Guidance for Industry

Postmarketing Adverse Event Reporting for Medical Products and Dietary Supplements During an Influenza Pandemic
 
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U.S. Department of Health and Human Services
Food and Drug Administration
Office of Counterterrorism and Emerging Threats (OCET)
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Center for Food Safety and Applied Nutrition (CFSAN)

December 2008
Procedural

 

TABLE OF CONTENTS

 

1. INTRODUCTION
2. BACKGROUND
3. PREPAREDNESS FOR ADVERSE EVENT REPORTING DURING AN INFLUENZA PANDEMIC
   1. Information on Pandemic Influenza Preparedness
   2. Development of a Continuity of Operations Plan in the Case of an Influenza Pandemic.
   3. FDA Expectations for Adverse Event Reporting During an Influenza Pandemic
      1. Reporting Requirements During Federal Government Response Stages 0, 1, 2, 3, and 4
      2. Enforcement Approach  During Federal Government Response Stages 5 and 6

APPENDIX 1:  CURRENT REQUIREMENTS FOR POSTMARKETING SAFETY REPORTS           

Guidance for Industry ^1.
Postmarketing Adverse Event Reporting for Medical Products and Dietary Supplements During an Influenza Pandemic

 

 

I.          INTRODUCTION

This guidance provides recommendations to industry regarding postmarketing adverse event reporting for drugs, biologics, medical devices and dietary supplements during an influenza pandemic. FDA anticipates that during an influenza pandemic, industry and FDA workforces may be reduced, while reporting of adverse events ^2. related to widespread use of influenza-related products may increase.  The extent of these possible changes is unknown.  This guidance discusses FDA’s intended approach to enforcement of adverse event reporting requirements for medical products and dietary supplements during the Federal Government Response Stages ^3. of an influenza pandemic.  FDA believes this approach will make it possible for firms with reporting responsibilities to focus their limited resources on reports related to influenza-related products and other specific types of reports indicated in this guidance, as well as on reports related to any other products presenting special concerns as specified by FDA. ^4.  

This guidance does not address monitoring and reporting of adverse events that might be imposed as a condition for products authorized for emergency use under section 564 of the Federal Food, Drug, and Cosmetics Act (FD&C Act) (21 U.S.C. 360bbb-3). ^5.   This guidance also does not address monitoring and reporting of adverse events as required by regulations establishing the conditions for investigational use of drugs, biologics, and devices. (See 21 CFR parts 312 and 812.)

FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

 

II.        BACKGROUND

Pandemic preparedness is a global responsibility.  It is expected that widespread human outbreaks of pandemic influenza, whether overseas or in the United States, will affect industry’s normal functions.  Although overseas outbreaks may not seem to directly affect domestic operations, international medical product and dietary supplement production, availability, and adverse event reporting may be disrupted if a firm’s international sites are affected. Thus, industry should develop plans to ensure continuity of operations during an influenza pandemic (discussed in section IV.B).  It is important that firms consider the adverse event reporting functions of their U.S. locations and their international locations in the face of a potential pandemic. 

Table 1 summarizes Federal Government Response Stages mapped to the World Health Organization (WHO) Global Pandemic Phases.  This guidance provides recommendations for reporting adverse events based on the Federal Government Response Stages.

 

Table 1. WHO Global Pandemic Phases and the Federal Government Response Stages ^6.

WHO Phases		Federal Government Response Stages
Inter-Pandemic Period
1	No new influenza virus subtypes have been detected in humans.  An influenza virus subtype that has caused human infection may be present in animals.  If present in animals, the risk of human disease is considered to be low.	0	New domestic animal outbreak in at-risk country
2	No new influenza virus subtypes have been detected in humans.  However, a circulating animal influenza virus subtype poses a substantial risk of human disease.
Pandemic Alert Period
3	Human infection(s) with a new subtype but no human-to-human spread, or at most rare instances of spread to a close contact.	0	New domestic animal outbreak in at-risk country
		1	Suspected human outbreak overseas
4	Small cluster(s) with limited human-to-human transmission but spread is highly localized suggesting that the virus is not well adapted to humans.	2	Confirmed human outbreak overseas
5	Larger cluster(s) but human-to-human spread still localized suggesting that the virus is becoming increasingly better adapted to humans, but may not yet be fully transmissible (substantial pandemic risk).
Pandemic Period
6	Pandemic phase: increased and sustained transmission in general population.	3	Widespread human outbreaks in multiple locations overseas
		4	First human case in North America
		5	Spread throughout United States
		6	Recovery and preparation for subsequent waves

III.       PREPAREDNESS FOR ADVERSE EVENT REPORTING DURING AN INFLUENZE PANDEMIC

A.        Information on Pandemic Influenza Preparedness

The Department of Health and Human Services (HHS) manages the U.S. Government avian and pandemic flu information Web site (www.pandemicflu.gov), which displays both the current “WHO Pandemic Alert Phase” and the “U.S. Pandemic Stage.”  Manufacturers should keep abreast of the current federal government response stage.  In addition, to facilitate communication between FDA and industry, firms should ensure that all contact information provided to FDA on forms and reports is up-to-date.  FDA also recommends that firms subscribe to the Agency’s MedWatch E-list, ^7. which is used to notify E-list subscribers about medical product and dietary supplement safety issues.

B.        Development of a Continuity of Operations Plan in the Case of an Influenza Pandemic

Each firm should develop a continuity of operations plan (COOP) to ensure that its operations continue during all stages of pandemic influenza.  Guidance on developing COOP plans is available.  For example, the U.S. Department of Homeland Security (DHS) has issued a Pandemic Influenza Preparedness, Response, and Recovery Guide for Critical Infrastructure and Key Resources, ^8. which addresses the development and implementation of a “Continuity of Operations – Essential (COP-E)” plan.  The DHS Federal Emergency Management Agency (FEMA) Web site ^9. also provides information on pandemic influenza COOP planning.

This guidance is limited to FDA recommendations for reporting adverse events during a period of pandemic influenza.  Each firm’s pandemic influenza COOP plan should include instructions for reporting adverse events.

C.        FDA Expectations for Adverse Event Reporting During an Influenza Pandemic

1.         Reporting Requirements During Federal Government Response Stages 0, 1, 2, 3, and 4

During Federal Government Response Stages 0 through 4 (see Table 1), normal adverse event reporting processes should be maintained. All adverse event data should be handled using each firm’s usual standard operating procedures, and regulatory and statutory requirements for adverse event reporting must be met.

Firms should develop and prepare to implement their COOP in the event that an influenza pandemic reaches Federal Government Response Stages 5 and 6.

2.         Enforcement Approach  During Federal Government Response Stages 5 and 6

FDA anticipates that during Stage 5 of an influenza pandemic, industry and FDA workforces may be reduced at the same time that reporting of adverse events related to influenza-related products may increase.  However, the extent of these possible changes is unknown. FDA encourages all firms to plan for these circumstances to maintain the highest feasible level of adverse event monitoring and reporting throughout the pandemic period. Recognizing that a pandemic may reduce a firm’s capacity to comply with adverse event reporting requirements, however, FDA offers this general guidance to help manufacturers strategize use of their resources.

As explained below, FDA does not intend to object if, during Federal Government Response Stage 5, certain required adverse event reports are not provided within the timeframes required by statute and regulation, provided that any delayed reports are then provided during Federal Government Response Stage 6.
 
Table 2 indicates which reports firms may generally store if necessary during Stage 5, without FDA objection.  Where Table 2 says that during Stage 5, a type of report may be stored if necessary, this indicates that FDA does not intend to object if firms maintain newly received information regarding the underlying adverse events but do not submit reports in the timeframes mandated by statute or regulation.  However, any delayed reports must be submitted after Stage 5 ends.   

This guidance is not intended to discourage adverse event reporting during Stage 5 by firms that are able to continue reporting operations.  Firms that are able to report more than the minimum described in Table 2  should prioritize the order of report submission.  For example, reports with regulatory timeframes of 30 days or less (e.g., 15-day reports, 30-day reports) should be submitted before periodic safety reports.  During Stage 5, all firms are strongly encouraged to submit as many required reports as possible to minimize reporting burdens once Stage 5 has ended. 

As indicated in Table 2, if FDA has specified a product as presenting special concerns, firms must submit required adverse event reports as FDA indicates, regardless of the more general recommendations in Table 2.  Aside from this circumstance, in Table 2, reporting recommendations for drugs and biologics are prioritized by type of product so that reporting can focus on products that are likely to have greater use and may necessitate greater monitoring during pandemic influenza.  Further, 15-day reports have priority over periodic reports. For medical devices, the reporting priority is specified by outcome (i.e., fatal outcome vs. nonfatal outcome).  Table 2 also includes reporting recommendations for other products and additional details.

During Stage 6, it is expected that firms will resume fulfilling all reporting requirements on time as well as submit reports that were stored during Stage 5.  Firms are generally expected to submit stored reports to FDA within 6 months of the date that Stage 6 begins. Firms should prioritize the order of submission for stored reports.  For example, reports with regulatory timeframes of 30 days or less (e.g., 15-day reports, 30-day reports) should be submitted before periodic safety reports.  

Firms that cannot meet adverse event reporting requirements at the minimum levels identified   in this guidance should consult the appropriate FDA organizational unit responsible for adverse event reporting compliance.