National Preparedness: Efforts to Address the Medical Needs of Children in a Chemical, Biological, Radiological, or Nuclear Incident
Released: 2013-04-30T00:00:00


Highlights: section_title: Why GAO Did This Study
paragraphs: The nation remains vulnerable to terrorist and other threats posed by CBRN agents. Medical countermeasures--drugs, vaccines, and medical devices--can prevent or treat the effects of exposure to CBRN agents, and countermeasures are available in the SNS for some of these agents. Children, who make up 25 percent of the population in the United States, are especially vulnerable because many of the countermeasures in the SNS have only been approved for use in adults. HHS leads the federal efforts to develop and acquire countermeasures.

GAO was asked about efforts to address the needs of children in the event of a CBRN incident. This report examines (1) the percentage of CBRN medical countermeasures in the SNS that are approved for pediatric use; (2) the challenges HHS faces in developing and acquiring CBRN medical countermeasures for the pediatric population, and the steps it is taking to address them; and (3) the ways that HHS has addressed the dispensing of pediatric medical countermeasures in its emergency response plans and guidance, and ways that state and local governments have addressed this issue. To address these objectives, GAO reviewed relevant laws, agency documents, and reports, and interviewed HHS officials, industry representatives, and subject-matter experts. GAO also reviewed a stratified sample of emergency response plans from seven state and seven local governments, based on geographic location and population size, to assess how these governments address pediatric dispensing.

section_title: What GAO Found
paragraphs: According to the Department of Health and Human Services (HHS), about 60 percent of the chemical, biological, radiological, and nuclear (CBRN) medical countermeasures in the Strategic National Stockpile (SNS) have been approved for children, but in many instances approval is limited to specific age groups. In addition, about 40 percent of the CBRN countermeasures have not been approved for any pediatric use. Furthermore, some of the countermeasures have not been approved to treat individuals for the specific indications for which they have been stockpiled. For example, ciprofloxacin is stockpiled in the SNS for the treatment of anthrax, plague, and tularemia, but is not approved for these indications. Countermeasures may be used to treat unapproved age groups or indications under an emergency use authorization (EUA) or an Investigational New Drug (IND) application submitted to the Food and Drug Administration (FDA).

HHS faces a variety of economic, regulatory, scientific, and ethical challenges in developing and acquiring pediatric CBRN medical countermeasures. High costs and the high risk of failure associated with testing and research of pharmaceutical products on children, difficulties in meeting regulatory requirements for approving CBRN countermeasures, and scientific and ethical obstacles to safely evaluating countermeasures for children all pose challenges to developing pediatric countermeasures. Despite these challenges, HHS has taken steps to focus agency efforts on the pediatric population, adapt pediatric formulations from existing medical countermeasures, and prepare and review materials for EUAs and INDs in advance of public health emergencies.

HHS addresses dispensing of pediatric medical countermeasures in more than half of its 12 response plans and in its guidance, and seven state and seven local government plans that GAO reviewed included details about pediatric dispensing. Seven of the 12 HHS plans include information about pediatric medical countermeasures; however, HHS officials stated that these plans are intended to provide guidance for emergency response at the federal level, and not at the state or local levels, which is where dispensing would occur. CDC and FDA also provide guidance on pediatric dispensing that state and local governments can use in their planning. For example, CDC developed guidance about receiving, distributing, and dispensing contents from the SNS to help state and local emergency management and public health personnel plan for the use of countermeasures from the SNS. Response plans for all 14 of the state and local governments that GAO reviewed also included details about dispensing to the pediatric population during an emergency. For example, these seven states and seven local governments all adopted some version of a "family member pick-up" policy--sometimes referred to as a "head of household" policy--which would allow adults to pick up medicines for other family members, including children, during an event.

In commenting on a draft of this report, HHS concurred with our findings. HHS emphasized that the needs of the pediatric population have been a priority for HHS and that the department is continuously progressing in this area.

section_title: Letter
paragraphs: The 2001 anthrax attacks and the 2011 earthquake and tsunami in Japan  raised concerns that the United States is vulnerable to intentional and  unintentional threats from chemical, biological, radiological, and nuclear  (CBRN) agents. Rapid diagnosis, treatment, and prevention could  mitigate the public health impact of a release of CBRN agents, and there  are medical countermeasures available for some of these agents.  Members of Congress, federal commissions, and other experts have  noted the need for the United States to develop and acquire medical  countermeasures to protect the public, and children in particular, from  public health emergencies involving CBRN agents. In 2010, the National  Commission on Children and Disasters reported that children, who make  up nearly 25 percent of the U.S. population, are more susceptible to  CBRN threats and require different countermeasures, dosages, and  delivery systems than adults.

The Department of Health and Human Services (HHS) is responsible for  leading federal efforts to prepare for and respond to public health and  medical CBRN incidents, including identifying needed medical  countermeasures to diagnose, treat, prevent, or mitigate potential health  effects from exposure, as well as engaging with industry to develop and  acquire the countermeasures.countermeasures may not be developed to a point where they are  available for acquisition, HHS’s responsibility extends to overseeing and  supporting research, as well as the development of these  countermeasures by manufacturers. In 2006, HHS established the Public  Health Emergency Medical Countermeasures Enterprise (PHEMCE), a  federal interagency body that includes various HHS agencies and offices,  as well as other federal departments, to provide recommendations to the  Secretary of HHS on medical countermeasure priorities and development  and acquisition activities. HHS’s Centers for Disease Control and  Prevention (CDC) manages the U.S. Strategic National Stockpile (SNS)— the national repository of medications, medical supplies, and equipment  for HHS’s use in mitigating the potential effects of exposure to CBRN  agents and other public health emergencies. PHEMCE annually reviews  the contents of the SNS to help HHS prioritize the maintenance and  acquisition of medical countermeasures. CDC is responsible for  distributing medical countermeasures from the SNS to states. In most  instances, states are in turn responsible for distributing the  countermeasures to local governments to dispense to affected  populations. In addition, HHS’s Food and Drug Administration (FDA)  reviews safety, efficacy, and product quality data on medical  countermeasures and approves, licenses, or clears them for specific  indications and for use by various populations, including children.

You raised questions concerning pediatric medical countermeasures that  are available in HHS’s SNS, as well as medical and public health  preparedness and response activities that are in place at the federal,  state, and local levels to address the needs of the pediatric population in  the event of a CBRN incident. This report addresses (1) the percentage of  CBRN medical countermeasures in the SNS that are approved for  pediatric use; (2) the challenges HHS faces in developing and acquiring  CBRN medical countermeasures for the pediatric population, and the  steps it is taking to address them; and (3) the ways that HHS has  addressed the dispensing of pediatric medical countermeasures in its  emergency response plans and guidance, and ways that state and local  governments have addressed this issue.

To determine the percentage of CBRN medical countermeasures in the  SNS that are approved for pediatric use, we reviewed and analyzed HHS  documentation, such as the PHEMCE annual reviews of the contents in  the SNS, and determined that the information was sufficiently reliable.  We interviewed officials from the HHS agencies and offices that are  responsible for CBRN emergency preparedness—including the Office of  the Assistant Secretary for Preparedness and Response (ASPR), the  Biomedical Advanced Research and Development Authority (BARDA),  the National Institutes of Health (NIH), CDC, FDA, the Children’s HHS  Interagency Leadership on Disasters (CHILD) Working Group, as well as  officials from PHEMCE. We also analyzed BARDA and CDC reports on  their investments and interviewed HHS officials.

To identify challenges that HHS faces in developing and acquiring CBRN  medical countermeasures for the pediatric population and steps it is  taking to address those challenges, we reviewed relevant laws, our earlier  reports, HHS documents, and other reports and information from  subject-matter experts on emergency preparedness and pediatric health.  We also interviewed officials from ASPR, BARDA, CDC, FDA, NIH, and  PHEMCE, as well as industry officials and other expert groups, such as  the American Academy of Pediatrics, Trust for America’s Health, the  Center for Infectious Disease Research and Policy, and state and local  organizations, such as the Association of State and Territorial Health  Officials and the National Association of County and City Health Officials.

To determine the ways that HHS has addressed the dispensing of  pediatric medical countermeasures in its emergency response plans and  guidance, and to assess how state and local governments have  addressed pediatric dispensing, we reviewed HHS documents, such as  the department’s 12 emergency response plans for specific CBRN threats  and CDC’s emergency operations plan and guidance on dispensing  medical countermeasures. In addition, we reviewed a sample of  emergency response plans from seven states and seven local  governments to assess how state and local governments address  pediatric dispensing. Our findings related to the documentation and  responses from the state and local governments are for illustrative  purposes only and are not generalizable to other state and local  governments’ emergency response plans. We interviewed HHS and CDC  officials responsible for addressing information in emergency response  plans and providing guidance to state and local governments on  dispensing pediatric medical countermeasures. We also interviewed state  and local health officials and interest groups, such as the Association of  State and Territorial Health Officials and the National Association of  County and City Health Officials, to confirm our understanding about how  dispensing CBRN medical countermeasures to children is handled during  emergencies.

We conducted this performance audit from July 2012 through March 2013  in accordance with generally accepted government auditing standards.  Those standards require that we plan and perform the audit to obtain  sufficient, appropriate evidence to provide a reasonable basis for our  findings and conclusions based on our audit objectives. We believe that  the evidence obtained provides a reasonable basis for our findings and  conclusions based on our audit objectives.
subsections: section_title: Background
paragraphs: Since the terrorist attacks of 2001, HHS has worked to prepare for and  mitigate potential consequences resulting from the intentional or  unintentional release of CBRN agents. This work has involved the efforts  of various agencies, industry, and subject-matter experts to develop,  acquire, and store medical countermeasures.

The development of medical countermeasures generally begins with  research on able-bodied adults, according to the National Commission on  Children and Disasters. However, children have unique anatomical,  physiological, and psychological differences that can predispose them in  some circumstances to more serious or different adverse effects during  public health emergencies compared to adults. HHS classifies children as  part of the “at-risk population” and evaluates CBRN medical  countermeasures for this group after developing them for the general  adult population. The at-risk population generally has unique  characteristics that may interfere with an individual’s ability to access or  receive medical countermeasures. For example, individuals who have a  limited ability to receive or respond to information because of hearing,  vision, speech, or cognitive limitations would need to have information  provided in such a way that they could understand it. In addition, before,  during, and after an emergency, individuals may lose the support of  caregivers, family, or friends. If separated from their caregivers, young  children may be unable to identify themselves, and may lack the cognitive  ability to assess situations and react appropriately. The National  Commission on Children and Disasters and other experts in the field of  pediatrics and emergency preparedness have reported that a disparity  exists in the quality of adult and pediatric emergency care, especially in  HHS’s efforts to acquire FDA-approved pediatric medical  countermeasures.
subsections: section_title: Roles and Responsibilities of HHS’s Agencies and Offices
paragraphs: HHS leads the federal public health and medical response to potential  CBRN incidents, including identifying needed medical countermeasures  to prevent or mitigate potential health effects from exposure and engaging  with industry to develop and acquire the countermeasures. The following  agencies and offices within HHS have responsibilities related to medical  countermeasures.

ASPR is responsible for leading federal government efforts to  research, develop, evaluate, and acquire medical countermeasures to  diagnose, prevent, treat, or mitigate the potential health effects from  exposure to CBRN agents. Within ASPR, BARDA, which was  established by the Pandemic and All-Hazards Preparedness Act of  2006, is responsible for overseeing and funding advanced  development and acquisition of CBRN medical countermeasures.

NIH is responsible for conducting and coordinating basic and applied  research to develop new or enhanced medical countermeasures for  CBRN agents.

FDA is responsible for regulating the development and approval of  drugs, biologics, diagnostics, and devices, which includes assessing  the safety, efficacy, and quality of CBRN medical countermeasures  before approval and postmarket.

CDC is responsible for maintaining the SNS and supporting state and  local public health departments in their efforts to respond to public  health emergencies, including providing guidance and  recommendations for the mass distribution and use of medical  countermeasures.

section_title: CBRN Threats and Medical Countermeasures
paragraphs: Since 2004, the Department of Homeland Security (DHS), in consultation  with the Secretary of HHS, has determined that certain CBRN agents  pose a threat to the nation that could affect national security. HHS has  used these material threat determinations to assess the potential public  health and medical consequences of the CBRN agents, and to establish  specific medical requirements for developing countermeasures.  Assessing the medical consequences and establishing medical  requirements are both interim steps in determining the types and  quantities of medical countermeasures required to respond to the agents.

CBRN agents differ from one another in their potential to cause  widespread illness and death. In the event of a release of a CBRN agent,  medical countermeasures may be needed for rapid diagnosis, treatment,  and prevention of infection, illness, and injury, but the dose and  formulation of the countermeasures needed for an individual may vary  according to traits such as the individual’s age and weight, especially  when considering the needs of children. For example, in some cases, it  is desirable to have multiple formulations of countermeasures available— such as oral liquid suspensions and tablets—to facilitate patient  compliance. There are an increasing number of available medical  countermeasures to protect the nation against CBRN agents. Supplies of  countermeasures that are available are generally held in the SNS for use  in a public health emergency. The SNS is designed to supplement and  resupply state and local public health departments in the event of a  national public health emergency such as a CBRN incident.

To acquire medical countermeasures for use during a CBRN incident  where there is a lack of a significant commercial market, Congress  authorized the appropriation of approximately $5.6 billion and the use of a  Special Reserve Fund for the procurement of certain countermeasures.  The Special Reserve Fund has been used to acquire CBRN medical  countermeasures for the SNS. The Pandemic and All-Hazards  Preparedness Reauthorization Act of 2013 reauthorizes the Special  Reserve Fund and authorizes $2.8 billion over 5 years, from fiscal year  2014 through fiscal year 2018.

section_title: FDA Approval and Emergency Authorization of Medical Countermeasures
paragraphs: In general, drugs, devices, diagnostics, and biologics such as vaccines,  including CBRN countermeasures, cannot be marketed legally in the  United States without FDA approval. To approve a countermeasure, FDA  requires manufacturers to sufficiently demonstrate the safety, efficacy,  and product quality of the countermeasure for the intended indication and  population specified in the application. When products are approved,  clinicians might prescribe them for unapproved indications or to  unapproved populations, also referred to as “off-label use.” Generally, a  doctor-patient relationship should exist for off-label dispensing of a  medical countermeasure. In a CBRN incident, dispensing of  countermeasures for approved or off-label indications may have to occur  outside of the doctor-patient relationship.medicines and vaccines used in normal, standard medical care for the  pediatric population are prescribed using this off-label practice. However,  one possible consequence of off-label use of countermeasures by  children is that some children, depending on weight or growth rates, may  not receive the most appropriate dose of a medical countermeasure. In  addition, some children may be at risk for side effects that are unique to   According to HHS, many  children, including adverse effects on their growth and development. To  encourage the study of more drugs for pediatric use, Congress passed  the Best Pharmaceuticals for Children Act in 2002, which provides  financial incentives to product sponsors, and the Pediatric Research  Equity Act of 2003. These laws encourage or require product sponsors to  conduct pediatric studies, and also include labeling requirements,  including labeling updates that result from pediatric drug studies.

Although FDA regulates the use of medical countermeasures by  approving their use by specific populations and for specific indications,  during a public health emergency—such as a CBRN incident—FDA can  authorize the use of those countermeasures by populations or for  indications for which they have not been approved. This can occur in one  of two ways. First, FDA can authorize the use of countermeasures that  are unapproved, or approved but for a different indication, in a declared  emergency to diagnose, treat, or prevent serious or life-threatening  diseases or conditions caused by CBRN agents, when there are no  adequate, approved, and available alternatives, and other criteria are  met. This is referred to as an Emergency Use Authorization (EUA). In order for FDA to authorize the emergency use of a countermeasure, it  must be reasonable to believe that, based on the evidence available, the  product may be effective in diagnosing, treating, or preventing such  disease or condition. In addition, the known and potential benefits of the  product must outweigh the known and potential risks.

section_title: Medical Countermeasure Research, Development, Acquisition, and Support
paragraphs: 21 U.S.C. § 360bbb. The Secretary of HHS has delegated authority to make such  determinations to the Commissioner of FDA. While INDs may be submitted for a variety of  purposes, in this report we use the term IND to refer to only those submitted for expanded  access to medical countermeasures during an emergency. centers and small biotechnology companies for basic and applied  research and early development. Once an organization’s research is at  the advanced development stage and moving toward the development of  a product that will meet HHS’s specific requirements, it may partner with  an established pharmaceutical or manufacturing company to continue the  advanced development. Within HHS, the product transitions from NIH to  BARDA to support its advanced development. If a countermeasure is  not FDA-approved or licensed, its acquisition into the SNS is typically  funded by the Project BioShield Special Reserve Fund. If a  countermeasure is FDA-approved or licensed, CDC generally purchases  the countermeasure for the SNS.

Public health emergency response planning for CBRN incidents requires  efforts at the federal, state, and local levels. Governments at each level  have developed emergency response plans that outline their respective  responsibilities during public health emergencies, which include  responsibilities for distributing and dispensing medical countermeasures  to the public. The federal government is responsible for planning the  federal response to CBRN incidents. HHS has developed response plans  for specific CBRN agents to help coordinate the federal response to such   Federal assistance to state and local governments would  emergencies.be provided if resources were unavailable or if state and local  governments were overwhelmed and requested public health or medical  assistance from the federal government. HHS would then direct CDC to  distribute medical countermeasures from the SNS to the states.

Once CDC distributes medical countermeasures from the SNS to a state,  in most instances the state then distributes the countermeasures to local  governments, based on established plans. State and local governments  are responsible for developing plans for receiving, distributing, and  dispensing medical countermeasures from the SNS. These plans are  intended to describe all functions that are required to accomplish these  tasks, in order to get medical countermeasures to the affected population  as quickly and efficiently as possible. Some states plan to receive  countermeasures and immediately turn them over to a local jurisdiction  for staging, distributing, and dispensing during an emergency. Other  states plan to receive medical countermeasures at a state warehouse  facility and then deliver them directly to points of dispensing (POD) or  hospitals. Each state is responsible for determining the best method for  its circumstances and resources. Local governments, in turn, are  responsible for receiving and dispensing medical countermeasures in a  timely and efficient manner.

section_title: More than Half of CBRN Medical Countermeasures Have Been Approved for at Least Some Children
paragraphs: About 60 percent of CBRN medical countermeasures in the SNS have  been approved for children, but in many instances approval is limited to  specific age groups. Specifically, PHEMCE officials stated that about   38 percent of the CBRN medical countermeasures in the SNS have been  approved for children of all ages for treatment of certain CBRN threats.  For example, ciprofloxacin and doxycycline as antimicrobials indicated for  postexposure prophylaxis of inhalational anthrax, atropine as a treatment  for exposure to nerve gas, and raxibacumab as an anthrax antitoxin have  all been approved for use in the pediatric population for these indications.  In addition, 22 percent of the CBRN medical countermeasures in the SNS  have been approved for use by some, but not all, pediatric age groups for  treatment of certain CBRN threats. For example, Prussian blue—a  medical countermeasure that removes certain internalized radiological  particles from the body—is approved for children ages 2 and above for  that indication, but has not been approved for those less than 2 years of  age. PHEMCE officials stated that the remaining 40 percent of the CBRN  countermeasures have not been approved for any pediatric use. For  example, anthrax vaccine adsorbed (AVA) has not been approved for use  by any children. Furthermore, some of the CBRN medical  countermeasures in the SNS have not been approved to treat individuals  of any age for the specific indications for which they have been  stockpiled. For example, ciprofloxacin is stockpiled in the SNS for the  treatment of anthrax, plague, and tularemia, but is not approved for these  indications. It is, however, approved for postexposure prophylaxis of  inhalational anthrax in all age groups. In addition, for certain CBRN  threats, there are no countermeasures available in the SNS because  treatments for the conditions do not exist beyond supportive care.

According to HHS officials, almost all medical countermeasures in the  SNS can be used by children in an emergency if already approved for  children or if FDA authorizes their use through an EUA or if an IND  protocol is in effect. Even products that are not approved for a CBRN  indication may be used in a public health emergency under an EUA— after an emergency has been declared—or under an IND protocol. HHS  officials told us that almost all medical countermeasures that are not  approved for use by the pediatric population can be used in an  emergency under an EUA. However, some countermeasures, such as  AVA vaccine, lack sufficient data to support their use by the pediatric  population under an EUA. This vaccine would need to be administered to  the pediatric population under an IND protocol. HHS officials explained  that two different IND protocols for AVA have been developed in  preparation for a potential anthrax-related public health emergency. The  first protocol is designed to provide children access to the vaccine. It  would require parents or guardians to sign consent forms to allow their  children to receive anthrax vaccine during an emergency. The second  IND protocol would require parents or guardians to sign consent forms to  allow their children to participate in a research study after receiving the  vaccine. (See app. I for additional information on the regulatory status of  types of CBRN medical countermeasures in the SNS for the pediatric  population.)

Although HHS can provide information on the proportion of SNS  countermeasures that can be used by children, it cannot provide  information on the funds invested in procuring these countermeasures.  HHS does not separately track the funds that it has invested in the  acquisition and development of pediatric medical countermeasures  because it does not account separately for investments related to the  different populations. HHS procures CBRN medical countermeasures for  the SNS based on, among other things, the list of material threats to the  nation, public health response and medical consequence assessments,  and available resources. Since 2004, BARDA has invested over $4 billion  of Project BioShield’s Special Reserve Fund, which supports advanced  development and manufacturing of potential CBRN medical  countermeasures, in contracts to support medical countermeasure  development in healthy and at-risk populations, including the pediatric  population. In addition, between 2009 and 2012, CDC’s budget to  maintain or acquire licensed CBRN medical countermeasures for the  SNS was over $1.5 billion; however, no funds were specifically  designated exclusively for products to be used only by the pediatric  population.

section_title: HHS Faces Challenges in Developing and Acquiring Pediatric Medical Countermeasures but Is Taking Steps to Address the Needs of the Pediatric Population
paragraphs: HHS faces economic, regulatory, scientific, and ethical challenges in its  efforts to develop and acquire CBRN medical countermeasures for  children in an emergency. Despite these challenges, HHS is taking steps  to focus on the pediatric population and develop pediatric formulations of  existing medical countermeasures.
subsections: section_title: HHS Faces Economic, Regulatory, Scientific, and Ethical Challenges in Developing and Acquiring Pediatric Medical Countermeasures
paragraphs: HHS faces a variety of interrelated challenges in developing and  acquiring pediatric CBRN medical countermeasures, including economic,  regulatory, scientific, and ethical issues that impede the ability of HHS to  address the needs of children during a CBRN incident. Economic  challenges facing HHS include the high failure rate of research,  development, approval, and licensure of most drugs, vaccines, and  diagnostic devices. Agency and industry officials told us that the risk of  failure in developing countermeasures for children is even higher than the  risk in developing them for the adult population. This risk, as well as a  lack of a commercial market for most CBRN medical countermeasures,  has made it difficult for HHS to attract companies willing to invest in such  development and has therefore impeded HHS’s ability to acquire the  needed countermeasures. In addition, various reports have stated that  insufficient economic incentives are available to encourage the private  sector to invest millions of dollars to develop potential new pediatric  medical countermeasures.desirable to have oral liquid formulations available for young children who  cannot swallow pills, it is not always practical to develop and acquire  them for the SNS because such countermeasures for children can be  more costly to procure and maintain, have shorter shelf lives, and may  exceed manufacturer capability, as opposed to alternatives such as pill  crushing and mixing that can be explored for all but the youngest children.  CDC estimated that it would cost approximately $3 billion to purchase  sufficient quantities of oral liquid formulations of countermeasures for the  SNS to support the needs of all children—an amount well over CDC’s  approximately $600 million annual budget for CBRN medical  countermeasures over the past 5 years. Further, because the shelf life of  liquids is shorter than that of tablets, oral liquid formulations would require  more frequent investments. Finally, even if such funds were available, the  manufacturing capacity to meet such acquisition requests may not be  available.

According to CDC officials, while it is  The FDA regulatory pathway for developing pediatric CBRN medical  countermeasures also poses unique challenges making it more difficult  than for adult countermeasures. The Institute of Medicine, the National  Biodefense Science Board, HHS, and FDA have stated that it is difficult to  meet FDA’s requirements for data from adequate and well-controlled  clinical investigations to support the approval of pediatric medical  countermeasures because large, complex clinical trials are needed to  prove safety and efficacy. As a result of this regulatory challenge, FDA  has increasingly relied on alternative sources of data in order to approve,  license, or authorize the use of medical countermeasures by children. For  example, FDA allows researchers to submit evidence of efficacy obtained  from historical inferences and appropriate studies in animals in  accordance with FDA’s Animal Rule. Another challenge to developing countermeasures for children is that manufacturers are permitted, under  certain circumstances, to avoid testing drugs for use by children. For  example, manufacturers of CBRN countermeasures often seek an orphan  drug designation for a new countermeasure, which, if granted, exempts  the manufacturer from the requirement to conduct pediatric studies under  the Pediatric Research Equity Act.

There are scientific challenges in obtaining sufficient pediatric safety and  efficacy information to appropriately inform the use of CBRN medical  countermeasures for children. For example, FDA officials told us that  extrapolating data to support efficacy information on a medical  countermeasure from animal studies presents not only regulatory, but  also complex scientific challenges to understanding how children would  react to exposure to CBRN agents. NIH and industry officials told us that  exposure in juvenile animal models is also not well understood. For  example, extrapolating data from animal studies presents other scientific  challenges in understanding the response to the medical  countermeasures used to prevent or treat the disease or condition.  Appropriate animal models have not yet been developed for many CBRN  agents. In addition, the presentation of the disease or condition that  humans manifest following exposure to a CBRN agent may not be the  same as that for animals following exposure to the same CBRN agent,  thus complicating the task of researchers that are relying on animal  models. Further, there is an initial hurdle of extrapolating data from animal  models for adults first; only after those data have been extrapolated and  applied to the adult population can researchers extrapolate to children.  For example, in order to develop or indicate a countermeasure for use in  children, scientists generally take an existing countermeasure that has  already been developed for adults and then adjust certain variables such  as weight-based dosing and delivery mechanisms to test the safety and  efficacy of the countermeasure in children. This is not straightforward  because children may have special susceptibilities to the CBRN agent  and special age- and weight-dependent responses to the medical  countermeasures.

Finally, HHS faces ethical challenges in its efforts to develop and acquire  pediatric medical countermeasures because, absent a CBRN event, it is  generally not ethical or feasible to obtain dosing, safety, and efficacy data  for children when there is no potential direct benefit to them in the context  of a clinical trial. FDA-regulated clinical trials that include children as  subjects must consider both the risks to which a child may be exposed in  a clinical investigation and whether the proposed intervention offers a  prospect of direct benefit to the child. Because children can be enrolled  as subjects in research only when directly necessary and when the  research is ethically sound, industry officials we met with stated that  researching CBRN medical countermeasures’ effect on children is nearly  impossible. Industry officials told us that knowing that CBRN medical  countermeasure research has a clear, direct benefit to a child  participating in a study would always be unlikely because diseases  caused by CBRN agents do not generally occur naturally.

section_title: HHS Is Taking Steps to Focus on the Pediatric Population and Develop Pediatric Formulations of Existing Medical Countermeasures
paragraphs: Although challenges persist in developing and acquiring pediatric medical  countermeasures, HHS is beginning to address gaps in the SNS for  pediatric medical countermeasures by focusing agency efforts on  children, developing pediatric formulations of medical countermeasures in  the SNS, and preparing and reviewing EUA and IND application materials  in advance of emergencies.

HHS is taking steps to focus department-wide efforts on children’s CBRN  medical countermeasure needs. In 2010, FDA announced its Medical  Countermeasures Initiative, which is intended to foster the development  and availability of medical countermeasures, including those intended to  be used by children. FDA officials said the initiative has improved the  regulatory pathway for advancing the development and acquisition of  medical countermeasures, for example, by clarifying and streamlining its  review process and countermeasure requirements, which may entice  manufacturers to develop new, novel medical countermeasures, including  countermeasures with pediatric applicability. In addition, in 2010, HHS  increased its focus on children’s needs with the establishment of the  CHILD Working Group, which was formed to identify and integrate  activities related to the needs of children across all HHS inter- and  intragovernmental disaster planning activities and operations. The CHILD  Working Group has developed recommendations for how HHS can  improve the delivery of care to children who are affected by disasters. In  2011, in the area of medical countermeasures, the CHILD Working Group  recommended that HHS provide clarity in the regulatory pathway for  pediatric medical countermeasures; obtain the appropriate data, when  available, to provide clinical pediatric dosing and use guidance for  existing medical countermeasures; and gather safety and efficacy data  from nontraditional sources to support the use of pediatric medical  countermeasures under EUAs and for eventual FDA approval.According to HHS officials, many of the recommendations from the  CHILD Working Group are being adopted by HHS. For example, in 2011,  HHS developed the Pediatric Obstetric Integrated Program Team, which  includes pediatric and obstetric subject-matter experts who advise  PHEMCE on pediatric and obstetric medical countermeasure issues. This  integrated program team is intended to recommend that pediatric medical  countermeasure needs are consistently considered throughout the entire  medical countermeasure development process and that pediatric subject- matter experts help consider complex ethical, scientific, and legal issues  associated with studies that are necessary for the licensure and approval  of medical countermeasures for children. In 2012 the integrated program  team conducted a review of the contents of the SNS to determine the  suitability of the contents for use by children, and it subsequently used the  review to make recommendations to PHEMCE, and to petition for new  medical countermeasure development. The content of the review is a  work product of the integrated program team, and HHS has no plans to  formally issue it. According to HHS, the findings and recommendations  were considered during the 2012 SNS Annual Review. Further, in 2012,  BARDA announced that where feasible and appropriate, it would be  including development of medical countermeasures for the pediatric  population as part of all base contracts moving forward.

HHS has taken steps to support the development of CBRN medical  countermeasure formulations for children, and has begun to base the  pediatric dosing information on other evidence, such as by extrapolating  from relevant and historical data of the countermeasure.  Countermeasures are not approved for an indication unless data on the  safety and efficacy of the countermeasure are available for a particular  population, such as children. According to FDA officials, the agency has  determined that in a smallpox emergency, the investigational smallpox  vaccine under development may be authorized for use under an EUA in  populations with compromised immune systems, including children.  Specifically, in 2007 a second-generation smallpox vaccine, developed  for persons determined to be at high risk for infection, was licensed based  on data from clinical trials and the routine vaccination of infants in the  United States through 1972. The vaccine was not studied in pediatric  populations; however, this second-generation vaccine was similar to the  vaccine that was routinely used to vaccinate infants in the United States  through 1972 and had been demonstrated to be safe and effective in  children. Therefore, FDA has determined that this vaccine could be used  in pediatric populations under its license in a smallpox emergency.  Similarly, pralidoxime chloride, prescribed as an antidote to treat nerve  agent poisoning, has also been approved for use by children based on  the extrapolation of efficacy data from both the adult and pediatric  populations. In addition, FDA has used historical data from other  countries to support EUAs or product approvals for pediatric indications  when analogous U.S. data were neither available nor obtainable. For  example, according to FDA officials, in 1987, a radiological incident in  Brazil provided the majority of the pediatric data that FDA reviewed to  assess the safety and efficacy of a radiological countermeasure. The data  included the use of the countermeasure by both adults and children. The  review allowed FDA to approve the countermeasure for children ages 2  and older in 2003.

PHEMCE has also encouraged adapting and manufacturing of oral liquid  formulations of existing medical countermeasures in order to ease  dispensing of countermeasures in the SNS for children. For example,  BARDA is contracting with industry partners to manufacture a liquid form  of a countermeasure that removes certain radioactive particles from the  body through the intestinal tract. Additionally, PHEMCE is considering  lowering the recommended age at which children should be administered  oral liquid suspensions of doxycycline in lieu of crushed tablets. CDC  officials told us that they would like to have more oral liquid suspensions  considered for the SNS; however, PHEMCE officials have reported that  crushing tablets would be an acceptable alternative and would have  benefits for storage, dispensing, and dosing. As a result, FDA and CDC  have developed instructions for crushing certain approved medical  countermeasures for use by people who cannot swallow tablets or  capsules. The crushing instructions include instructions for mixing the  countermeasures with food or drink to make them more palatable to  children. Crushing instructions generally include weight-based dosing  instructions, the number of doses required per day, and instructions for  how to crush pills and mix them.

Relevant component agencies within HHS collaborate to prepare and  review materials for EUAs and INDs in advance of public health  emergencies to ensure that sufficient data are available to support  authorizations for the use of certain medical countermeasures by  children. According to CDC officials, the agency assesses, on a regular  basis, the contents in the SNS and updates and assembles data and  information for those countermeasures that are not approved for use by  children so that in the event of a public health emergency, the contents  can be disseminated to states quickly. Specifically, to prepare for such an  emergency, CDC collaborates with BARDA, NIH, FDA, and  manufacturers to develop the EUA and IND submissions in advance of an  actual incident, so that all medical countermeasures in the SNS can be  used by children. In addition, they consult with the American Academy of  Pediatrics on pediatric issues.

section_title: HHS and State and Local Governments Address Dispensing of Pediatric Medical Countermeasures in Their Response Plans
paragraphs: More than half of HHS’s emergency response plans that we examined  included information about pediatric medical countermeasures. CDC and  FDA developed guidance on pediatric dispensing for state and local  government use. The state and local plans we examined also provided  details about dispensing to the pediatric population during an emergency.
subsections: section_title: More than Half of HHS’s Response Plans We Reviewed Include Information about Dispensing Pediatric Medical Countermeasures
paragraphs: Of the 12 HHS CBRN response plans we reviewed, more than half  included information about dispensing pediatric medical  countermeasures. Specifically, 7 of these threat-specific plans contained  information about medical countermeasures that could be dispensed for  use by children in the event of a CBRN incident. The type of information  included varied by plan. For example, two of the plans for responding to  biological threats identified preferred and alternative countermeasures,  and the appropriate dosages, that should be dispensed to children during  an event. For a chemical incident, one of the plans indicated a  premedication that should be used in pediatric patients before intubating  them.included information about medical countermeasures that could be used  by children, although one plan noted that an EUA would be required  before some of the countermeasures could be dispensed to the pediatric  population. Although more than half of HHS’s response plans included  information about dispensing specific countermeasures to children, HHS  officials told us that the purpose of these plans is to provide guidance for  emergency responses at the federal level, and not instructions for use at  the state and local level, which is where dispensing to children would   The response plans for nuclear or radiological incidents also  occur. While these plans are intended primarily to support the federal  response, they could also be used by state and local governments to  inform their activities as part of planning their own response to a public  health emergency.

HHS officials told us that they were moving away from the use of  separate, threat-specific response plans and were developing a single  “all-hazards” response plan. This all-hazards plan would include sections for responding to specific CBRN events. According to HHS  officials, these sections would address pediatric dispensing, including  EUA and IND requirements. Additionally, a briefing paper about the  pediatric population in disasters would be included in the all-hazards plan.

section_title: CDC and FDA Guidance for State and Local Governments Includes Information on Pediatric Dispensing
paragraphs: Both CDC and FDA developed guidance for the dispensing of CBRN  medical countermeasures from the SNS to the public, including children.  For example, CDC developed guidance about receiving, distributing, and  dispensing contents from the SNS to help state and local emergency  management and public health personnel plan for the use of  countermeasures from the SNS. The guidance, which could be used as  a reference document or as a checklist by local and state planners,  referred to the pediatric population in multiple sections, including an  appendix about pediatric dispensing considerations. For example, the  guidance described how the color “pink” is used to identify pediatric  supplies included in the SNS. Additionally, the appendix noted that the  SNS has limited amounts of oral suspensions of certain countermeasures  for use by children and offered potential solutions for state and local  governments to consider when addressing this shortage. These solutions  included assigning someone the responsibility of mixing suspensions at a  POD site or compounding tablets of medical countermeasures into oral  suspensions.

In addition, CDC and FDA developed other guidance on dispensing  medical countermeasures, including to the pediatric population, which  could be shared with and used by state and local governments. For  example, CDC developed a website and training opportunities for state  and local governments to use when planning for dispensing medical  countermeasures. The information shared through the website and  training addresses dispensing in general, for the most part, although a  small portion of the training touches on dispensing to the pediatric  population. FDA also developed guidance on dispensing pediatric  medical countermeasures. For example, because it can be difficult for  children to swallow pills, FDA developed instructions for how to crush and  mix doxycycline with water and then add to food to mask the taste of  doxycycline. Additionally, FDA, with CDC, developed an information sheet  about using doxycycline for the prevention of anthrax that state and local  governments could share with their populations during an event. This  sheet included dosing instructions for administering doxycycline to  children.

CDC and FDA also collaborated to prepare, in advance of an actual  CBRN incident, information about medical countermeasures that require  an EUA or IND to have ready to share with state and local governments  should an emergency occur.countermeasure would be dispensed to children under an EUA or IND  protocol, should there be a need. State and local governments could   This included information about how a  then, in turn, share this information with their populations in the event of  an emergency. For example, CDC and FDA developed an EUA fact sheet  with instructions for administering doxycycline to children at home. CDC  officials told us that they have information available for all medical  countermeasures that could be used by children under an EUA.  Information about pediatric dispensing under an EUA or IND protocol  would be sent electronically—rather than in hard copy—to state and local  governments because dispensing information can change and hard  copies could become outdated.

section_title: State and Local Government Plans Provide Details about Pediatric Dispensing
paragraphs: State and local governments have provided details about pediatric  dispensing in their emergency response plans. All seven of the state  response plans we reviewed addressed the dispensing of  countermeasures to the pediatric population during a CBRN incident.  Although the states’ plans varied in format, they were consistent with one  another in terms of the type of information they included about dispensing  to children. For example, more than half of the states included information  about pediatric dosing or formulations. Additionally, all seven states  adopted some version of a “family member pick-up” policy—sometimes  referred to as a “head of household” policy—which would allow adults to  pick up medicines for other family members, including children, during an  event. This policy is intended to eliminate disruptions to the dispensing  process while simultaneously reducing patient numbers and increasing  the number of persons treated during an incident. In addition, each state’s  plan provided other information about how medical countermeasures  would be dispensed to children, either under a family member pick-up  policy or through a POD.

One state’s medical countermeasure dispensing guidance noted that  a POD should have specialized items for dispensing to children, such  as scales for weighing children (if they are present and their parents  do not know their weights) and mixing equipment to make pediatric  portions. Additionally, the state’s Point of Dispensing Field Operations  Guide suggested that the POD include a staff member who can be  responsible for ensuring drugs are properly packaged and instructions  for children are given.

One state’s plan discussed how oral antibiotic suspensions and  syrups would be provided for the treatment of children who have  trouble swallowing tablets, and that converting ciprofloxacin and  doxycycline tablets into oral suspensions was recommended as an  alternative for providing additional quantities of pediatric prophylactic  regimens, due to the limited quantities of oral suspensions in the SNS.  The plan included instructions for reconstituting these medical  countermeasures.

One state’s plan provided information about dispensing  countermeasures to unaccompanied children who request treatment  at PODs. The issue of consent for emergency care to a child in a  disaster was discussed. Officials from this state told us that it works  closely with the state’s health care coalitions to ensure that the  regional guidelines include pediatric-focused strategies. Additionally,  because pediatric doses are not stored in the SNS in large quantities,  the state and local jurisdictions rely on partnerships with community  and chain pharmacies to compound and reconstitute medications for  children in an emergency.

As we found with the states, all seven of the local governments that  provided us with plans addressed dispensing countermeasures for the  pediatric population during a CBRN incident. Like the states’ plans, the local governments’ plans varied in their format but were consistent with  one another in terms of the type of information they included about  dispensing to children. For example, more than half of the plans included  information about screening children at a POD. Additionally, all seven  local governments plan to implement versions of family member pick-up  policies in the event of an emergency. The local governments’ plans also  included other ways to address the needs of the pediatric population  when dispensing medical countermeasures. For example,

One local government’s POD plan described different types of  dispensing, one of which is called “slow dispensing.” Slow dispensing  requires children under the age of 9 to pass through medical  screenings, if they go to the POD.

Another local government’s plan described the setup of a special  assistance station at a POD, where individuals could obtain  medication for children under 9 years of age. Special assistance  personnel could determine appropriate pediatric dosing by referring to  available weight charts.

Finally, one local government’s plan discussed allowing “fast-tracking  protocols,” which would allow individuals with children to be diverted  from the main lines and directed to a Help Desk to receive assistance.

CDC officials noted that state and local governments handle the  dispensing of countermeasures to children in the same way as for adults;  that is, the dispensing of countermeasures for both children and adults  occurs at POD sites. However, CDC officials also told us that special  considerations can still be made for children—for example, by  establishing separate family lines in the PODs. We found examples of this  consideration in some of the plans we reviewed.

section_title: Agency Comments
paragraphs: We provided a draft of this report to HHS for comment. In its written  comments, reproduced in appendix II, HHS concurred with our findings.  HHS reiterated information provided in our report, including that the  development, procurement, and dispensing of medical countermeasures  for the pediatric population is integrated into the PHEMCE’s framework  for public health preparedness across multiple component agencies, that  state and local jurisdictions play an important role in responding to public  health emergencies, and that the pace of progress in drug development is  limited by the complex issues that surround the testing of  countermeasures in children. In addition, HHS emphasized that the needs  of the pediatric population have been a priority for HHS since the origins  of Project Bioshield, and that the department is continuously progressing  in this area. HHS also provided technical comments that we incorporated  as appropriate.

We will send copies of this report to the Secretary of Health and Human  Services and interested congressional committees. We will also make  copies available at no charge on GAO’s website at http://www.gao.gov.

If you or your staff have any questions about this report, please contact  me at (202) 512-7114 or crossem@gao.gov. Contact points for our  Offices of Congressional Relations and Public Affairs may be found on  the last page of this report. Key contributors to this report are listed in  appendix III.

section_title: Appendix I: Pediatric CBRN Medical Countermeasures in the Strategic National Stockpile
paragraphs: Table 1 presents additional information about certain types of chemical,  biological, radiological, and nuclear (CBRN) medical countermeasures  available in the Strategic National Stockpile (SNS) by CBRN threat, as  well as their regulatory status, for the pediatric population. The  information presented is a general overview of countermeasures that are  available for the pediatric population in the event of a CBRN incident, and  does not include a complete list of all of the variations of each  countermeasure.

section_title: Appendix II: Comments from the Department of Health and Human Services

section_title: Appendix III: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact

section_title: Staff Acknowledgments
paragraphs: In addition to the contact named above, Tom Conahan,   Assistant Director; Kaitlin Coffey; Kelly DeMots; Carolina Morgan;   Monica Perez-Nelson; and Roseanne Price made key   contributions to this report.

section_title: Related GAO Products
paragraphs: National Preparedness: Improvements Needed for Measuring Awardee  Performance in Meeting Medical and Public Health Preparedness Goals.  GAO-13-278. Washington, D.C.: March 22, 2013.

National Preparedness: Countermeasures for Thermal Burns.   GAO-12-304R. Washington, D.C.: February 22, 2012.

Chemical, Biological, Radiological, and Nuclear Risk Assessments: DHS  Should Establish More Specific Guidance for Their Use. GAO-12-272.  Washington, D.C.: January 25, 2012.

National Preparedness: Improvements Needed for Acquiring Medical  Countermeasures to Threats from Terrorism and Other Sources.   GAO-12-121. Washington, D.C.: October 26, 2011.

National Preparedness: DHS and HHS Can Further Strengthen  Coordination for Chemical, Biological, Radiological, and Nuclear Risk  Assessments. GAO-11-606. Washington, D.C.: June 21, 2011.

Public Health Preparedness: Developing and Acquiring Medical  Countermeasures Against Chemical, Biological, Radiological, and  Nuclear Agents. GAO-11-567T. Washington, D.C.: April 13, 2011.

National Security: Key Challenges and Solutions to Strengthen  Interagency Collaboration. GAO-10-822T. Washington, D.C.:   June 9, 2010.

Combating Nuclear Terrorism: Actions Needed to Better Prepare to  Recover from Possible Attacks Using Radiological or Nuclear Materials.  GAO-10-204. Washington, D.C.: January 29, 2010.

Project BioShield Act: HHS Has Supported Development, Procurement,  and Emergency Use of Medical Countermeasures to Address Health  Threats. GAO-09-878R. Washington, D.C.: July 24, 2009.

Project BioShield: HHS Can Improve Agency Internal Controls for Its New  Contracting Authorities. GAO-09-820. Washington, D.C.: July 21, 2009.

Project BioShield: Actions Needed to Avoid Repeating Past Problems  with Procuring New Anthrax Vaccine and Managing the Stockpile of  Licensed Vaccine. GAO-08-88. Washington, D.C.: October 23, 2007.


Question-summary annotations: questions: question: What does the HHS state regarding CBRN approval for pediatric medical countermeasures?
answer: According to the Department of Health and Human Services (HHS), about 60 percent of the chemical, biological, radiological, and nuclear (CBRN) medical countermeasures in the Strategic National Stockpile (SNS) have been approved for children, but in many instances approval is limited to specific age groups.
child_questions: question: To what extent has approval been limited?
answer: In addition, about 40 percent of the CBRN countermeasures have not been approved for any pediatric use.  Furthermore, some of the countermeasures have not been approved to treat individuals for the specific indications for which they have been stockpiled.

question: What CBRN countermeasures have not been approved?
answer: For example, ciprofloxacin is stockpiled in the SNS for the treatment of anthrax, plague, and tularemia, but is not approved for these indications.

question: In what situations can countermeasures be used to treat unapproved age groups?
answer: Countermeasures may be used to treat unapproved age groups or indications under an emergency use authorization (EUA) or an Investigational New Drug (IND) application submitted to the Food and Drug Administration (FDA).

questions: question: What challenges does HHS face regarding CBRN countermeasures?
answer: HHS faces a variety of economic, regulatory, scientific, and ethical challenges in developing and acquiring pediatric CBRN medical countermeasures.
child_questions: question: What are examples of such challenges?
answer: High costs and the high risk of failure associated with testing and research of pharmaceutical products on children, difficulties in meeting regulatory requirements for approving CBRN countermeasures, and scientific and ethical obstacles to safely evaluating countermeasures for children all pose challenges to developing pediatric countermeasures.
child_questions: question: What has HHS done despite these challenges?
answer: Despite these challenges, HHS has taken steps to focus agency efforts on the pediatric population, adapt pediatric formulations from existing medical countermeasures, and prepare and review materials for EUAs and INDs in advance of public health emergencies.

questions: question: What does HHS address in more than half of its response plans?
answer: HHS addresses dispensing of pediatric medical countermeasures in more than half of its 12 response plans and in its guidance, and seven state and seven local government plans that GAO reviewed included details about pediatric dispensing.
child_questions: question: What did the HHS state regarding these response plans?
answer: Seven of the 12 HHS plans include information about pediatric medical countermeasures; however, HHS officials stated that these plans are intended to provide guidance for emergency response at the federal level, and not at the state or local levels, which is where dispensing would occur.

question: What other organizations provide guidance on pediatric dispensing?
answer: CDC and FDA also provide guidance on pediatric dispensing that state and local governments can use in their planning.
child_questions: question: What guidance does the CDC provide on pediatric dispensing?
answer: For example, CDC developed guidance about receiving, distributing, and dispensing contents from the SNS to help state and local emergency management and public health personnel plan for the use of countermeasures from the SNS.

question: What guidance do the HHS's response plans have on pediatric dispensing during an emergency?
answer: Response plans for all 14 of the state and local governments that GAO reviewed also included details about dispensing to the pediatric population during an emergency. For example, these seven states and seven local governments all adopted some version of a "family member pick-up" policy--sometimes referred to as a "head of household" policy--which would allow adults to pick up medicines for other family members, including children, during an event.

questions: question: To what extent is the nation vulnerable to CBRN threats?
answer: The nation remains vulnerable to terrorist and other threats posed by CBRN agents.
child_questions: question: How can the nation react to these threats?
answer: Medical countermeasures--drugs, vaccines, and medical devices--can prevent or treat the effects of exposure to CBRN agents, and countermeasures are available in the SNS for some of these agents.

question: Which demographic is especially vulnerable?
answer: Children, who make up 25 percent of the population in the United States, are especially vulnerable because many of the countermeasures in the SNS have only been approved for use in adults.

question: What role does the HHS play regarding CBRN threats?
answer: HHS leads the federal efforts to develop and acquire countermeasures.

questions: question: What was GAO asked about?
answer: GAO was asked about efforts to address the needs of children in the event of a CBRN incident.

question: What does this report examine?
answer: This report examines (1) the percentage of CBRN medical countermeasures in the SNS that are approved for pediatric use; (2) the challenges HHS faces in developing and acquiring CBRN medical countermeasures for the pediatric population, and the steps it is taking to address them; and (3) the ways that HHS has addressed the dispensing of pediatric medical countermeasures in its emergency response plans and guidance, and ways that state and local governments have addressed this issue.
child_questions: question: What did GAO do to address these objectives?
answer: To address these objectives, GAO reviewed relevant laws, agency documents, and reports, and interviewed HHS officials, industry representatives, and subject-matter experts.

question: Why did GAO review a stratified sample of emergency response plans?
answer: GAO also reviewed a stratified sample of emergency response plans from seven state and seven local governments, based on geographic location and population size, to assess how these governments address pediatric dispensing.