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FDA Pandemic Influenza Preparedness Strategic Plan
United States Department of Health and Human Services
Food and Drug Administration
Rockville, MD

March 17, 2008

Table of Contents

1. Executive Summary
2. Strategic Plan Overview
3. Background
   
   
   1. The Pandemic Influenza Threat
   2. National Strategy for Pandemic Influenza
   3. HHS Pandemic Influenza Plan
      
      
4. FDA Roles and Responsibilities
5. FDA Accomplishments
6. FDA Objectives and Actions
   
   
   1. Vaccine and Other Biologics Development, Production, and Regulatory Review
   2. Anti-Viral Drug Development, Production, and Regulatory Review
   3. Device Development, Production, and  Regulatory Review
   4. Food and Feed Safety
   5. Emergency Preparedness, Response, and  Communication
   6. Enforcement
      
      
7. Tables of FDA Objectives and Actions

Appendix: List of Abbreviations/Acronyms

Glossary

I.      Executive Summary

In general, influenza viruses tend to be species-specific, such that an influenza virus that affects birds usually does not affect people.  However, exceptions do occur.  In 1997, a highly pathogenic avian influenza virus (belonging to a subtype known as H5N1¹) appeared to cross the species barrier and result in severe illness and death in humans in Asia.  Since then, highly pathogenic avian influenza has spread to bird populations in other areas within and outside Asia and also has caused illness and death among humans in a growing number of countries.  Most human cases of H5N1 avian influenza (AI, also known informally as “bird flu”) appear to be the primary result of close or direct contact with infected birds, but there is concern that the virus could mutate into a form that is easily transmitted between humans.  If efficient and sustained human-to-human transmission of a new influenza subtype occurs, experts believe the result would be an influenza pandemic because humans would not have any previous immunity to the virus. 

Therefore, to prepare for an influenza pandemic, the Food and Drug Administration (FDA) developed this FDA Pandemic Influenza Preparedness Strategic Plan.  The FDA Pandemic Influenza Preparedness Strategic Plan coordinates with and complements the President’s National Strategy for Pandemic Influenza, the Implementation Plan for the National Strategy for Pandemic Influenza, and the Department of Health and Human Service’s (HHS’s) Pandemic Influenza Plan and the HHS Pandemic Influenza Implementation Plan – Part 1(discussed in parts III.A, III.B, and III.C). 

Part II, Strategic Plan Overview, describes the formation of an FDA Task Force to prepare the FDA Pandemic Influenza Preparedness Strategic Plan, the principles that shaped or guided the plan’s development, and recurring themes.  For example, coordination among Federal, State, local, and tribal governments and private sector parties and communication are two important principles in preparing for and ultimately minimizing the effects of an influenza pandemic.  Other key principles shaping the plan include the following:

• Domestic vaccine production capacity sufficient to provide vaccines for the entire United States population is critical, as is development of a vaccine against each circulating influenza virus with pandemic potential and, ideally, development of a vaccine that confers cross-protective immunity;
• Development of anti-viral drug products and devices is important in preparing for, and responding to, an influenza pandemic; and
• Availability of improved point-of-care diagnostic devices to detect and also differentiate between seasonal influenza viruses and novel influenza A viruses having pandemic potential.  This differentiation could be critical for effective patient management and pandemic influenza preparedness and response.  Healthcare providers will need guidance to use point-of-care tests effectively and to use results in patient management, both in pre-pandemic and pandemic influenza phases.

Facilitating the development of vaccines, anti-viral drug products, and devices before an influenza pandemic occurs means we must take a proactive role in working with manufacturers, academia, and others to identify promising new therapies and to determine how we might ensure that our review of such products is as efficient as possible.  It also means communication and teamwork between public and private parties will be important so all parties are aware of new developments and can use their resources effectively.

Part III, Background, provides basic information about influenza viruses, the National Strategy for Pandemic Influenza, and the HHS Pandemic Influenza Plan.  The former plan coordinates pandemic influenza preparedness and response at all government levels, the private sector, individual citizens, and international entities.²  The latter plan is a “blueprint” for pandemic influenza preparedness and response planning within HHS and also provides guidance on specific aspects of pandemic influenza planning and response for State and local preparedness plans.³  These two plans and their associated implementation plans provide a framework for the FDA Pandemic Influenza Preparedness Strategic Plan.

Part IV, FDA Roles and Responsibilities, describes the FDA centers and offices that will have important roles in preparing for, and responding to, an influenza pandemic.  It also describes the subgroups within the FDA Task Force and their main responsibilities.  In brief:

• The Center for Biologics Evaluation and Research leads the Vaccine and Other Biologics Development, Production, and Regulatory Review Subgroup;
• The Center for Drug Evaluation and Research leads the Anti-viral Drug Development, Production, and Regulatory Review Subgroup;
• The Center for Devices and Radiological Health leads the Device Development, Production, and Regulatory Review Subgroup;
• The Center for Food Safety and Applied Nutrition and the Center for Veterinary Medicine lead the Food and Feed Safety Subgroup;
• The Office of Crisis Management and the Office of External Relations lead the Emergency Preparedness, Response, and Communication Subgroup; and
• The Office of Regulatory Affairs leads the Enforcement Subgroup. 

Additionally, the Office of International Programs manages FDA’s international activities and interactions with the Office of the Secretary, HHS and advises the centers and offices regarding our international pandemic influenza preparedness activities.

Part V, FDA Accomplishments, describes some recent actions we have taken to prepare for a possible influenza pandemic. 

Part VI, FDA Objectives and Actions, lists various pandemic influenza preparedness activities that are or will be critical to the development, review, and approval of vaccines, anti-viral drug products, and devices or to safeguarding food and animal feed.  It also lists activities for protecting Americans against fraudulent or counterfeit pandemic influenza products.  This part describes our objectives, the actions to be taken to further those objectives, and “deliverables” (the expected result or end-product for a particular action). 

Part VII, Tables of FDA Objectives and Actions, summarizes our intended actions, deliverables, and timeframes in relation to our larger pandemic influenza preparedness objectives.  We have organized the tables according to the individual subgroups within the FDA Task Force on Pandemic Influenza Preparedness. (We discuss the FDA Task Force on Pandemic Influenza Preparedness in the next section.)

II.     Strategic Plan Overview

Pandemic influenza is a significant public health threat to our nation and to the world.  Across the globe, officials are developing plans to prepare for, and respond to, the next influenza pandemic.  Though no influenza pandemic has struck the United States in decades, scientists are concerned that the highly pathogenic avian influenza strain (H5N1) currently circulating in wild and domestic birds in Asia, Europe, the Middle East, and Africa could mutate into a form capable of efficient and sustained human-to-human transmission which could result in a global outbreak (a pandemic).  Preparedness planning is imperative to lessen the impact of such a pandemic.  To this end, on November 1, 2005, the President issued a National Strategy for Pandemic Influenza that called for comprehensive and coordinated pandemic preparedness planning at all levels of government and the private sector.  On November 2, 2005, the Secretary of Health and Human Services, Michael O. Leavitt, released the HHS Pandemic Influenza Plan which provides a blueprint for all HHS pandemic influenza preparedness planning and response activities. 

To increase the Nation’s preparedness for an influenza pandemic, in November 2005, the (then Acting) Commissioner for Food and Drugs, Andrew von Eschenbach, M.D., established an FDA Task Force on Pandemic Influenza Preparedness to set into operation FDA's participation in the President's National Strategy for Pandemic Influenza and the HHS Pandemic Influenza Plan.  The FDA Task Force members included representatives from the Center for Biologics Evaluation and Research (CBER), Center for Drug Evaluation and Research (CDER), Center for Devices and Radiological Health (CDRH), Center for Food Safety and Applied Nutrition (CFSAN), Center for Veterinary Medicine (CVM), National Center for Toxicological Research (NCTR), Office of Regulatory Affairs (ORA), Office of the General Counsel’s Food and Drug Division (OGC), Office of Counterterrorism Policy and Planning, Office of Crisis Management, Office of International Programs, Office of Pediatric Therapeutics, Office of Policy and Planning, the Office of Science and Health Coordination, and the Office of External Relations.

The FDA Task Force’s key charges were to:

• Develop a comprehensive action plan to accelerate the development, production, and regulatory review of vaccines, anti-viral drug products, diagnostics, personal protective equipment (PPE), and other devices as pandemic countermeasures;
• Develop a comprehensive food and feed security strategy;
• Protect the safety and security of regulated medical products;
• Enhance emergency preparedness and response capabilities; and
• Pursue enforcement actions to curtail production, shipment, trade, and use of fraudulent or counterfeit products.

The Task Force also was charged with developing an implementation strategy for the FDA Pandemic Influenza Preparedness Strategic Plan. 

This FDA Pandemic Influenza Preparedness Strategic Plan reflects the diligent work of the FDA Task Force on Pandemic Influenza Preparedness and its subgroups and serves as the basis for the implementation strategy.  It was originally completed and made public on March 14, 2007.  This updated version reflects the continued assessment of FDA’s objectives, actions, deliverables and timeframes by the Task Force subgroups and we expect to continue to update the FDA Pandemic Influenza Preparedness Strategic Plan periodically as circumstances warrant.

The following principles guided our development of this plan:

• Preparedness will require coordination among Federal departments and agencies, State, local, and tribal governments, foreign governments, and private sector parties (such as industry, healthcare professionals, and academia).
• Communication is essential to minimizing the health effects of an influenza outbreak and for preparing for such an outbreak.
• Domestic vaccine production capacity sufficient to provide vaccines for the entire United States population is critical, as is the development of a vaccine against each circulating influenza virus with pandemic potential and, ideally, the development of a vaccine that confers cross-protective immunity. 
• Development of anti-viral drug products, other biologic products, and diagnostics, PPE, and other devices is important in preparing for, and responding to, an influenza outbreak.
• Protection of human food and animal feed will include identifying food and feed at risk of AI contamination and identifying methods to inactivate influenza viruses.
• Protecting consumers from fraudulent or counterfeit products is also important in preparing for an influenza outbreak.
• Ensuring that our workforce has appropriate administrative and technological support and the best available public health information to remain effective throughout a pandemic influenza period is necessary.

These principles are similar to or complement those used in the HHS Pandemic Influenza Plan. 

Consistent with the FDA Task Force’s charges and guiding principles, the FDA Pandemic Influenza Preparedness Strategic Plan has several recurring themes.  For example, to accelerate product development, we have to be proactive in working and communicating with industry, academia, and others, including sister agencies, such as the Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH), within HHS to determine which approaches will be the most efficient and the most effective.  In many cases, this means we will assume a leadership role in identifying important issues and communicating about scientific and regulatory developments.  These communications can take many different forms and range from hosting or participating in meetings and conferences to posting information on our Web site. 

In all cases, teamwork and cooperation between FDA’s centers and offices, between HHS agencies, between Federal, State, local, and tribal governments, or between the United States and other countries or international organizations (such as the World Health Organization (WHO), the Food and Agriculture Organization of the United Nations (FAO), and the World Organisation for Animal Health (better known as the OIE)) are essential for a better understanding of potential pandemic influenza issues and better solutions.

In addition, active involvement by all stakeholders is critical for an effective national response.  For example, while we can facilitate product development and regulatory review and help ensure that products are available, other parties (such as academia, industry, and other government agencies) must fund and conduct the research (including clinical testing) necessary to invent a product, investigate its safety and effectiveness, and, ultimately, manufacture the product.   

III.    Background

A.     The Pandemic Influenza Threat

Influenza A viruses have the capacity to infect many different animal hosts.  The influenza A viruses typically seen in one animal species may sometimes infect and cause illness in another species.  The potential for genetic mixing of different influenza A viruses within human or animal hosts, or the spontaneous mutation of individual viruses, creates the possibility that a new influenza A virus could develop.  A new influenza A virus could be highly infective and easily transmissible from person to person, thereby creating a pandemic.  If a pandemic influenza virus were to develop, 25 percent to 35 percent of the United States population could become ill, and many infected individuals could die.⁴

Currently, the H5N1⁵ influenza A virus is spreading in domestic and migratory birds in Asia, Europe, the Middle East, and Africa, and has infected humans primarily in Asia and the Middle East.  The virus is endemic in many bird species in Asia, so eradication is unlikely.⁶  As of March 11, 2008, there have been 372 confirmed human cases reported to the WHO, and 235 of those infected have died.⁷  To plan and prepare for possible pandemic influenza, the Federal government has developed strategic plans with associated implementation plans, two of which are discussed below.  FDA’s Pandemic Influenza Preparedness Strategic Plan coordinates with and complements the President’s National Strategy for Pandemic Influenza and the HHS Pandemic Influenza Plan and their associated implementation plans.

B.     National Strategy for Pandemic Influenza

In November 2005, President George W. Bush released the National Strategy for Pandemic Influenza.⁸  This strategic plan leverages and coordinates pandemic influenza preparedness and response at all levels of government, the private sector, individual citizens, and international entities.  The National Strategy is intended to: (1) stop, slow, or otherwise limit the spread of a pandemic to the United States; (2) limit the domestic spread of a pandemic, and mitigate disease, suffering and death; and (3) sustain infrastructure and mitigate impact to the economy and the functioning of society.  The pillars of the National Strategy are: (1) preparedness and communication; (2) surveillance and detection; and (3) response and containment.  The National Strategy provides a framework for the FDA Pandemic Influenza Preparedness Strategic Plan and guides our planning and actions.

In May 2006, the President issued the Implementation Plan for the National Strategy for Pandemic Influenza.⁹  The implementation plan translates the National Strategy into over 300 actions for Federal departments and agencies and establishes clear expectations for State and local governments and non-federal entities; actions involving regulatory oversight of countermeasures (such as anti-viral drugs, vaccines, diagnostic devices, and PPE) are FDA’s responsibility. 

C.     HHS Pandemic Influenza Plan

Secretary of Health and Human Services Michael O. Leavitt released the HHS Pandemic Influenza Plan on November 2, 2005.¹⁰  This plan consists of two parts: the HHS Strategic Plan and a Public Health Guidance for State and Local Partners.  The HHS Strategic Plan outlines key planning assumptions that we have adopted for our plan.  In addition, the HHS Strategic Plan identifies necessary capabilities and pandemic planning and response actions, sorted by the WHO’s pandemic phases.  The plan assigns lead roles and responsibilities for response actions to specific HHS agencies and offices.  We use the HHS Strategic Plan to identify and guide actions where we are the designated lead.  Key pandemic response elements identified by HHS, such as surveillance, investigation, and protective public health measures; vaccine, anti-viral drug, and device products; healthcare and emergency response; and communication and public outreach are all actions that we addressed while developing the FDA Pandemic Influenza Preparedness Strategic Plan.

In December 2006, HHS issued the “HHS Implementation Plan.”¹¹  The HHS Implementation Plan implements the strategy laid out in HHS Strategic Plan and the Public Health Guidance for State and Local Partners and itemizes the specific roles and responsibilities of HHS operational and staff divisions in planning for and responding to an influenza pandemic.  The document identifies specific steps that operationalize and implement the actions and expectations outlined for HHS in the National Strategy.  In addition, it identifies additional actions for successfully accomplishing the activities laid out in both the National Strategy and the HHS Strategic Plan.  The HHS Implementation Plan is divided into two parts.  The first part discusses HHS-wide issues, such as international activities, international and domestic surveillance, public health interventions, medical response, vaccines, anti-viral drugs, diagnostic devices, PPE, communications, and State and local preparedness.  These issues require coordination of efforts across HHS operational divisions.  The first part details the specific steps needed to meet the challenges of an influenza pandemic response and the critical capabilities as identified in both the National Strategy and the HHS Strategic Plan, and, as with those plans, guided our own planning and actions.

The second part of the HHS Implementation Plan includes detailed continuity of operations plans that ensure that the essential functions of each HHS operating division are identified and maintained in the presence of an expected decrease in staffing levels during an influenza pandemic. 

IV.    FDA Roles and Responsibilities

We are responsible for protecting the public health by helping to ensure the safety and effectiveness of human and animal drugs, human biological products, and devices, and the safety of our nation’s food supply, cosmetics, and radiation-emitting products.  We also advance the public health by helping to speed the availability of beneficial, innovative medical products and by helping the public get the accurate, science-based information it needs to use medical products and foods to improve health.  Additionally, recognizing the global nature of public health issues, we collaborate with foreign counterpart regulatory agencies and international organizations in carrying out our mission.

We play a vital role in the Nation’s preparedness for, and potential response to, an influenza pandemic.  This FDA Pandemic Influenza Preparedness Strategic Plan provides a solid foundation for a cross-cutting initiative involving many of our centers and offices.  The principal centers and offices, and their roles, are as follows:

• The Center for Biologics Evaluation and Research (CBER) leads the Task Force’s Vaccine and Other Biologics Development, Production, and Regulatory Review Subgroup and is responsible for:
  • Facilitating the development, production and regulatory review of biological products;
  • Interacting with Federal entities, such as other HHS components, and industry, the public, and other pandemic influenza preparedness entities, as appropriate, on vaccine development for influenza and pre-investigational new drug application (pre-IND), investigational new drug application (IND), emergency use authorization (EUA), or biologics license application (BLA) interactions;
  • Conducting post-market surveillance and enforcement activities relating to biological products;
  • Assisting and coordinating in the vaccine and other biologics effort with Federal entities, such as the HHS Office of the Assistant Secretary for Preparedness and Response, CDC, and NIH; and
  • Conducting related outreach to industry, foreign public health authorities, the public, and other stakeholders regarding vaccines and other biologics. 
  • Within CBER, the Office of the Director, the Office of Vaccines Research and Review, the Office of Compliance and Biologics Quality, the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, the Office of Cell, Tissue, and Gene Therapies, the Office of Communication, Training and Manufacturers Assistance, the Office of Management, and the Office of Information Technology are responsible for the objectives outlined in this plan and work together to ensure that action items are addressed. 
• The Center for Drug Evaluation and Research (CDER) leads the Task Force’s Anti-Viral Drug Development, Production, and Regulatory Review Subgroup and is responsible for:
  • Facilitating the development and production of anti-viral drug products as exemplified in the regulatory review of anti-viral drug products;
  • Conducting post-marketing surveillance and enforcement activities relating to anti-viral drug products;
  • Interacting with Federal entities, such as other HHS components, industry, the public, and other pandemic influenza preparedness entities, as appropriate on anti-viral drug development for influenza and pre-IND, IND, EUA, or new drug application (NDA) interactions;
  • Working with the Department of Defense (DOD) and FDA Shelf Life Extension Program (SLEP) and the HHS-managed Strategic National Stockpile (SNS) to facilitate understanding of issues related to stockpile-specific packaging and labeling of anti-viral drug products; and 
  • Maintaining, through the Drug Shortage Group, the Critical Products Program database to facilitate monitoring and addressing supply and shortage issues for anti-viral drug products. 
• The Center for Devices and Radiological Health (CDRH) leads the Task Force’s Device Development, Production, and Regulatory Review Subgroup and is responsible for:
  • Facilitating device development, regulatory review, and production of diagnostic devices, PPE (e.g., medical gloves, masks, respirators, and protective gowns), and other devices that may be needed during an influenza pandemic; 
  • Conducting post-market surveillance to monitor the safety and effectiveness of influenza-related devices (including devices used for diagnosis, devices used to administer therapeutics, PPE, and devices used for supportive care);
  • Lending technical expertise and assistance to international efforts to prepare for a potential influenza pandemic;
  • Supporting efforts to ensure an adequate supply of influenza-related devices through cooperative interactions with manufacturers and distributors and coordination with the SNS to determine the adequacy of stocks and actions required to meet targeted amounts;
  • Using an Emergency Shortages Database to identify and monitor supplies of certain devices that have the potential to be in short supply during influenza outbreaks;
  • Processing EUA submissions for devices after a declared emergency related to an outbreak of pandemic influenza;
  • Educating device users on how to use influenza-related devices in a safe and effective manner; and
  • Communicating influenza-related device activities and information to industry, consumers, State, local, and tribal governments and other stakeholders.
• The Center for Food Safety and Applied Nutrition (CFSAN) and the Center for Veterinary Medicine (CVM) share the lead roles in the Task Force’s Food and Feed Safety Subgroup and are responsible for:
• Coordinating food and feed safety activities and plans with Federal and State agencies, industry, and others;
  • Identifying foods and animal feeds that are at elevated risk of contamination and investigating the effectiveness of food and feed processing and preparation practices for inactivating influenza viruses;
  • Developing and disseminating recommendations on measures to prevent the spread of avian influenza (AI) virus via FDA-regulated foods and animal feeds;
  • Developing and evaluating analytical methods for identifying AI in foods; and
  • Prohibiting the extra-label use of influenza anti-viral drug products in animals when such use presents a risk to the public health.
• The Office of Crisis Management (OCM)/Office of Emergency Operations manages FDA’s Emergency Operations Center (EOC) which will coordinate our emergency response activities for an influenza pandemic.  As with all emergency response efforts, our EOC will serve as FDA’s focal point for communication and coordination activities with the Secretary’s Operations Center (SOC) and HHS agencies.  The EOC uses the Incident Command Structure to maintain situational awareness, enhance collaboration and coordination, communicate critical information, and make and implement decisions during emergencies.  OCM developed an FDA Pandemic Influenza Emergency Response Plan which further identifies the EOC’s role and responsibilities and its relationships with other FDA, HHS, and government entities during an influenza pandemic.
• OCM and the Office of External Relations (OER) share lead roles for the Task Force’s Emergency Preparedness, Response, and Communication Subgroup and are responsible for:
  • Identifying roles and responsibilities for emergency preparedness, response, and internal and public communication, including the implementation of pandemic influenza preparedness exercises and training;
  • Ensuring continuity of business operations;
  • Developing and implementing risk communication plans; and
  • Interacting with HHS, and other Federal, State, local, and tribal entities during an influenza pandemic.  
• The Office of Regulatory Affairs (ORA) leads the Task Force’s Enforcement Subgroup.  Compliance experts, including members from ORA and OGC, compose the Task Force’s Enforcement Subgroup and are responsible for identifying enforcement roles and responsibilities, including the implementation of enforcement actions to curtail illegal activity, such as the marketing of counterfeit pandemic influenza anti-viral drug products, vaccines, devices, or other therapeutics.  However, the Enforcement Subgroup will not address compliance issues associated with legally-marketed or legitimate pandemic influenza products; such issues will be considered by the vaccine, anti-viral and diagnostics subgroups (mentioned in the preceding bullets). 
• The Office of International Programs (OIP) leads, manages, and coordinates FDA’s international pandemic influenza preparedness activities and also coordinates our international activities with the Office of the Secretary, HHS, and other Federal departments, as necessary.  OIP is responsible for:
  • Capacity building and technical cooperation initiatives with foreign agencies and international organizations; and
  • Interactions on international issues with the HHS Office of Global Health Affairs (OGHA), Federal departments and agencies, and foreign agencies and international organizations.
• Each Task Force Subgroup, or the Task Force as a whole, also may determine whether to establish a “rapid response team”¹² to achieve one or more of its identified actions or address a new and time-sensitive issue. 

V.     FDA Accomplishments

Even before we issued this plan, we had taken various steps to prepare for a possible influenza pandemic. The following accomplishments are examples of steps that FDA took both prior to the development of this plan and those that have occurred more recently as we continue our work on pandemic influenza preparedness.  These actions have included:

• Licensing, on April 17, 2007, the first vaccine in the US for humans against the H5N1 influenza virus.  This inactivated influenza vaccine is indicated for immunization of persons 18 through 64 years of age who are at increased risk of exposure to the H5N1 influenza virus subtype contained in the vaccine.
• Licensing additional influenza vaccines to immunize people 18 years of age and older against influenza caused by strains of seasonal influenza virus.  With the licensing of FluLaval on October 5, 2006 and Afluria on September 28, 2007, the United States now has six licensed influenza vaccine manufacturers.  Having additional manufacturers will enhance the capacity to produce more doses of influenza vaccine every year and will contribute to the nation’s pandemic influenza preparedness.
• Approving the expansion of the population for use of the nasal influenza vaccine FluMist to include children between the ages of 2 and 5, on September 19, 2007.  This approval offers a needle-free option for young children receiving influenza vaccination.
• Approving, on December 21, 2005, the use of Tamiflu (oseltamivir phosphate) for prevention (prophylaxis) of influenza in children 1 to 12 years of age.  This new indication gives health care providers an option for preventing influenza in children following close contact with an infected individual. We also discussed at FDA’s Pediatric Advisory Committee (PAC) on November 18, 2005, an Adverse Event safety update on Tamiflu.  The advisory committee provided a public forum to discuss the safety of Tamiflu use in children as part of a routine drug safety update required by the “Best Pharmaceuticals for Children Act.”  We continued to monitor adverse event reports and then worked with the manufacturer to update the labeling on November 13, 2006 with regard to possible side effects, particularly in children, and to include instructions that pharmacists could use to prepare a suspension from Tamiflu capsules during a public health emergency if the marketed oral suspension was not available.  An update on the adverse event labeling also was provided at the annual PAC meeting on November 16, 2006; and neuropsychiatric adverse event reports for all four FDA approved anti-influenza anti-viral drugs were discussed at the November 27, 2007, PAC meeting.
• Working, throughout 2006, with the manufacturer of Tamiflu to address various manufacturing and shelf life issues and approving, on December 3, 2007, a supplemental new drug application received November 6, 2007, for an extension of the expiration dating from 5 years to 7 years for Tamiflu capsules.
• Approving, on March 29, 2006, the use of Relenza (zanamivir for inhalation) for prevention (prophylaxis) of influenza in adults and children 5 years of age and older.  This new indication provides an additional option for health care providers to consider in the prevention of influenza.
• Approving, on July 2, 2007, 30 mg and 45 mg capsules for Tamiflu.  Previously, Tamiflu was available in 75 mg capsules and powder for oral suspension for pediatric patients.  Approval of the new strength capsules provides additional options for pediatric patients.
• Clearing, on May 8, 2007, the first respirators for use by the public during public health medical emergencies, such as an influenza pandemic, to help reduce the user’s exposure to airborne germs.
• Clearing a device that simultaneously detects and identifies 12 specific respiratory viruses, including influenza A and B, on January 3, 2008.  This is the first FDA cleared device for the detection and differentiation of influenza A subtypes H1 and H3 and it speeds up the current process of detecting and identifying respiratory viruses (result within a day vs. several days). In addition, on January 4, 2008, we cleared a device that simultaneously identifies four common respiratory viruses, including influenza A and B, and also provides results in as few as three hours.  These are the first influenza nucleic acid amplification devices cleared by FDA.  These devices have the advantage of providing test results with high sensitivity and specificity, and of speeding up the usual process of detecting and identifying respiratory viruses. Having devices that accurately detect, identify and differentiate respiratory viruses improves the medical community's ability to determine the cause of a respiratory illness and initiate the appropriate treatment, contributing to pandemic influenza preparedness.       
• Clearing, on February 3, 2006, CDC’s Influenza A/H5 (Asian lineage) Virus Real-Time RT-PCR¹³ Primer and Probe Set.  Testing with these reagents will help diagnose influenza in patients who are infected with these specific viruses (influenza A/H5 Asian lineage) and provide epidemiological information for surveillance purposes.  The test provides preliminary results on suspected H5 influenza samples within four hours once a sample arrives at the lab and testing begins. Previous testing technology would require at least two to three days before providing results. 
• In connection with the activity described immediately above, in the Federal Register of March 22, 2006, we issued a classification final rule (71 FR 14377) and a special controls guidance document (71 FR 14534) related to our classification of the new Influenza A/H5 (Asian lineage) Virus Real-time RT-PCR Primer and Probe Set.  Under the special controls applicable to this classification, the distribution of these devices is limited to labs with experienced personnel having training in standardized molecular diagnostic techniques and expertise in viral diagnosis and appropriate biosafety equipment and containment.  These documents provide clear guidance and recommendations to aid manufacturers in developing new avian flu in vitro diagnostics, and help assure the continued safety and effectiveness of these tests.
• Issuing a final rule to prohibit the extra-label use of human influenza anti-viral drug products in the adamantane and neuraminidase inhibitor drug classes in chickens, turkeys, and ducks.  We took this measure to help preserve the effectiveness of these drugs for treating or preventing influenza infection in humans.  The final rule appeared in the Federal Register on March 22, 2006 (71 FR 14374).
• Sending Warning Letters to several firms who had made unproven claims that their products would treat or prevent “avian flu” or other forms of influenza.  We have issued over 50 Warning Letters and have taken enforcement actions concerning such products.  For example, in cooperation with U.S. Customs and Border Protection, we intercepted products at the border that purported to be "generic" Tamiflu, but which, in fact, contained Vitamin C and other substances that are not approved to prevent or treat influenza.  Although the products were similar in appearance to genuine Tamiflu, they offer no therapeutic benefit.  In another recent case, we worked with the Federal Bureau of Investigation to arrest an individual in Texas who administered counterfeit influenza vaccine to employees attending a corporate-sponsored health fair.  In June 2006, an individual was sentenced to 36 months in prison after a federal jury convicted him of smuggling foreign, unlicensed influenza vaccines into the United States and attempting to sell the illegal vaccines to hospitals.  In January 2006, a Licensed Practical Nurse, who operated a series of unauthorized vaccine clinics, was sentenced to nine months in prison after pleading guilty to dispensing drugs without a valid prescription.  The nurse admitted to diluting some of the vaccine with saline to increase the quantity of her supply.  This dilution reduced the quality and effectiveness of the vaccine.
• Issuing two final guidance documents on May 31, 2007, pertaining to seasonal and pandemic influenza vaccines.  These guidance documents will help manufacturers in the development and evaluation of new vaccines for seasonal and pandemic influenza and, as a result, help address the increased demand for influenza vaccine.  They are titled, “Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines” and “Guidance for Industry: Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines.”  The guidance documents are available on our Web site at www.fda.gov/cber/gdlns/trifluvac.htm and at www.fda.gov/cber/gdlns/panfluvac.pdf respectively.
• Issuing a guidance document pertaining to “In Vitro Diagnostic Devices to Detect Influenza A Viruses: Labeling and Regulatory Path.”  This guidance document, originally issued April 10, 2006 and subsequently updated May 1, 2007,  addresses recommendations for fulfilling labeling requirements applicable to all in vitro diagnostic devices intended to generally detect influenza A (or A/B) virus directly from human specimens, with a particular emphasis on ensuring appropriate labeling for legally marketed influenza A (or A/B) test devices whose clearances are not based on data addressing performance with regard to novel influenza A viruses infecting humans (including H5N1). The guidance document is available at our Web site at www.fda.gov/cdrh/oivd/guidance/1594.html.
• Issuing a draft guidance document on September 29, 2006, to provide important advice to manufacturers on using cell cultures to produce needed vaccines against infectious diseases, including vaccines to address emerging and pandemic influenza threats.  The document, titled “Characterization and Qualification of Cell Substrates and Other Biological Starting Materials Used in the Production of Viral Vaccines for the Prevention and Treatment of Infectious Diseases,” is available at our Web site at www.fda.gov/cber/gdlns/vaccsubstrates.htm.
• Convening, in cooperation with WHO and NIH, influenza vaccine experts for an international scientific public workshop in Bethesda, Maryland on December 10 and 11, 2007. The goals of this workshop were to identify our understanding of pandemic influenza protective immunity, to identify the gaps in our ability to assess pandemic vaccine influenza vaccine efficacy, and to propose and develop criteria and procedures to bridge these gaps.  It is anticipated that the suggestions and recommendations should facilitate development of a global research agenda to improve assessment of efficacy for pandemic influenza vaccines.
• Conducting two training workshops for foreign officials:
  • In cooperation with the Vietnamese Department of Science and Training, a training workshop on good clinical practices.  The workshop was held in Hanoi, Vietnam, on October 2 through 6, 2006.  The workshop was in support of HHS’s international efforts for pandemic influenza preparedness.  The training is also viewed as the first formal activity pursuant to the HHS-Vietnam Ministry of Health Agreement on Health and Sciences Cooperation signed by Secretary Leavitt and Minister Tran Thi Chien on July 26, 2006.  The training included 30 participants from the Ministry of Health, medical administrators from institutions in Hanoi, Ho Chi Minh City, and Hue, and local industry.  The training will better equip the Vietnamese to provide oversight to clinical trials of potential avian influenza vaccines and anti-viral drugs that are being tested in the country.
  • A CGMP Workshop in Rockville, Maryland on May 15 through 18, 2007, for participants from fifteen international medical products regulatory agencies.   FDA experts in CGMP regulatory review, compliance, and inspections offered insight and instruction on GMP regulatory review, compliance, and inspections to enhance the safety and quality of manufacturing of pharmaceuticals, especially in meeting the medical needs associated with avian/pandemic influenza. 
• Meeting with foreign regulatory authorities to develop strategies for harmonizing, where feasible, regulatory pathways to facilitate the development and production of pandemic influenza vaccines.  An FDA delegation attended a meeting hosted by Health Canada and co-sponsored by FDA and the WHO in Ottawa, Ontario, Canada, on March 9 through 11, 2006.  At the conclusion of the meeting, there was general agreement among the participants on the pathways and requirements for licensure of pandemic influenza vaccines.  It was decided that the formation of working groups would be the best way to develop strategy and to outline a framework of globally consistent regulatory approaches based on the available science.  Working groups established soon after developed draft consensus documents representing such an approach.  Draft consensus documents were reviewed at a WHO-affiliated meeting hosted by FDA, in Bethesda, Maryland, in June 2006 and in Geneva, Switzerland in June 2007, hosted by WHO. The document is undergoing finalization.
• Organizing and participating in a meeting co-sponsored by the National Academy of Engineering and the Institute of Medicine on “Vaccine Production: Potential Engineering Approaches to a Pandemic,” with HHS, WHO, the Department of State, academia, and industry.  The meeting was held on April 10 through 11, 2006 at Case Western University in Cleveland, Ohio.  The meeting’s goals were to:
  • Identify challenges to manufacturing influenza vaccines, including rapid production for pandemic influenza;
  • Discuss specific approaches for increasing influenza vaccine production using both existing and "next generation" technologies;
  • Provide a venue where a "community" of interested academic and industrial engineers, government regulators, and other scientists and physicians can bring an engineering perspective to critical demand situations; and
  • Identify research opportunities for young researchers and others new to the field.
• Conducting or participating in various meetings regarding Current Good Manufacturing Practice (CGMP) for vaccines.  These meetings occurred from August 2005 through November 2007 in the United States and in Europe.  The goal of these meetings was to:
  • Communicate regulatory expectations and promote the use of robust quality systems;
  • Provide examples of CGMP problems seen in the vaccine industry and the consequences of those problems; and
  • Elicit meaningful dialogue with the industry and our foreign regulatory counterparts on CGMP issues for vaccines.
• Convening a meeting of FDA’s Vaccines and Related Biological Products Advisory Committee on November 16, 2005, to discuss the use of Madin-Darby canine kidney (MDCK) cells for manufacturing influenza inactivated vaccine.¹⁴  As we are aggressively supporting multiple efforts to increase manufacturing capacity, using both new and existing technologies, this meeting provided an opportunity to actively engage sponsors and manufacturers interested in developing new technologies for manufacturing influenza vaccines.
• Preparing, and later updating, information on avian influenza and food safety.  We first issued this information on March 29, 2004, and updated it in 2005 and 2006.  The document addresses questions that the public may have regarding food safety and is available at our website at http://www.cfsan.fda.gov/~dms/avfluqa.html.
• Posting center- and commodity-specific information and advice related to pandemic influenza on FDA’s Web site.  For example, we have posted information on FDA-regulated PPE at http://www.fda.gov/cdrh/ppe/index.html.  The Web site includes questions and answers on PPE and influenza outbreaks, including avian flu.  It is intended to provide technical and regulatory information on masks, respirators, gloves, and gowns to individuals in health care and other occupational settings and to the general public.

The objectives, actions, and deliverables discussed in part VI below build on our earlier efforts.  They are also consistent with, or elaborate upon, various Federal actions described in the Implementation Plan for the National Strategy for Pandemic Influenza and the HHS Pandemic Influenza Implementation Plan – Part 1.

VI. FDA Objectives and Actions

In general, our Pandemic Influenza Preparedness Strategic Plan identifies various activities that are or will be critical to the development, review, and approval of products for diagnostic, therapeutic, preventive, or other uses, safeguarding food and feed, and protecting Americans from fraudulent or counterfeit products.  Our plan also addresses information dissemination and the need for continuity of business operations if a pandemic occurs. 

We discuss various agency actions in this section of the plan.  For each major topic, we include:

• Our objectives,
• Actions to be taken to further those objectives, and
• “Deliverables” or the expected result or end-product of a particular action, and the timeframes for such “deliverables,” resources permitting.

As noted earlier, the HHS Pandemic Influenza Plan identifies necessary capabilities and pandemic planning and response actions, sorted by the WHO’s pandemic phases.  WHO uses the phase system in its own WHO Global Influenza Preparedness Plan to inform the world about the seriousness of a particular threat and the need to launch progressively intense preparedness and response activities.  The WHO phases are grouped into periods as follows: an “inter-pandemic period” where a virus exists in animals, but there are no human cases of disease; a “pandemic alert period;” and a “pandemic period.”  There are two phases within the inter-pandemic period; phase 1 is when there is low risk of human cases.  Phase 2 is when there is a higher risk of human cases.  In the “pandemic alert” period, the new virus is causing disease in humans.  There are three phases within the pandemic alert period; phase 3 is when there is no or very limited human-to-human transmission, while phase 4 is when there is evidence of increased human-to-human transmission.  Phase 5 is when there is evidence of significant human-to-human transmission.  In the “pandemic” period, phase 6 occurs when there is “sustained transmission in general population.” 

While the WHO phase system informs the world about the global risk for an influenza pandemic and global response capabilities, the Implementation Plan for the National Strategy for Pandemic Influenza contains another framework for Federal government actions.  The Implementation Plan for the National Strategy for Pandemic Influenza describes the Federal government approach to an influenza pandemic response by characterizing the stages of an outbreak in terms of the immediate and specific threat a pandemic influenza virus poses to the United States population.  The stages are:  

Stage 0: New Domestic Animal Outbreak in At-Risk Country;
Stage 1: Suspected Human Outbreak Overseas;
Stage 2: Confirmed Human Outbreak Overseas;
Stage 3: Widespread Human Outbreaks in Multiple Locations Overseas;
Stage 4: First Human Case in North America;
Stage 5: Spread throughout United States; and
Stage 6: Recovery and Preparation for Subsequent Waves.¹⁵

Under the Implementation Plan for the National Strategy for Pandemic Influenza, the Federal government response at each stage is, itself, divided into objectives, immediate actions, policy decisions, and communications and outreach activities.  According to the Implementation Plan for the National Strategy for Pandemic Influenza,

“Immediate Actions” reflect those agreed-upon measures that would be triggered as each landmark for increasing risk to the U.S. population was passed.  “Policy Decisions” reflect issues that would have to be considered by the Federal Government at the time, in the context of the available information about the pandemic and the status of our response.  Finally, “Communications and Outreach” describes the high-level objectives of the guidance that is provided to the public; institutions; State, local, and tribal authorities; and our international partners.¹⁶

For example, at Stage 0, the objectives are to: (1) Track outbreaks to control/resolution; (2) provide coordination mechanisms, logistical support, and technical guidance; and (3) monitor for recurrence of disease.  The actions for Stage 0 are to: (1) “Initiate dialogue with FAO, other relevant international health organizations, and other international partners to ensure complete coordinated support (Department of State (DOS) and [United States Department of Agriculture]USDA);” (2) “initiate dialogue with affected nation through diplomatic, animal health, and human health channels to ascertain situation, offer scientific, technical, and, potentially, economic and trade assistance, and encourage full and open sharing of information (DOS, HHS, and USDA);” (3) “prepare to deploy rapid response team including influenza epidemiology, diagnostics, public-health management, and communications, as part of bilateral and multilateral teams to assess situation and requirements for successful animal disease eradication and human disease prevention effort (DOS, USDA, U.S. Agency for International Development (USAID), Department of Defense (DOD), and HHS);” (4) “prepare to supply testing protocols and deploy reagents and equipment to support diagnostic requirements for both animal and human testing (USDA, HHS, DOD, and DHS);” and (5) “prepare to deploy animal disease response materiel, including PPE (USDA and USAID).”  The policy decision for Stage 0 is “deployment of countermeasures to affected country as part of the U.S. contribution to an animal disease control and eradication effort.”¹⁷

For more information regarding the Federal government’s response stages and the components of each stage, we refer readers to the Implementation Plan for the National Strategy for Pandemic Influenza. 

The WHO phases and their accompanying public health goals,¹⁸ and the corresponding Federal government response stages, are as follows:

FDA’s Pandemic Influenza Preparedness Strategic Plan does not link specific objectives or actions to the WHO phases because the majority of our objectives and actions span all six WHO phases.  Nevertheless, we have described the WHO phases above because the HHS and WHO plans refer to the WHO phases and because FDA’s Pandemic Influenza Preparedness Strategic Plan complements the HHS Pandemic Influenza Plan.

In the tables of FDA Objectives and Actions (Part VII of this document), we have cross-referenced our objectives and actions, where appropriate, to the Implementation Plan for the National Strategy for Pandemic Influenza.  This will enable readers to understand how this plan fits within the Implementation Plan for the National Strategy for Pandemic Influenza, and subsequently the HHS Pandemic Influenza Implementation Plan – Part 1 which also references the National Strategy actions.  However, this FDA Pandemic Influenza Preparedness Strategic Plan may contain additional details or activities that are narrower in scope than those in the national or HHS implementation plans.

A.     Vaccine and Other Biologics Development, Production, and Regulatory Review

Vaccines are very effective in preventing viral diseases in humans, but vaccine development and production are complex processes.  In very broad terms, vaccines use inactivated (killed) or live attenuated (weakened) bacteria or viruses that are identical or similar to those that cause a disease.  Vaccines work by stimulating the body’s immune system such that, when the disease-causing agent enters the body, the body’s immune system recognizes the agent and mounts an immune response. 

Seasonal influenza vaccine is unique in that its composition changes almost every year.  Public health experts annually evaluate world-wide epidemiological data to determine the strains of the virus that manufacturers will use to make the influenza virus vaccine administered in the fall.  Currently, seasonal influenza vaccines licensed in the United States are produced using fertile hen’s eggs as part of a complex and exacting process.  Companies and researchers are actively studying new manufacturing methods, such as cell-culture based and recombinant technologies, along with adjuvants²⁴ and other dose-sparing techniques. 

For seasonal influenza, vaccines are the primary method for preventing and controlling influenza.  Our experience with seasonal influenza vaccines has helped us devise regulatory policies and strategies for pandemic influenza vaccines.  Because seasonal influenza vaccine manufacturers will likely produce pandemic influenza vaccines, increases in manufacturing capacity and improvements to existing processes directly impact our ability to produce pandemic influenza vaccines.  We also are using knowledge gained from past experience with counterterrorism products and with the 2004/2005 influenza vaccine shortage to facilitate the regulatory review of new BLAs and supplements to existing applications for influenza vaccines. 

Furthermore, to enhance preparedness and vaccine quality, we have increased our post-approval surveillance of influenza vaccine manufacturers by inspecting manufacturing facilities annually.

Vaccines would be an important part of an influenza pandemic response and, along with other FDA-regulated products, would help prevent transmission or spread of the pandemic influenza virus.  Those other FDA-regulated products include anti-viral drugs, which might be used in selected situations, either to protect against influenza illness or to treat individuals who have contracted the virus.  They also include medical devices, particularly diagnostic devices that would help confirm whether an individual had contracted the virus thus helping public health authorities decide how to treat individuals and to prevent further transmission. 

Other products of biological origin also serve an important role in addressing an influenza pandemic.  Blood, cell, and tissue products are critical in supporting health care and emergency response.  We are working with other HHS components, other Federal departments and agencies, and blood and tissue organizations to enhance preparedness by focusing on safe and available blood, cell, and tissue products.

Objective VI.A.1: Facilitate vaccine development, production, and regulatory review.

Action VI.A.1.a:  Assist efforts to increase manufacturing capacity and product diversity through meetings with vaccine manufacturers.  The meetings will address issues such as facility design, non-clinical and clinical studies, and manufacturing.

Deliverables:

• Meetings with vaccine manufacturers to discuss design plans for vaccine facilities.
• Expedited review of BLAs and supplemental applications that could increase both the number of manufacturers and the overall supply of vaccine.

Timeframe: 

• Initial meetings with manufacturers to provide guidance on vaccine facility design and commissioning began in 2004.  Routine follow-up discussions occurred in fiscal year 2006 and 2007 and will continue in fiscal year 2008.
• Upon submission of complete BLAs or supplemental applications.

Action VI.A.1.b:  Implement early interactions and communications with sponsors through face-to-face, pre-submission meetings and conferences to provide guidance to encourage novel manufacturing and delivery technologies for the development of pandemic influenza vaccines.

Deliverables:

• A draft guidance document on the requirements of characterizing cell substrates used to manufacture viral vaccines, including cell-based influenza vaccines.
• Expedited scheduling of meetings with sponsors to ensure timely and relevant regulatory guidance.

Timeframe:  

• We issued a draft guidance in September 2006.  We completed a review of the comments we received on the draft in fiscal year 2007and will issue a final guidance in 2008.
• This is an ongoing activity.

Action VI.A.1.c:  Provide information regarding the clinical data needed for the regulatory evaluation and acceptance of seasonal and pandemic influenza vaccines for use as investigational new drugs and as licensed products under a BLA, or other regulatory pathways.

Deliverables: 

• Work with NIH and manufacturers to make vaccines against potential pandemic strains of influenza available to the public.
• Convene a scientific workshop focusing on correlates of protection of immunity to assess the current state of knowledge, identify gaps in the science and plan future research.

Timeframe: 

• We will perform an expedited review upon submission of applications or supplements.
• Scientific workshop convened in December, 2007.

Action VI.A.1.d:  Develop and deliver reference strains and reagents for pandemic influenza vaccines to manufacturers.

Deliverables:  New candidate pandemic virus reassortants²⁵ for use in manufacturing and improved virus vaccine donor strains.

Timeframe:   

• Work is underway to produce an H5 reassortant in FY08.
•   Work is underway to develop improved donor strains and progress will depend on research results.

Action VI.A.1.e:  Develop, calibrate, and distribute reagents (antigen and antisera²⁶) for potency testing.

Deliverables:  Strain-specific antiserum and antigen reagents for use in determining vaccine potency and performance of lot-release testing on influenza vaccines prior to their distribution.

Timeframe:  This occurs on an annual basis for seasonal influenza vaccines.  Reagents are prepared for candidate pandemic vaccines as manufacturers put them into production.

Action VI.A.1.f:  Standardization of influenza vaccine related tests used for clinical development, vaccine production, and lot release to reduce variability of these tests and to ensure consistent results or outcomes.

Deliverables:  Standardized tests.

Timeframe:  Research is already underway; progress will depend on research results.

Objective VI.A.2:  Conduct post-market surveillance and oversight activities relating to vaccines.

Action VI.A.2.a:  Facilitate efforts to increase capabilities for monitoring adverse events in the Vaccine Adverse Events Reporting System (VAERS) and healthcare databases.

Deliverables: 

• Work with CDC, Centers for Medicare and Medicaid Services (CMS), manufacturers, and other Federal departments and agencies to detect and monitor adverse events associated with pandemic influenza vaccines.
• A pilot project to expand the Vaccine Safety Datalink database was initiated in 2006 and will continue to evaluate methods for improving rapid analysis of administrative databases for influenza vaccine safety surveillance.
• A pilot project to use Medicare data for influenza vaccine safety surveillance.
• Work with the Department of Veterans Affairs’ Veterans Health Administration (VHA) to expedite linkage of veterans’ influenza vaccination records with the VHA electronic medical record database and to expedite real-time reporting of adverse events after influenza vaccination, and assess adverse event reports after influenza vaccination in the VHA population.

Timeframe: 

• Monthly internal reporting of VAERS safety surveillance summaries for the 2007-2008 seasonal influenza vaccine, as a pilot for subsequent monitoring of seasonal and pandemic influenza vaccines.
• The pilot project to expand the Vaccine Safety Datalink was initiated in October 2006 and data analyses continued during 2007.  In 2008 the project will evaluate methods for improving rapid analysis of administrative databases for influenza vaccine safety surveillance.
• The pilot project using Medicare data was implemented during the 2006-2007 influenza season and HHS has awarded funds to continue development during the 2007-2008 influenza season.
• We initiated a pilot project in collaboration with VHA in September 2007 to assess veterans’ vaccination record linkage with the VHA electronic medical record database, and to gather preliminary data evaluating adverse events after influenza vaccination in the VHA population. 

Action VI.A.2.b:  Ensure ongoing optimization of compliance at existing licensed influenza vaccine manufacturing facilities to ensure preparedness for rapid pandemic influenza vaccine production. 

Deliverables: 

•    Annual (rather than biennial) CGMP inspections of all licensed influenza vaccine manufacturing facilities.
• Facilitation of remediation efforts when compliance problems are identified.

Timeframe: 

• Annual inspections were implemented in fiscal year 2005 and are continuing.
• Facilitation has occurred and will continue if additional problems are identified.

Objective VI.A.3:  Assist and coordinate with Federal entities, such as the HHS Office of the Assistant Secretary for Preparedness and Response (ASPR), CDC, and NIH, to encompass various aspects of pandemic influenza planning related to vaccines.

Action VI.A.3.a:  Work with HHS to develop a plan for expediting manufacturing expansion and capacity and work with other HHS component agencies, as needed, on issues involving the SNS.

Deliverables:

• A plan for expediting manufacturing expansion and capacity.
• Publication of the interim final rule titled, “Exceptions or Alternatives to Labeling Requirements for Products Held by the Strategic National Stockpile.”²⁷
• Participation in the HHS Vaccine Working Group that was established for the purpose of intra-agency consultation for vaccine stockpile issues.
• A framework/process for strain selection of novel influenza viruses with pandemic potential for inclusion in the stockpile.
• A plan for assessing the stability of vaccine stockpile.

Timeframe: 

• A draft plan – “Expansion of Egg-Based Influenza Vaccine Manufacturing Facilities: Compressed Facility Establishment Pathway” – was completed in October 2005. This plan was used to inform HHS as it considered contracts for egg-based facility expansion.
• The SNS labeling interim final rule was published in the Federal Register in December, 2007.
• Participant as a member of the HHS Vaccine Working Group in 2007 and will continue in 2008.
• Collaboration with HHS Vaccine Working Group to consider options and make recommendations for the selection of strains to be included in the stockpile.  This process will continue as new surveillance data and scientific information becomes available.
• Ongoing collaboration with HHS Vaccine Working Group to develop an appropriate stability testing plan for stockpiled H5N1 vaccines.

Action VI.A.3.b:  Explore scientific, legal, and policy issues related to the use of veterinary vaccine facilities to increase human vaccine manufacturing capacity during an emergency.

Deliverables:  Engage in discussions with USDA and other regulators regarding the feasibility of the use of veterinary vaccine facilities for human products.

Timeframe:  

• Issue was discussed with USDA on several occasions in 2006 and also at a WHO-sponsored meeting that included other foreign regulatory agencies and manufacturers.  

Objective VI.A.4:  Work with industry, foreign public health authorities, and other stakeholders to assess preparedness and to develop strategies for harmonizing, where feasible, regulatory expectations for pandemic influenza vaccines to help increase the speed and efficiency of their development and production.

Action VI.A.4.a:  Convene national regulatory authorities from around the world, under the aegis of the WHO, to work towards regulatory preparedness/convergence for pandemic influenza vaccines to maximize response preparedness in the event of an influenza pandemic. 

Deliverables: 

• FDA, as part of international working groups, will develop strategies and outline a framework of globally consistent regulatory approaches based on the available science.    
• Consensus document representing such an approach.   

Timeframe:  

• Working group meetings are an ongoing activity.
• Draft consensus documents were reviewed at a WHO-affiliated meeting hosted by FDA in Bethesda, Maryland, in June 2006 and at a meeting in Geneva, Switzerland in June 2007, hosted by WHO.

Objective VI.A.5:  Educate and exchange information with industry, foreign public health authorities, and other stakeholders on regulatory considerations.

Action VI.A.5.a:  Establish regular communications with foreign regulatory counterparts under our information sharing agreements.

Deliverables:  Exchanges of information and collaboration on technologies and overcoming challenges.

Timeframe: 

• Communications began and occurred throughout 2006 and subsequent communications occurred in 2007 and will continue in 2008.   
• A working group meeting with foreign regulators took place in November 2007 to review data requirements for applications for influenza vaccines as well as scientific and policy/regulatory approaches to identify similarities and differences.

Action VI.A.5.b:  Conduct outreach regarding CGMPs and quality systems to encourage consistent and uninterrupted production of quality vaccines. 

Deliverables: 

• Presentations and interactions with industry and foreign counterparts on CGMP challenges.

Timeframe:  

• This is an ongoing activity. A meeting occurred in March 2007, in Barcelona, Spain, and in August 2007, in Cambridge, Maryland and in November 2007 in San Antonio, Texas.  Another meeting is scheduled for March 2008, in Vienna, Austria.

Action VI.A.5.c:  Exchange information with and educate vaccine manufacturers on regulatory considerations.

Deliverables:  Organization of and participation in regular “Vaccine Roundtable” meetings.

Timeframe:  Meetings are scheduled at regular intervals.  Meetings focus on selected topics, ranging from pre-approval through post-approval activities. The last roundtable meeting occurred in September 2007 and the next one is scheduled for Spring 2008.

Objective VI.A.6:  Work with the Office of the Secretary within HHS, CDC, the American Association of Blood Banks (AABB), and other organizations to develop responses to emerging potential threats to the safety and availability of blood, cell, and tissue products needed to support public health and medical care.

Action VI.A.6.a:  Enhance existing regular communications and collaborative strategic activities focusing on pandemic influenza preparedness and responses within CBER and within HHS, CDC, and with industry organizations to ensure coordinated responses to emerging potential threats to blood, cell, and tissue product safety and/or availability.

Deliverables:  Work with tissue and blood professional organizations and other stakeholders, including the AABB Interorganizational Task Force on Pandemic Influenza and the Blood Supply, to assist their efforts to develop pandemic influenza planning strategies.

Timeframe: 

• CBER actively serves as liaison participants in meetings with key stakeholders.  Meetings have occurred in fiscal year 2006, continued in 2007, and will continue in fiscal year 2008 to address the safety and availability of blood and tissue products to support public health and medical care.
• CBER, in coordination with HHS, continues to work with AABB on evaluating the feasibility of walking donor programs to help assure the availability of a local blood supply in the face of an extreme emergency.

B.     Anti-Viral Drug Development, Production, and Regulatory Review

Unlike vaccines (which are intended to trigger an immune response in the body that will confer some protection against a virus), anti-viral drug products target the virus itself.  For example, an anti-viral drug might be designed to interfere with a virus’s ability to attach itself to human cells, thereby preventing the virus from infecting the human cells.  As another example, an anti-viral drug might be designed to interfere with the virus’s ability to replicate itself, either by preventing the virus from releasing or replicating its genetic material or by preventing the virus from releasing viral particles that would then go on to infect other human cells.

Like vaccine development, anti-viral drug development presents its own challenges.  In general, understanding how a virus works and/or knowing its composition is very important for anti-viral drug development.  For example, assume that a virus has a specific protein sequence on its surface, and the anti-viral drug is designed to bind to that protein sequence to prevent the virus from working properly.  It would be important to avoid targeting a protein sequence that also happens to appear in human cells, because then the anti-viral drug could target human cells as well as the virus.

Some drug products might be proposed to act against influenza viruses indirectly, such as influencing host defenses against infection.  Such drug products would go through a development and review process similar to that for drugs with direct anti-viral activity, and the review process would take into account the drug’s specific characteristics and mechanism of action. 

Although detailed information on a potential pandemic influenza virus is lacking (because an influenza pandemic does not yet exist), we have considerable experience in reviewing and approving anti-viral drug products for numerous viral diseases, including drugs for influenza.  Information from the study of an anti-viral drug in circulating influenza is likely to be relevant to potential pandemic influenza strains because the targets of most influenza anti-viral drug products are shared across many viral strains and subtypes.  For example, even though it may not be possible to predict how the drug will affect new viral strains, the drug’s clinical effects and anti-viral resistance profiles in seasonal influenza outbreaks contribute to the evaluation of the drug’s likely utility in future circumstances.  Drug development experience with influenza anti-viral drug products in the interpandemic period is, therefore, important to assessing drugs that may be suitable for stockpiling.  Agencies and sponsors may also be able to apply and build upon such experience to assess new information that may become available in an influenza pandemic situation as well as for ongoing assessments when the pandemic influenza subtype evolves into circulating seasonal influenza strains after an influenza pandemic.  

Anti-viral drugs would be an important part of an influenza pandemic response along with other FDA-regulated products, such as vaccines (which would immunize individuals against a pandemic influenza virus or elicit cross-reactive antibodies) and medical devices, particularly diagnostic devices (which would help confirm whether an individual had contracted the virus and help public health authorities decide how to treat individuals and to prevent further transmission). 

Objective VI.B.1:  Facilitate anti-viral drug development and regulatory review.

Action VI.B.1.a:  Evaluate and analyze initial pre-clinical data on drug safety, efficacy, and viral resistance from pre-IND, IND, and pre-EUA proposals and submissions.  Refer potential sponsors in very early development to the National Institute for Allergy and Infectious Diseases’s (NIAID) drug screening program.  Facilitate communications with sponsors using written responses, teleconferences, or face-to-face meetings, as appropriate to specific situations. 

Deliverables:

• Reviews of pre-IND materials, INDs, and pre-EUA submissions.  
• Refer potential sponsors to the Web site for the NIAID drug screening program (www.niaid.nih.gov/dmid/viral).
• Advice and comments to sponsors via fax, letter, teleconference, or meeting, as appropriate, based on our review of the submitted material.

Timeframe:  

• Our goal is to complete reviews in reduced timeframes.
• We will refer potential sponsors to the Web site in response to inquiries.
• Our goal is to provide advice and comments to sponsors in a timely manner as appropriate to the submission’s contents.

Action VI.B.1.b:  Provide advice to industry and other Federal departments and agencies on clinical trial designs to evaluate the safety and efficacy of new anti-viral drug products or new formulations or dosing regimens of existing anti-viral drug products.

Deliverables:

• We will provide regulatory advice to industry and other Federal departments and agencies regarding the design of clinical trials of existing and new anti-viral drug products against influenza.
• Review of clinical trial protocols to test anti-viral drug products for safety and efficacy during the interpandemic period.
• Advice and comment on protocol design for multi-center and multi-national randomized clinical trials.

Timeframe:  We have already reviewed several protocols in fiscal year 2006 and subsequently, and as appropriate, have provided advice on development questions.  Future timelines in fiscal year 2008 and beyond for the deliverables mentioned immediately above will be as appropriate to the submissions received.  Our goal is to provide prompt responses.

Action VI.B.1.c:  Review pre-EUA, IND, NDA, or BLA submissions and public or non-public information in support of potential uses of unapproved anti-viral drug products under an IND or EUA. 
 
Deliverables:

• A Standard Operating Procedure (SOP) for issuing an EUA.
• Updates to our existing application tracking systems to accept pre-EUA submissions.
• Reviews of information from pre-EUA submissions, INDs, NDAs, and BLAs, and labeling, as appropriate.

Timeframe: 

• We prepared a draft SOP during the second quarter of fiscal year 2008.
• The application tracking system was updated in the first quarter of fiscal year 2008.
• We will expedite reviews as appropriate to the information submitted and the pandemic influenza phase.    

Action VI.B.1.d:  Provide information on our Web site (http://www.fda.gov/cder/ode4/preind/default.htm) to encourage early pre-IND interactions.
 
Deliverables:  An updated Web site. 

Timeframe:  We have already posted updated contact information and links to drug label information.  We will post additional updates as new information becomes available.

Objective VI.B.2:  Expedite review of NDAs, BLAs, abbreviated new drug applications (ANDAs), and supplements for anti-viral drug products that may be relevant to preparedness for an influenza pandemic.

Action VI.B.2.a:  Prioritize pandemic influenza-related submissions in the Office of Generic Drugs (OGD), consistent with OGD review procedures. 

Deliverables:  A template memorandum for expected ANDA submissions in anticipation of their receipt.  (The memorandum would seek permission from the Director of CDER to raise the review priority in OGD.)

Timeframe:  CDER prepared and cleared a template memorandum in fiscal year 2006.

Action VI.B.2.b:  Employ expedited review mechanisms for NDAs, BLAs, ANDAs, and supplements, as appropriate.

Deliverables:  Rapid completion of reviews and labeling.

Timeframe:  We will complete reviews consistent with priority review or other available expedited review mechanisms. 

Objective VI.B.3:  Identify new targets for influenza viruses that may lead to identification of new classes of anti-viral drug products, and evaluate alternative drug development pathways, including the use of biomarkers and animal models that may expedite the availability of novel and promising anti-influenza therapies. 

Action VI.B.3.a:  Actively consider input from the scientific community by working with NIH/NIAID and participating in an expert panel on influenza to better understand the current challenges and opportunities in anti-viral drug development.  The desired outcomes are:

• To help FDA in considering:
• Whether there are animal models of influenza that will adequately predict human disease and responses;  
• Animal models for studying novel viral strains to support and supplement clinical trial data in naturally occurring disease;
• The relative contributions of studies in which volunteers have been exposed to weakened laboratory strains of a virus to test the effects of anti-viral drugs (challenge studies); and
• The appropriate design of clinical trials to maximize the efficient acquisition of data.
• To support IND and EUA uses in emergency situations, as appropriate.

Deliverables:  Participation in an NIH/NIAID expert panel.

Timeframe:  An expert meeting, with invited FDA participation, was convened by NIH/NIAID in November 2006.

Action VI.B.3.b:  Clarify the recommendations for pre-EUA submissions for pandemic influenza anti-viral drug products.

Deliverables:  A concept paper that provides recommendations on how an anti-viral drug product can be eligible for an EUA and advice, on a case-by-case basis, in response to product-specific inquiries.

Timeframe:  Active planning and initial drafting of a draft document for internal use was completed, with revisions to continue as appropriate depending on the development of additional relevant information.  We will continue to provide advice in response to product-specific inquiries, as appropriate to the inquiries received.

Action VI.B.3.c:  Use scientific information from expert meetings, literature, etc., to identify and prioritize anti-influenza drug development issues.

Deliverables:  A list of issues with discussion points.  Subsequent ongoing literature monitoring as appropriate and feasible.

Timeframe:  We included information from literature articles in the discussion of NIH/NIAID panel meeting plans during fiscal years 2006 and 2007.  Monitoring of issues from the literature is an ongoing activity.

Objective VI.B.4:  Facilitate product manufacturing and capability to address surge capacity. 

Action VI.B.4.a:  Facilitate the expansion of domestic manufacturing capacity to produce anti-viral drugs against influenza. 

Deliverables: 

• Work with current manufacturers of anti-viral drug products to expand domestic production.
• Identification of possible mechanisms, if needed, to permit other manufacturers to produce proprietary anti-viral drug products, including discussion of sublicensure proposals from existing manufacturers.
• Identification of alternate manufacturers capable of performing rate-limiting steps in manufacture. 
• Expedited inspections of new manufacturing sites.
• Expedited review of information related to new manufacturing sites and manufacturing processes and controls.

Timeframe:  This is an ongoing activity with deliverables related to manufacturer-initiated submissions.  Our goal is to complete reviews in reduced timeframes.  Preliminary discussions of sublicensure proposals have taken place, and we will update them as appropriate to information becoming available.  We have reviewed several manufacturing supplements already.

Action VI.B.4.b:  Monitor drug supply issues and maintain a database of supply status and production capacity to enhance anticipation and assessment of shortages. 

Deliverables:  Updates on supply and shortage issues and our Critical Products Program database.

Timeframe:  We have updated the Critical Products Program database in fiscal year 2006 and will update it, as appropriate, thereafter.  We will provide updates on shortage issues as needed in response to reports of expected or actual shortage situations.

Objective VI.B.5:  Active monitoring and passive surveillance of adverse events reported with anti-viral drug products used for pandemic influenza.

Action VI.B.5.a:  Work with HHS agencies to use existing surveillance systems, such as MedWatch, and develop post-emergency surveillance plans.   

Deliverables: 

• A post-emergency surveillance plan.  
• Review of adverse event reports submitted to MedWatch associated with anti-viral drug products used for pandemic influenza.
• Active monitoring for adverse events among patients presented for care in a network of emergency departments.  This monitoring will occur through the existing National Electronic Injury Surveillance System Cooperative Adverse Drug Event Project maintained by CDC and FDA.

Timeframe: 

• Active discussions occurred during fiscal year 2007 for the surveillance plan, with the plan’s final form subject to revision as more information becomes available. 
• Annual review of influenza anti-viral drug adverse events for each influenza season (October to May) will be completed by the fourth quarter of each fiscal year as appropriate to the level of the influenza season and reporting activity.
• Monitoring adverse events is an ongoing activity.

Objective VI.B.6:  Facilitate the deployment of stockpiled drugs in the event of an influenza pandemic.

Action VI.B.6.a:  Work with the CDC’s Coordinating Office for Terrorism Preparedness & Emergency Response, Division of the Strategic National Stockpile (COTPER/DSNS) and industry, repackagers, and relabelers to facilitate advance development of packaging, labeling, and specialized instructions if there are requests to modify any of these for the purpose of addressing stockpile-specific storage or distribution issues for products which are in the stockpile or may be added to the stockpile.  Respond to the CDC’s COTPER/DSNS on the regulatory status of proposed novel packaging and labeling of anti-viral drug products.  For example, new labeling may be necessary when investigational new drug products in the SNS are approved or licensed, or new, yet unapproved, packaging (such as unit of use or unit dose packaging) may be necessary in order to distribute a product effectively during a public health emergency. 

Deliverables: 

• We have provided and will continue to provide a response or a plan of action to the CDC’s COTPER/DSNS on inquiries regarding repackaging and relabeling.   
• Priority review and action, as appropriate, on NDA supplements for packaging changes.

Timeframe: 

• During an influenza pandemic alert period, we will expedite the request for technical advice and provide a response no later than 60 days after receipt of an inquiry and as appropriate to the urgency of the matter.  
• During an influenza pandemic alert period, we will review NDA supplements for packaging changes on a priority basis as appropriate. 

Action VI.B.6.b:  Participate in an interagency working group to develop specific recommendations for anti-viral drug products to include in Federal and non-Federal stockpiles.

Deliverables:  Technical advice on scientific and regulatory issues, as appropriate, during discussion and drafting of the recommendations.

Timeframe:  We have provided technical advice and input on various draft interagency documents, and will consider this an ongoing activity as appropriate to requests received. 

Action VI.B.6.c:  Work with the CDC’s COTPER/DSNS to determine the eligibility of future stockpiled products for the SLEP. 

Deliverables: 

• We will address requests from the CDC’s COTPER/DSNS for the eligibility of future stockpiled products for participation in the SLEP. 
• Work with SNS and SNS contractors to develop new expiry labeling to facilitate SLEP compliance.

Timeframe: 

• We will address requests from the CDC’s COTPER/DSNS for the eligibility of future stockpiled products for SLEP within 60 days.
• We will respond to SNS and SNS contractors’ requests to develop new expiry labeling within 60 days of a request.

Action VI.B.6.d:  Consider expanding the existing SLEP beyond the Federal government. 

Deliverables:  A determination regarding the extension of SLEP beyond the Federal government.

Timeframe: 

• The determination whether to extend SLEP was made in the first quarter of fiscal year 2007. Discussions regarding SLEP continue with HHS.

Action VI.B.6.e:  Develop an after-action report addressing deployment of FDA-regulated products from the SNS. 

Deliverables:  A completed report pertaining to FDA-regulated products after the first wave of products has been deployed from the SNS.

Timeframe:  Within 90 days after an event of such significance that it requires deployment of FDA-regulated products from the SNS.

Action VI.B.6.f:  Coordinate with other Federal departments and agencies and State, local, and tribal public health departments that are developing plans to store anti-viral drug products at the SNS or at other designated sites and will be distributing anti-viral products through private distributors and/or other carriers to designated sites.  FDA’s input would be to help ensure proper conditions that comply with the product’s labeled storage conditions.

Deliverables:  Consultations with pharmaceutical manufacturers and distributors and with State, local, and tribal public health departments on possible storage facilities and storage requirements.

Timeframe:  Fiscal years 2007, 2008, and ongoing as needed.

C.     Device Development, Production, and Regulatory Review

Like vaccines and anti-viral drug products, devices would play an important role in an influenza pandemic.  Rapid diagnostic devices, for example, are critical components of an effective pandemic influenza preparedness and response program.  Diagnostic devices, by helping determine whether a person was infected with a pandemic influenza virus (as opposed to a seasonal influenza virus), would serve as a disease monitoring tool and help healthcare professionals determine the best treatment for that individual.  Diagnostic devices could also help determine which infection control measures to pursue (such as immunizing individuals in a specific area after diagnostic devices had confirmed that an individual in that area had contracted a pandemic influenza virus) and other public health responses to reduce the spread of disease.  PPE devices, such as masks, respirators, and gloves, could help prevent infection among healthcare professionals and, as a result, prevent the loss of valuable medical expertise and resources at a time when the demands on healthcare resources would be great.  Other devices, such as ventilators and endotracheal tubes, may help relieve symptoms in persons affected by pandemic influenza or help their recovery. 

Devices can present unique challenges or considerations, too.  For example, can the device be used more than once and still remain safe and effective?  If the device is intended to deliver a drug, will it be able to deliver an anti-influenza drug in a manner that does not affect the drug’s safety or effectiveness?

We have considerable experience with device development, production, and regulatory review.  For example, on February 3, 2006, we cleared a new laboratory test to diagnose H5 influenza strains in patients suspected of being infected with the virus.  The test, known as the Influenza A/H5 (Asian lineage) Virus Real-time RT-PCR Primer and Probe Set, will give preliminary results on suspected samples within hours; this represents a significant improvement over earlier testing technologies that required two to three days before producing results.  Also, in May, 2007, we cleared for marketing filtering face pieces that can help reduce a person’s exposure to airborne particles during a public health medical emergency, such as an influenza pandemic.

The Medical Device User Fee Modernization Act (MDUFMA) has better positioned FDA to review new devices more effectively and efficiently.  MDUFMA supports close collaboration with stakeholders and increased communications with applicants.  These efforts help applicants improve the quality of their submissions to FDA and help us provide more rapid, better-focused reviews.  Our ultimate objective is to make important new safe and effective medical devices available to patients and health care providers more quickly while continuing to ensure device quality, safety, and effectiveness once a product is on the market.

Objective VI.C.1:  Facilitate development and regulatory review of influenza-related devices, including diagnostics and PPE devices.

Action VI.C.1.a:  Implement early interactions and communications with sponsors through face-to-face, pre-submission meetings and conference calls.    

Deliverables:

• Expedited scheduling of meetings with sponsors.
• Greater meeting opportunities for sponsors. 

Timeframe:  This is an ongoing activity.

Action VI.C.1.b:  Timely review and approval or clearance of devices.

Deliverables:  Expedite review of devices that may be needed for an influenza pandemic, as appropriate.

Timeframe:  This is an ongoing activity.

Action VI.C.1.c:  Work with manufacturers to help ensure compliance with quality systems regulations (QSRs).

Deliverables: 

• Identification of device manufacturers with QSR issues that would or could affect safety and effectiveness.  We will work with such manufacturers to address quality issues.   
• For those manufacturers with identified QSR issues, coordination and expedited scheduling and performance of inspections for PPE, influenza-related diagnostics, and other support devices such as ventilators, resuscitator bags, and endotracheal tubes.

Timeframe:  This is an ongoing activity.

Objective VI.C.2:  Anticipate shortages and support efforts to prevent shortages of key devices.

Action VI.C.2.a:  Work with manufacturers to support efforts to ensure an adequate supply of diagnostics, PPE, and other devices that are expected to be in high demand during influenza outbreaks and for which short supplies are predicted. 

Deliverables: 

• Continuous liaisons with manufacturers and coordination with other HHS agencies or working groups to address medical products supply and availability.
• Updates to the list of the devices commonly used to manage influenza patients, including devices used for infection control.  Identification of the devices that may be in short supply if demand increases. 
• Updated contact information on manufacturers and the estimated number of select products available for immediate distribution, as well as the time that would be necessary to increase production to meet public health needs.  We will verify the information every six months to ensure its accuracy.   

Timeframe: 

• Continuous liaisons with manufacturers and coordination with other HHS agencies or working groups is an ongoing activity.
• We prepared a list of devices in September 2006.  Updating the list is an ongoing activity.
• We prepared contact information on manufacturers and the estimated number of select products in September 2006.  Updating the contact information is an ongoing activity.

Action VI.C.2.b:  After a declaration of an emergency by the Secretary of HHS due to pandemic influenza, review available scientific data and process EUAs for devices expeditiously.

Deliverable:  As EUA submissions are received, the scientific data will be evaluated and processed

Timeframe:  Documentation will be reviewed expeditiously and relevant questions will be directed to the sponsor. 

Objective VI.C.3:  Ensure continued safety and effectiveness of influenza-related devices during the post-market phase of the product life-cycle. 

Action VI.C.3.a:  Continue post-market monitoring and data analysis of adverse event reports on influenza-related devices to ensure the continued safety and effectiveness of marketed devices. 

Deliverables:  

• Prompt action on evidence of potential harm or increased risk to users of these devices. 
• Exchange of relevant information, as needed, with foreign regulatory authorities. 
• Continuous education of professionals and consumers on adverse event reporting mechanisms.

Timeframe:  This is an ongoing activity.   

Action VI.C.3.b:  Require, as appropriate, post-market studies or information gathering on influenza-related devices.  This can be accomplished in three different ways depending on the type of product involved and the applicable regulatory requirements.  It may be required: (1) under section 522 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360l) and 21 CFR part 822, provided that the statutory and regulatory criteria are satisfied; (2) as a special control; or (3) as a condition of approval for class III devices.²⁸

Deliverables:  Work with manufacturers in the planning of post-market studies, as appropriate, and provide recommendations on the types of useful data to be collected in these studies. 

Timeframe:  We will provide recommendations within 60 days after receiving the premarket submission.

Objective VI.C.4:  Educate device users on how to use influenza-related devices in a safe and effective manner.

Action VI.C.4.a: Develop educational materials on the uses of these devices, including appropriate warnings, precautions, and limitations. 

Deliverables:  

• Consultation with other agencies, such as CDC (including the National Institute for Occupational Safety and Health), the Occupational Safety and Health Administration (OSHA), and the Environmental Protection Agency (EPA), which may also provide advice regarding the selection and use of these devices, to ensure accurate and consistent messages.
• The posting of new information and the updating of existing material on our Web site.

Timeframe:  

• Consultation with other Federal departments and agencies is an ongoing activity.
• Posting of new information and updating existing material occurred in 2006 and was ongoing in 2007.  We will post updates as new information becomes available.

Objective VI.C.5:  Enhance communication with stakeholders.

Action VI.5.a:  Communicate FDA influenza-related device activities and information to industry, consumers, State, local, and tribal governments and other stakeholders.  Collaborate with other Federal and international health agencies on public messages related to the use of influenza-related devices to ensure consistency and accuracy.

Deliverables:  Influenza information on our Web site that is up-to-date and consistent with information disseminated by other Federal and international agencies.

Timeframe:  This is an ongoing activity.

D.     Food and Feed Safety²⁹

In general, national and international public health authorities and organizations believe that human consumption of properly cooked or prepared food poses no risk of acquiring AI.  However, birds are capable of transmitting AI to other birds, and there is some evidence suggesting that felids³⁰ can become infected after eating raw, infected birds. 

As an agency with significant responsibilities to protect human food and animal feed, we have a role in determining whether the AI virus presents a risk to human food or animal feed (due to the use of avian-derived ingredients in the food or feed) and in identifying methods to inactivate the AI virus in food or feed.  Our experience with other foodborne pathogens (such as Salmonella enterica, serovar Enteritidis) and novel diseases (such as bovine spongiform encephalopathy (or “mad cow” disease)) will be helpful in dealing with the AI virus and a possible human pandemic influenza virus.

Objective VI.D.1:  Assess the likelihood of food and feed contamination with highly pathogenic avian and human pandemic influenza virus.

Action VI.D.1.a:  Monitor global avian influenza activity in wild and domestic avian species and pandemic influenza activity in humans to identify the potential for food and/or feed contamination.

Deliverables:  

• Stronger collaboration with and communication on influenza surveillance with CDC and USDA.
• Sharing of information with other Federal, State, local, and tribal government departments and agencies and international public health and animal health organizations.

Timeframe:  This is an ongoing activity.

Action VI.D.1.b:  Identify FDA-regulated foods (including dietary supplements) and animal feeds that are at elevated risk of contamination with infectious AI or pandemic influenza virus.

Deliverables:

• A list of FDA-regulated foods and feed ingredients that contain avian-derived materials.
• Identification of foods (in addition to whole shell eggs) that contain domestic or imported avian-derived ingredients.
• A determination of the risk of contamination of food derived from marine and freshwater fish and shellfish from harvest waters that are potentially contaminated by infected waterfowl and domestic poultry.
• An estimate of the likely level and frequency of contamination of ready-to-eat foods by infectious respiratory droplets from human cases of pandemic influenza.

Timeframe:  Began in fiscal year 2006.

Action VI.D.1.c:  Investigate the effectiveness of food and feed processing and preparation practices for inactivating influenza viruses by:

• Determining typical food processing and preparation practices for FDA-regulated foods that contain eggs and avian tissues;
• Conducting a literature search on the survivability of influenza viruses in various conditions and in various food and feed matrices;
• Working with USDA’s Agricultural Research Service (ARS) to determine the upper limits of virus titers in egg contents for various HPAI strains and time/temperature requirements for the inactivation of different HPAI strains in eggs and meat from game birds;
• Communicating with the egg industry to determine temperatures achieved during different cooking methods for eggs;
• Conducting in-house research on cooking and other processing methods to determine their effectiveness in inactivating influenza virus strains of interest in food; and
• Collecting information on current procedures and practices used for the treatment of poultry litter intended for use in animal feed.

Deliverables:  Up-to-date information on conditions necessary in food and feed processing for the inactivation of influenza viruses.

Timeframe:  Initial literature searches completed in fiscal year 2006, with additional data expected.

Action VI.D.1.d:  Develop analytical methods, reagents, and testing capability for identifying influenza virus in foods, as appropriate to protect the human food supply.

Deliverables:  Publication of validated methods for detecting influenza virus in FDA-regulated foods.

Timeframe:  Completion will occur in fiscal years 2008 and 2009.

Action VI.D.1.e:  In coordination with ORA, establish inspection plans for food and feed and, as appropriate, sampling plans for foods based on the potential for contamination by AI viruses and availability of laboratory methods.  Work with other Federal and State departments and agencies to enhance and increase the number of inspections of domestic products at elevated risk of contamination with AI viruses and imports from affected countries.  

Deliverables: 

• Inspection plans for foods and feed.
• Sampling plans for analysis of potentially contaminated foods and, if identified, foods associated epidemiologically with human illness.

Timeframe:  Fiscal year 2008.

Objective VI.D.2:  Enhance communication with stakeholders.

Action VI.D.2.a:  Communicate our influenza-related food and feed safety activities and information to industry, consumers, State, local, and tribal governments, and other stakeholders.  Collaborate with other Federal and international human/animal health departments and agencies on public messages related to AI and food and feed safety to ensure consistency and accuracy.

Deliverables:  Influenza information on our Web site that is up-to-date and consistent with information disseminated by other Federal and international departments and agencies.

Timeframe:  This is an ongoing activity.  We will update the Web site on an as needed basis.

Action VI.D.2.b:  Exchange with other Federal departments and agencies emerging data on the geographic distribution of AI strains of interest and of pandemic human strains, the tissue distribution of the AI virus, and the effects of factors important in food processing and preparation (e.g., temperature, pH, salt concentration) on inactivation of these viral strains. 

Deliverables:  Establishment of an information sharing forum with interagency membership, as appropriate.

Timeframe:  We established the forum in fiscal year 2006

Action VI.D.2.c:  Enhance biosecurity measures for the food, feed, and rendering industries to meet any additional risks posed by AI or an influenza pandemic.  Work with industry, Federal, State, local, and tribal departments and agencies, and others on biosecurity strategies.  Identify and review existing biosecurity documents.  Provide technical assistance to industry as it implements biosecurity measures.  Work with USDA, EPA, and State, local, and tribal governments on disposal options for birds and potentially contaminated materials from infected flocks.
 
Deliverables:  

• “Best practices” guidance documents for the food, feed, and rendering industries, as needed.
• A final rule on shell egg Salmonella Enteritidis prevention. 

Timeframe:  Fiscal year 2008.

Objective VI.D.3:  Preserve the effectiveness and supply of drugs approved for the prophylaxis and treatment of influenza in humans.

Action VI.D.3.a:  Prohibit the extra-label use of human influenza anti-viral drug products in chickens, turkeys, and ducks.

Deliverables:  An order prohibiting the extra-label use of influenza anti-viral drug products of the adamantane and neuraminidase inhibitor drug classes in chickens, turkeys, and ducks.    

Timeframe:  We issued a final rule on March 22, 2006 in the Federal Register (71 FR 14374).  The final rule became effective on June 20, 2006.  We may expand the list of animal species affected as new data become available. 

Action VI.D.3.b:  Educate producers, vet