The US Food and Drug Administration (FDA) on Thursday significantly revised and finalized guidance originally released in 2012 that will help industry understand what types of safety data needs to be collected in late-stage premarket and postapproval clinical investigations.
“This guidance provides recommendations on when to consider selective safety data collection and how to do so to maintain a balance between eliminating the collection of data that will not be useful and collecting sufficient data to allow adequate characterization of the safety profile of a drug,” FDA says, changing its terminology from “Targeted Safety Data Collection” to “Selective Safety Data Collection.”
In response to public comments requesting more detail and examples, FDA says the draft guidance was revised and reorganized to clarify what types of safety data and what circumstances may be appropriate for selective collection, in addition to more detail on the draft guidance topics and additional information on safety data reporting issues.
In general, FDA says selective safety data collection may be appropriate for certain types of safety data when the following conditions are met:
- The number of patients and their characteristics, the duration of exposure and the dose range used in previous clinical investigations are sufficient enough to characterize the safety profile of the drug for common, non-serious adverse events.
- The occurrence of common, non-serious adverse events has been generally similar across multiple clinical investigations.
- The drug’s safety profile is established to the extent that it is reasonable to conclude that the occurrence of common, non-serious adverse events in the population to be studied will be similar to rates observed in previously conducted clinical investigations.
FDA also clarifies when selective safety data collection may be appropriate, noting the following types of clinical investigations:
- Clinical investigations of new indications of approved drugs, particularly if an existing safety database is relevant to such investigations, “including, for example, the similarity of the population studied in the new investigation to patients previously studied and the doses used.”
- Postapproval clinical studies and trials conducted to fulfill postmarketing requirements and postmarketing commitments, particularly when the study population in these types of studies is generally the same as or similar to the population from which the premarket safety database was derived, safety data collection can often be limited to the primary safety endpoint and other endpoints of interest.
- Late-stage premarket and postapproval outcome clinical trials: “Typically, a fairly substantial safety database is in existence before initiation of an outcome clinical trial, and this database already provides sufficiently precise estimates of common, non-serious adverse events (e.g., those that occur in 5 percent or more of exposures). Even when there is not extensive prior safety data, full data could be collected in a subset of patients (e.g., 1,000) with more-selective data collection in other patients.”
- Premarket clinical investigations for some original applications: Unless sufficient safety data already exist to adequately characterize the safety profile of a drug, comprehensive safety data collection is expected, FDA says, noting that if sufficiently comprehensive safety data become available before completion of clinical development for a novel drug or biologic, selective safety data collection in some late-stage investigations may be appropriate. For example, FDA says selective safety data collection may be appropriate in Phase III trials where the existing safety database adequately characterizes a drug’s safety for more common, nonserious adverse events; therefore, data on those events may not need to be collected.
- Postapproval clinical investigations in a different patient population or with different doses or other conditions of use: Selective safety data collection generally may not be appropriate in clinical investigations of marketed drugs in which there are important differences in the patient population, dose, dosage regimen, duration of use or route of administration compared with the conditions of use for the marketed indications. “For example, the safety database of a drug approved to treat active cancer generally would not be adequate to permit selective safety data collection in an investigation of the long-term use of that drug for adjuvant therapy or in the prevention of cancer in a healthy population. Even in this setting, however, it may be appropriate, in some cases, to collect common, non-serious adverse events in only a subset of the overall study population. An exception may also apply in cases where a lower dose or shorter duration of therapy is being investigated,” the agency says.
FDA also makes clear that some of the recommendations in this guidance may not align with the expectations of safety data collection in other regions or countries, which may lead to implementation difficulties for some clinical investigations.
“However, we believe this guidance will give sponsors the flexibility to design and implement protocols with selective safety data collection where appropriate,” FDA says.
The agency also added a section to the final guidance on the methods for selective safety data collection, highlighting areas when sponsors can limit safety data collection to a pre-identified subset of a study population and when to decrease the frequency of data collection.
FDA added another section at the end of the final guidance on, “Agreement between sponsors and FDA on a plan for selective safety data collection.” In it, FDA says sponsors should discuss its specified plan with the relevant FDA review division or divisions at the appropriate time (e.g., at the end-of-phase II meeting for selective safety data collection for a phase III trial). The agreement reached should be incorporated into the procedures for safety data collection in the protocol, the monitoring plan and other appropriate trial documents, FDA says.
Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket and Postapproval Clinical Investigations