FDA Guidance: Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket and Postapproval Clinical Investigations

 

The FDA finalized a guidance it originally released in 2012 that is aimed to help industry collect safety data in late-stage premarket and postapproval clinical investigations. The FDA says in the guidance that selective safety data collection may be possible for some late-stage premarket and postapproval clinical investigations because “certain aspects of a drug’s safety profile will be sufficiently well-established and comprehensive data collection is not needed.”

Safety Databases

Safety databases collect information to accurately assess and characterize the risks of a new drug. A sponsor collects safety-related data during the course of drug development and knowledge of a drug’s safety profile can change as more information comes in through its lifecycle. However, FDA notes that encouraging selective safety data collection in late-stage premarket and postapproval clinical investigations is consistent with the agency’s approach to safety assessment which is focused on information that is useful and adds to current knowledge.

FDA outlines the growing interest in larger, simpler trials to obtain outcome data, data on long-term effects of drugs, and data on comparative effectiveness and safety. According to the agency, excessive safety data collection may discourage the conduct of these types of trials by increasing the resources needed to perform them and be a disincentive to investigator and patient participation in clinical trials. Therefore, FDA believes its guidance will facilitate the conduct of larger trials without compromising the integrity and the validity of trial results or losing important information, facilitate investigators’ and patients’ participation in clinical trials, and help contain costs by making more-efficient use of clinical trial resources.

Selective Safety Data Collection

FDA issues several examples of selective safety data collection, including no collection of certain safety data, less-frequent collection of certain safety data, and collection of certain safety data from only a fraction of the total trial enrollment. The agency writes that in general, selective data may be appropriate for certain types of safety data if:

• The number of patients and their characteristics, the duration of exposure, and the dose range used in previous clinical investigations are sufficient to adequately 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, if an existing safety database is relevant to such investigations.

• Postapproval clinical studies and trials conducted to fulfill postmarketing requirements and postmarketing commitments. For example, 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.

• 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.

• 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.

Additionally, when selective safety data collection is suitable, it may be appropriate to limit collection of data or stop collection of some data, such as:

• Non-serious adverse events not associated with dose modification, drug discontinuation, or withdrawal from the trial.

• Routine laboratory monitoring as in many cases it may be possible to eliminate routine laboratory monitoring or to decrease the frequency of monitoring certain laboratory parameters.

• Information on concomitant medications; if existing data satisfactorily characterize all anticipated drug-drug interactions and metabolic pathways, additional detailed information on concomitant medications may be of limited use, particularly for drugs used only short term.

• Patient history and physical exams, where less-detailed histories and less-frequent physical exams for patients may be appropriate in some circumstances, especially in outcome clinical trials.

FDA writes that other considerations for safety data collection including the collection of complete safety data in population subsets and collection of complete safety data that identifies risk factors. The guidance also specifies that sponsors should be aware of data types that are generally not appropriate for selective safety data collection and should always be collected. This includes:

• Data on all serious adverse events.
• Data on non-serious adverse events that lead to dose modification, drug discontinuation, or withdrawal from the trial.

• Data on unscheduled study visits, hospitalizations, and accidental injuries because these events may reflect serious adverse events of the drug.

• In an oncology setting, data from all Grade 3 and Grade 4 adverse events, as well as Grade 2 adverse events that affect vital organs (e.g., heart, liver).

• In development programs for rare disease indications, complete safety data should be collected, because these trials generally have limited patient populations and are unlikely to meet the recommendations for selective safety data collection.

For these types of safety data, it is generally important to collect information on all occurrences to better understand the following:

• Causality;
• Incidence;
• Severity of adverse events;
• Populations that are at risk;
• Dose-response;
• Other factors that contribute to our understanding of the nature of the event and who is at risk.

In its final section, FDA added language titled, “Agreement between sponsors and FDA on a plan for selective safety data collection.” FDA writes that 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, according to the agency.