An FDA Form 483 may not be new, but it still brings fear of the unknown, regardless of tenure, to the clinical research industry. The implications of receiving a Form 483 are perhaps perceived differently by stakeholders, and some sites lack clarity regarding the purpose and anticipated results surrounding a Form 483.
At its most basic, an FDA Form 483 is a list of observations made during an inspection that may constitute violations of the Food, Drug and Cosmetic (FD&C) Act and other related Acts. The observations are communicated at the conclusion of the inspection and listed in descending order of importance. This is not an all-inclusive list, but a snapshot of issues seen during the inspection. Some common findings, according to the FDA, include protocol deviations, inadequate accountability for the investigational product, informed consent issues and failure to follow the investigational plan.
Steps to creating a CAPA plan
Receiving a Form 483 can seem daunting; however, it is also an opportunity for a site to address any internal issues and make the necessary changes. For instance, a common observation made by FDA investigators during an inspection is inadequate record keeping. Upon receiving notice of this finding, a site should immediately address how this became an issue in the first place. This is an opportunity for the site to take a step back and review internal processes. It is likely that the root of the problem can be easily fixed, for example, by switching from a traditional handwriting method to a digital recordkeeping process.
Depending on the severity of the observation, it is possible to avoid receiving a warning letter if an FDA Form 483 is responded to within an adequate amount of time—15 days or less. It is important to be clear and concise when crafting a response, and address each observation while outlining the corrections that will be made.
Regardless of how simple or complex the issue, it needs to be critically examined and analyzed. Once the root cause is determined, outlining a solution, or Corrective and Preventative Action (CAPA) Plan, is the next step. Once the plan to implement the corrective action is in place, it is important to continuously monitor the process and make adjustments accordingly.
After a Form 483 is issued, an Establishment Inspection Report (EIR) will be provided by the FDA when the inspection is determined to be “closed.” Any narrative reports from the investigator, including refusals, voluntary corrections or promises made by the site’s management, will be included in the EIR, as well as copies of forms issued by the FDA, including the FDA Form 483.
Once a response is carefully crafted and sent, there are two possible outcomes—the 483 response may satisfy regulators and the issues are considered resolved, or the response was considered unsatisfactory and a Warning Letter may be issued. Included in the Warning Letter is compiled evidence that supports the observations made during the inspection. Form 483s, EIRs and Warning Letters are public information and can be found on the FDA website: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/.
A Warning Letter is more severe than a Form 483; however, it still allows for time to voluntarily correct the problem. Maintaining communication with the FDA is of the utmost importance, as timelines to correct issues need to be clearly conveyed to regulators. The FDA will typically work closely with the site to discuss corrective action plans and a follow-up inspection.
Ultimately, a Form 483 or a Warning Letter does not signal the end of times for a research site. While the implications are serious, sites can act swiftly and carefully to correct these issues before severe enforcement action occurs. Addressing these issues is not only critical to meeting FDA regulations, it is a chance to ensure a site is operating efficiently and correctly.
Dr. Christophe Berthoux has been the chief executive officer at Synexus since September 2010. Synexus is the world’s leading site management organization (SMO), dedicated to the recruitment and management of clinical trials across the globe for over 24 years. Email comments and questions to email@example.com.
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