The process of developing, testing, and marketing a new drug is long and complex, and falls under the oversight of the U.S. Food and Drug Administration (FDA). Any pharmaceutical company beginning investigative work on a new drug must be able to assure the FDA of its safety and efficacy before entering into human trials, and must continue to report possible safety risks over the months or years that the trials take place.
Despite efforts to clarify and streamline the reporting process, however, the FDA still faces thousands of reports every year that don’t present ongoing clinical trial data in a way that gives them a clear picture of drug safety. According to a recent review by the FDA, 86% of the drug safety reports provided to the agency are either uninformative or completely unnecessary.
Initial Application for Clinical Trials
Once a pharmaceutical company has found a target molecule that they have screened for initial safety and effectiveness in in-vitro and animal trials, they must proceed to human clinical trials before they get final FDA clearance for marketing their product. In clinical trials, which can include participants in several states, sometimes even across the globe, the potential new drug is carefully tested for safety and therapeutic effectiveness in different human populations. It is also compared to other existing drugs, to see whether it is equally effective as other treatments already available.
Because clinical trials involve administering a new drug to thousands of people, the FDA requires that pharmaceutical companies submit thorough paperwork to assure them that nobody is likely to suffer dangerous adverse effects. This paperwork is called an Investigative New Drug application, or an IND.
An IND submitted to the FDA must contain chemical information about the drug itself, including who manufactures its components and how it is formulated. The IND must also detail what types of data will be collected, and the means of collection and analysis, by submitting a proposed clinical protocol. The protocol must be approved by an Institutional Review board before being implemented, and must explain how participants will be selected, how side effects will be documented, and what the endpoint of the study will be.
Perhaps most importantly, the pharmaceutical company must include all of their preclinical data in the IND, in order to allow the FDA to assess whether the drug can safely be moved along to human trials. While the trial is ongoing, the investigators must submit information about adverse events (side effects or injuries) to the FDA, in case there’s enough danger to warrant halting the trial.
Problems With Safety Reports
Unfortunately, despite publishing “expedited safety report” guidelines for drug investigators to use, the FDA still receives tens thousands of incomplete or indecipherable safety reports every year. The FDA found that investigators were often submitting every adverse event that occurred during the trial, even if it was statistically unlikely that the drug was a direct cause of the reported event. Although reporting every possible issue certainly sounds thorough and prudent, the extra information makes it much more difficult for the FDA to assess the drug’s safety, as they must work harder to find the events that are more likely to be drug-related.
To improve the situation, the FDA published new rules in 2010 that further clarify how to properly categorize adverse events in expedited safety reports. The investigators must make efforts to determine causality, instead of leaving that work to the FDA. Unfortunately, it doesn’t seem to be helping.
The FDA’s recent review looked at a random sample of expedited safety reports and found that nearly 8 out of 9 reports are either uninformative or completely unnecessary, as the reported adverse events did not qualify for reporting. The authors suggest that a fear of liability may be part of the problem — those who are running clinical trials will report everything out of an abundance of caution, for fear of being accused of hiding risks. For example, Johnson & Johnson has been accused of downplaying the bleeding risks of their anticoagulant, resulting in close to 20,000 Xarelto lawsuits filed by injured patients.
However, another likely problem is a lack of standardization in reporting. Different terms may be used by different investigators to indicate similar adverse events. Some researchers suggest that standardized electronic reporting forms might be a way to reduce possible confusion and allow for easier comparison of safety data across studies over a long period of time. Providing a standard list of adverse events to choose from, for example, would simplify the job of the report writer and make analysis of safety data much easier once it arrives on the desks of FDA staff.
It’s clear that there’s still work to be done to improve the way the FDA is informed of potential problems in clinical trials. The safety of clinical trial participants, is important to all parties involved, on both the pharmaceutical side and the regulatory side of the investigation. Hopefully both industry and government will be able to work together to develop and implement a system that will make reports easier for everyone. Because keeping patients safe means being sure that the right data is being collected and used to assess drug safety, and that the FDA can make sense of what they’re being given.