New FDA Guidance on Extent of Safety Data in Late Stage and Postapproval Clinical Investigations

On February 18, 2016, the U.S. Food and Drug Administration, FDA, published a new Guidance for Industry on "Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket and Postapproval Clinical Investigations".

The guidance provides a selective approach to safety data collection during late stage premarket and postapproval clinical investigations (e.g., phase 3 clinical trials, studies of new uses, long-term outcomes) based on what is already known abaout a drug´s safety profile. 

FDA believes that this guidance will give sponsors the flexibility to design and implement protocols with selective safety data collection where appropriate. The guidance does not affect reporting of postmarketing adverse events relevant to an approved drug or of investigational new drug application (IND) safety information. Those reporting requirements remain unchanged.

The selective approach can be used for the collection of safety data for common, non- serious adverse events that have been well-characterized through data collection in earlier stages of development. For example, "if safety data already collected on hundreds of patients indicate that 17 percent reported a headache when on drug treatment compared with 10 percent on placebo, collection of similar data in thousands of additional patients in a large phase 3 trial would minimally refine this value  and would require extensive resource utilization, while providing no important new information." In this situation, a limited collection of safety data might be appropriate.

Examples of selective data collection include, for example

  • no collection of certain safety data,
  • less-frequent collection of certain safety data,
  • Collection of certain safety data from only a fraction of the total trial group (e.g., 10 % of participants in a large trial).

Types of clinical Investigations that may be suited for the selective approach:

  • Clinical investigations of new indications of approved drugs,
  • Postapproval clinical studies and trials conducted to fulfill postmarketing requirements,
  • Late -stage premarket and postapproval outcome clinical trials,
  • Premarket clinical investigations for some original applications,
  • Postapproval clinical investigations in a different patient population or with different doses or other conditions of use. 

Types of data that may be appropriate for the selective approach:

  • Non-serious adverse events not associated with dose modification, drug discontinuation, or with withdrawal from the clinical trial,
  • Routine laboratory monitoring,
  • Information on concomitant medications
  • Patient history and physical exams.

Information on exposure in some patient groups (e.g., pediatric, pregnant etc.) is often limited and the selective approach may not be appropriate in those populations. Additionally, the selective data collection is not suitable in case of suspected causal relationships between a drug and an adverse event. To better characterize the relationship it might be important to continue collecting complete safety information throughout drug development.

Data that should always be collected (generally not appropriate for the selective approach):

  • 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,
  • In an oncology setting, data from all Grade 3 and 4 adverse events, as well as Grade 2 that affect vital organs,
  • In development programs for rare disease indications.

The methods for selective data collection include:

  • Limiting safety data collection to a pre-identified subset of study population,
  • Decreasing the frequency of data collection.

Specific safety data that will not be collected in the selective approach should be listed in the protocol.

A sponsor considering selective safety data collection should consult with the relevant FDA review division to determine whether such collection would be considered appropriate and to reach an agreement with the division on the details of the plan (e.g., at the end-of-phase 2 meeting for selective safety data collection for a phase 3 trial).

More detailed information can be found in the FDA Guidance for Industry on "Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket and Postapproval Clinical Investigations".

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