Response to Comments: Guidance on Antiviral Drug Use during an Influenza Pandemic
Robust Response to Comments
I. General overview
On June 3, 2008, the Department of Health and Human Services (HHS) released a draft document updating national guidance on pandemic influenza antiviral drug stockpiling and use (“Proposed Guidance on Antiviral Drug Use Strategies during an Influenza Pandemic”). This document was posted for a 30 day comment period which closed on July 3, 2008.
Comments were received by HHS’ Office of the Assistant Secretary for Planning and Evaluation, and were logged in according to when they were received. Following closure of the comment period, all comments were forwarded to staff in the National Vaccine Program Office and the Office of the Assistant Secretary for Preparedness and Response where each comment was reviewed. In this Response, we summarize all of the public comments and provide specific responses on the substantive issues raised in those comments. Many of these comments provided excellent recommendations to HHS and we have incorporated those recommendations into our updated versions of the pandemic antiviral drug guidance document. We are grateful to all of the members of the public who took the time to share their views with HHS on this issue.
All comments are available for the public to review at the HHS Public Reading Room, 200 Independence Avenue, S.W., Washington, D.C., 20201. Please call (202) 690-7453 between 9:00 a.m. and 5:00 p.m. to arrange access.
II. Distribution of Commenters
HHS received 28 comments on the proposed guidance document. The distribution of the commenters based on their sector is shown, below:
• Public health, individual or State/local agency, n = 5
• Healthcare provider, n = 4
• Healthcare organization, n = 3
• Pharmaceutical industry, n = 3
• Business or trade association, n = 3
• Public health organization, n = 2
• Academia, n = 2
• Labor organization, n = 2
• Military, n = 2
• Citizens group, n = 1
• Emergency services organization, n = 1
III. Summary of Comments and HHS Response
A. Scientific basis for the guidance
Department Summary of Comments
Several comments questioned the basis for the planning assumptions and the strength of evidence supporting the use of antiviral drugs for prophylaxis. One comment on the planning assumptions specifically suggested that the assumption of a 15% attack rate of pandemic illness with community mitigation was overly optimistic.
Department Response to Comments
HHS recognizes that the scientific basis for the planning assumptions is limited. The estimated 30% illness attack rate of an unmitigated pandemic was based on experience in the 1918 pandemic. The estimated 50% reduction in attack rate with effective implementation of community interventions as defined in the guidance Community Strategy for Pandemic Influenza Mitigation was derived from the observation that in the 1918 pandemic, cities that applied community measures more effectively experienced a 50% decrease in peak mortality. Although overall mortality reductions were less, we assume that planning before the pandemic and uniform implementation of community measures will increase effectiveness relative to the 1918 situation. Mathematical modeling results suggest that decreases in the attack rate of greater than 50% can occur with rates of adherence that likely are achievable.
The guidance document includes references to published studies that evaluate the impacts of antiviral drug treatment and prophylaxis. Estimates of post-exposure prophylaxis efficacy from randomized controlled trials of neuraminidase inhibitors show a 70 – 90% reduction in the rate of symptomatic illness. While there is no pandemic experience with use of these agents, in vitro studies show efficacy against all influenza subtypes and experience with treatment of persons infected with H5N1 avian influenza show a significant reduction in mortality.
B. Risks and uncertainties
Department Summary of Comments
Several comments identified potential risks and uncertainties that may affect the effectiveness of antiviral drug use during a pandemic or affect the willingness of organizations to stockpile and plan antiviral drug strategies. These included antiviral drug resistance, the risk of adverse events in those taking the drugs, the limited shelf-life (currently approved dating is 5 – 7 years), and the risk of seizure of private sector stockpiles by public health agencies.
Department Response to Comments
A section was added to the guidance document highlighting the risks and uncertainties associated with stockpiling and planning an antiviral drug strategy as part of a pandemic response, and responding to these concerns. Antiviral drug resistance does represent a threat to the potential effectiveness of treatment and prophylaxis. The emergence of oseltamivir resistance among influenza A (H1N1) viruses that cause seasonal influenza infections illustrates this potential. Other influenza subtypes, however, remain susceptible to oseltamivir and there is no evidence that antiviral drug use led to the development of resistance or that resistance may spread from H1N1 to other influenza subtypes. In addition, H1N1 and other influenza viruses remain susceptible to zanamivir.
Adverse events associated with oseltamivir or zanamivir treatment or prophylaxis are uncommon. Oseltamivir is associated with gastro-intestinal symptoms (e.g., nausea, vomiting) but these rarely lead to discontinuation of the drug. Recently, neurobehavioral abnormalities have been reported among persons taking oseltamivir although the relationship of this event with use of the drug is unclear. During a pandemic, ongoing monitoring for adverse events will occur allowing public health officials to provide advice, as needed.
Risks to organizations that stockpile antiviral drugs as part of a pandemic response strategy include that the drugs may expire before a pandemic occurs or that State public health agencies may seize private sector stockpiles. The former risk can be mitigated by programs offered by both neuraminidase inhibitor manufacturers where organizations or businesses pay an annual fee to the manufacturer to maintain a stockpile that is updated as needed and is delivered at the time of a pandemic with payment of the wholesale drug cost. While State health departments do have the authority to take private sector assets, with appropriate compensation, in a recent meeting convened by the Association of State and Territorial Health Officials (ASTHO) and including business and trade association representatives, health officials clearly stated their reluctance to use this authority except under extreme circumstances and their commitment to coordinate with the business community to reduce perceptions of risk.
C. Adherence with the guidance and equity
Department Summary of Comments
Several comments suggested that private sector organizations are unlikely to purchase antiviral drugs because of the cost and that implementation of the guidance will be limited. This contributed to concerns about equity and whether workers will be protected. One comment from a labor organization suggested that the guidance be made mandatory while a second emphasized that no worker should have to pay for the antiviral drugs needed to implement the guidance. Several commenters, including public health and healthcare organizations, suggested that the additional antiviral drugs needed to implement this guidance should be purchased by the Federal government and be maintained in the Strategic National Stockpile
Department Response to Comments
The National Strategy on Pandemic Influenza identifies preparedness and response as a shared responsibility among the public and private sectors. Public sector stockpiles have been established and exceed 73 million regimens, targeted primarily for treatment of those with pandemic illness. Many Federal agencies are leading by example and are acquiring additional stockpiles to support prophylaxis as recommended in the guidance. HHS has worked to reduce the barriers to stockpiling by private sector organizations and manufacturer programs have reduced cost and shelf-life concerns. The Center for Disease Control and Prevention’s Healthcare Infection Control Practices Advisory Committee has endorsed the recommendation for healthcare worker prophylaxis and in a survey conducted by the Emerging Infections Network of the Infectious Diseases Society of America, most respondents indicated that their organization is planning or considering purchasing antiviral drugs for their employees.
Nevertheless, it is likely that the guidance will not be implemented uniformly and that some organizations will not have the capacity or willingness to comply. In such settings, it is important to emphasize that antiviral drugs are only one component of a comprehensive program to protect workers and maintain essential services. Planning changes to workplace practices, engineering controls, use of respiratory protection devices, and improved hygiene all contribute to a comprehensive program that can be very effective. The expectation for critical infrastructure sector organizations is to plan and prepare for a pandemic and antiviral drugs are only one potential component of such planning.
D. Definition of groups targeted in the guidance for prophylaxis
Department Summary of Comments
Comments questioned whether workers at long-term care facilities (e.g., for elderly persons) are included as healthcare workers and are included in the outbreak prophylaxis recommendation. Another comment emphasized that school dormitories should be included in the recommendation for post-exposure prophylaxis for outbreak control in closed settings. A commenter suggested that the recommendation should be expanded to other critical infrastructure sector workers in addition to those in healthcare and emergency services, and there were several comments suggesting that family members of workers recommended for prophylaxis also receive antiviral drug prophylaxis.
Department Response to Comments
The basis for recommending antiviral prophylaxis for healthcare and emergency services workers for the duration of a community pandemic outbreak is that these workers are critical to an effective pandemic response, they will face an increased burden during a pandemic, and they are at increased risk of infection because of an increased risk of occupational exposure. No other critical infrastructure occupations meet these criteria. Therefore, for other critical infrastructure sectors, antiviral drug stockpiling and prophylaxis should be considered as part of a comprehensive strategy to maintain essential operations during a pandemic. The guidance makes clear that these recommendations are guidance and do not establish a standard of care or requirement that must be met; rather, it represents a prudent approach that can contribute to a more effective pandemic response.
Although healthcare and emergency services providers have expressed concern about protection of their family members during a pandemic, extending prophylaxis to families is not recommended in the guidance. Family members of healthcare and emergency services workers are not at increased risk of pandemic influenza compared with the general population – especially if the worker is protected by prophylactic antiviral drug use and other workplace measures. Since influenza is transmitted primarily by respiratory droplets, preventing infection of the worker will protect their family. Another rationale presented for prophylaxis of family members is to reduce the rate of illness in this group and reduce absenteeism potentially from caring for an ill family member. However, with effective community mitigation, and an assumed pandemic attack rate of 15%, the impact of family member illness on overall absenteeism would be small and unlikely to threaten maintenance of essential services. Finally, from an ethical perspective, given the absence of increased risk among family member, recommending prophylaxis for this group would decrease equity.
Revisions to the document indicate that school dormitories, if students have not been dismissed from school, may be considered a closed setting for post-exposure prophylaxis during an outbreak. Other examples of closed settings include long-term care facilities, jails and prisons, and ships. The document also indicates that workers in long-term care facilities are included with other healthcare workers in the recommendation for prophylaxis.
E. Antiviral drug production capacity: is it sufficient to support implementation?
Department Summary of Comments
Several comments questioned whether antiviral drug production capacity was sufficient to support full implementation of the guidance.
Department Response to Comments
This question may have arisen based on 2005 HHS guidance that private sector organizations not stockpile antiviral drugs because this could jeopardize the ability to complete public sector stockpile purchases and to have sufficient drug to meet demand during seasonal influenza outbreaks. Since 2005 both Roche (manufacturer of oseltamivir) and GSK (manufacturer of zanamivir) have increased their global production capacity. Sufficient supply and production is now available to achieve full implementation of this guidance and maintain sufficient supplies for seasonal influenza use.
F. Conflicts of interest
Department Summary of Comments
One comment asked whether any working group members had conflicts of interest with antiviral drug manufacturers and whether this could have led to recommendations for expanded stockpile purchases.
Department Response to Comments
The guidance document has been revised to include the statement that no interagency working group members had a conflict of interest with the antiviral drug manufacturers and that the manufacturers were not included or consulted during the process of developing the guidance.
G. Implementation
Department Summary of Comments
Several comments highlighted challenges to implementing the guidance and suggested the need for additional information and materials to support implementation.
Department Response to Comments
In response to these comments, a section was added to the guidance document on “Implementation of Antiviral Drug Recommendations.” This section discusses implementing a stockpiling program, preparedness activities, and response at the time of the pandemic. Potential barriers to stockpiling are discussed and approaches to overcome the barriers are suggested. Planning guidance emphasizes rapid implementation and timely diagnosis and dispensing. Educating workers is emphasized as well.
H. Antiviral drug stockpiling by families
Department Summary of Comment
One comment suggested that families should be able to stockpile antiviral drugs, just as businesses and other organizations in certain sectors are being encouraged to in this guidance.
Department Response to Comment
Antiviral drug stockpiling by families may contribute to a pandemic response by providing ill persons quicker access to antiviral treatment and reducing burden on healthcare and public health systems. Home stockpiling also can promote preparedness and resiliency by families. Home stockpiling also poses challenges: as a prescription medication, only a licensed healthcare provider can prescribe the drugs, and there are no data available on the ability of families to effectively store antiviral drugs at home, correctly identify when a family member has pandemic influenza, and take the drugs using the right dosing and regimen. The antiviral drug manufacturers, Roche and GSK, are developing a home kit that includes their products, oseltamivir or zanamivir, that will be specially packaged and labeled for stockpiling. Approval of these “medkits” by the Food and Drug Administration (FDA) will depend on studies showing that the kits can be appropriately maintained, the instructions understood, and the drug used appropriately at the correct time. Any HHS guidance on home stockpiling will depend on the results of these studies and FDA approval of these products.
