the drug manufacturer, the drug manufacturer is required to report the information to FAERS. A FAERS report includes information specific to the drug product (drug name, route of administration, dose, regimen, and manufacturer), and the patient (gender, age, adverse event, and patient outcome).

As you can imagine, a database of this size has the potential to be quite powerful. However, there are many limitations associated with FAERS and Vigibase® data. First, there is no certainty that the event was actually due to the product administered. Second, since these programs are voluntary, reports do not exist for every event for a given product. Therefore, data reported from these databases cannot be used to calculate the incidence of an adverse event. Third, since reporting is voluntary, the incentive for reporting is low, and the data may underrepresent the risk of an adverse event. While there are limitations, these databases serve as the front line for identifying previously unknown “safety signals” for drug products.

Results of the Adverse Event Reporting Process

The Agency analyzes the data reported to FAERS to constantly assess drug product safety. Every quarter, the FDA assesses the submitted data for any potential safety issues and reports the results in quarterly reports. When a quarterly report is made, further evaluation is performed leading to one of the following outcomes: 1) the drug is not associated with the risk and no regulatory action is required; or, 2) the drug may be associated with the risk, leading to additional safety assessment, product labeling modification, development of a REMS program, or in the most extreme cases, marketing suspension or withdrawal for reasons of safety.

Case example: Daytrana® (methylphenidate transdermal system)

In the second quarter of 2015, the FDA reported a safety signal for Daytrana®, a methylphenidate patch approved for treatment of Attention Deficit Hypersensitivity Disorder (ADHD) in pediatric patients. Patients using Daytrana® reported chemical leukoderma, a skin condition that causes loss of skin pigmentation in response to specific chemical compounds. While not harmful, chemical leukoderma is disfiguring.

In the case of Daytrana®, patients were reporting skin color loss in areas up to 8 inches in diameter, in the area where the patch was administered. In a small number of cases, chemical leukoderma occurred on body regions where the patch was never applied. In all reported cases, the loss of skin color was permanent.

This rare adverse event had not been observed in preclinical development of Daytrana®. An FDA review found that between April 2006 and December 2014, there were 51 chemical leukoderma FAERS reports and one published case report.

To make the public aware of this adverse event, the Agency required a labeling change for Daytrana® in 2015. This is just one example of how FAERS reporting is used to provide patients the latest drug safety information.

Leveraging Postmarketing Safety Data in 505(b)(2) Drug Development

In addition to serving a public safety role, Vigibase® and FAERS databases are important resources for future drug products. In fact, postmarketing data are used as supportive information in 505(b)(2) applications. Since these applications rely on information for drugs with prior human use, there is typically significant FAERS and Vigibase® data. These data can be used as a component of the safety assessment to complement other safety data.

Products developed under the 505(b)(2) pathway can leverage the information from predecessor drugs, effectively limiting or reducing the uncertainty that surrounds a new drug product. Premier Consulting utilizes these publicly available data sources to guide development strategies, support safety assessments, and develop product labeling among other uses.

As the 505(b)(2) experts, Premier Consulting has extensive experience with FAERS, Vigibase® and other postmarketing safety databases and how best to leverage this valuable information to inform all aspects of the drug development program. Our research services team can mine, analyze and summarize this data to support the safety profile of your drug product. Contact us to learn more.