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Several recent, highly quoted U.S. Food and Drug Administration (FDA) Warning Letters have resulted from focused sponsor/monitor inspections of well-established pharmaceutical companies and their outsourcing partners.1 Coupled with very public criticism of FDA's oversight abilities by the Office of Inspector General (OIG)2 and other governing bodies, the letters have galvanized sponsors to take a close look at their ability to withstand such regulatory scrutiny internally, and to develop proactively their internal capabilities and infrastructure to better manage their outsourced clinical development programs. Since virtually every biopharmaceutical and medical device sponsor uses contract research organization (CRO) services in its development activities, this should be a priority for companies of all sizes and stages.
This article delves into the newly illustrated focus of regulatory inspectors on the relationship between sponsors and monitors and on recommendations to build quality risk management into the clinical trials process. The discussion also includes some of the best practices being adopted to address these new pressures in leading sponsor organizations.
What the Regulations Say
Both FDA regulations and the International Conference on Harmonization's (ICH's) guidelines on good clinical practice (GCP) mandate sponsor oversight (see Figure 1) of all clinical research activities where transfer of regulatory obligations has occurred with external parties through contractual obligation. They also require careful selection and training of qualified individuals to manage the delegated activities. However, the importance of these seemingly simple concepts has grown significantly as the dynamics of developing products in a global environment, coupled with the increased complexity of protocols, medicine, regulations, and the heightened financial constraints of all development stage companies, has become the new norm.
What the Regulators are Doing
Traditionally, sponsor companies and their monitoring partners anticipated that there would be a relatively high likelihood of a regulatory inspection upon submission of a new marketing application (New Drug Application, Biologics License Application, or Pre-Market Approval). The focus on proactive preparation would be only for the most likely sites, where historically, selection was based on highest enrollment or other qualitative risk perception. Several sites would be targeted for each application, with the expectation that if significant violations were identified at some sites, FDA could perform sensitivity analysis excluding those sites before moving forward with the application review. The data at other sites was assumed to be reliable, and if data at those key sites held up under sensitivity analysis, the application could be approved.
Then, in Warning Letters to both Pfizer and Johnson & Johnson, FDA1 cited significant issues with lapses in decision-making, oversight, and the corrective and preventive actions required of all sponsors (see Figure 2), which could result in harm to subjects. These lapses are of the sort that always raise the scrutiny, criticism, and focus from the broader approach of recent inspections undertaken by FDA and the European Medicines Agency (EMA) of sponsors and monitors to ensure that clinical research is being conducted under the utmost care and rigor by all stakeholders.
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