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U.S. Department of Health and Human Services

Emergency Preparedness and Response

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Interim Questions and Answers: Emergency Use Authorization for Oral Formulations of Doxycycline for Post-Exposure Prophylaxis of Inhalational Anthrax


The statutory authority mentioned in the following question and answer document has been amended by PAHPRA, enacted in March 2013
 


 

Contents


EUA Overview

1. What is an emergency use authorization (EUA)?

FDA can issue an EUA to allow either the use of an unapproved medical product (e.g., drug, vaccine, or device) or the unapproved use of an approved medical product during certain types of emergencies with specified agents.

Section 564 of the Federal Food, Drug, and Cosmetic (FD&C) Act, as amended by the Project BioShield Act of 2004, permits authorization of such products to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by biological, chemical, radiological, or nuclear agents, if certain statutory criteria are met. The Secretary of the Department of Health and Human Services (HHS) has delegated the authority to issue an EUA under section 564 of the FD&C Act to the FDA Commissioner.

2. What is required before FDA issues an EUA?

The FD&C Act requires that, before an emergency use is authorized, the Secretary of HHS must declare an emergency justifying the emergency use based on one of the following grounds:

(1) The Secretary of the Department of Homeland Security determines that there is a domestic emergency, or a significant potential for a domestic emergency, involving a heightened risk of attack with a specified biological, chemical, radiological, or nuclear agent or agents; or

(2) The Secretary of the Department of Defense determines that there is a military emergency, or a significant potential for a military emergency, involving a heightened risk to United States military forces of attack with a specified biological, chemical, radiological, or nuclear agent or agents; or

(3) The HHS Secretary determines that there is a public health emergency under the Public Health Service (PHS) Act that affects, or has a significant potential to affect, national security, and involves a specified biological, chemical, radiological, or nuclear agent or agents, or a specified disease or condition that may be attributable to such agent or agents.

3. On what basis can the FDA issue an EUA?

Once the HHS Secretary has declared an emergency justifying the emergency use, the FDA Commissioner can authorize an emergency use only if, after consultation with the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC) (to the extent feasible and appropriate given the circumstances of the emergency), the Commissioner determines that certain statutory criteria have been met. Specifically, the Commissioner must conclude, as follows, that:

(1) The agent specified in the declaration of emergency can cause a serious or life-threatening disease or condition;

(2) Based on the totality of scientific evidence available (including data from adequate and well-controlled clinical trials, if available), it is reasonable to believe that the product may be effective in diagnosing, treating, or preventing—

(a) The serious or life-threatening disease or condition, or

(b) A serious or life-threatening disease or condition caused by a product authorized under section 564, or approved, cleared, or licensed under the FD&C Act or PHS Act, for diagnosing, treating, or preventing the disease or condition referred to in paragraph (1) and caused by the agent specified in the declaration of emergency;

(3) The known and potential benefits of the product outweigh the known and potential risks of the product when used to diagnose, prevent, or treat the serious or life-threatening disease or condition that is the subject of the declaration; and

(4) There is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating such serious or life-threatening disease or condition.

An EUA may remain in effect for up to 1 year based on the HHS declaration justifying the emergency use, unless such declaration is terminated or the EUA is revoked (e.g., if the criteria for issuance of the authorization are no longer met or other circumstances make revocation appropriate to protect the public health or safety) before 1 year. Both the declaration of an emergency and EUAs issued under that declaration may be renewed, if justified, after 1 year. The law requires FDA to publish in the Federal Register a notice that announces each EUA and termination or revocation of an authorization and that provides an explanation of the reasons for the action.

4.  Are there any limits on the use of an EUA product?

For unapproved products, the law requires the FDA Commissioner (to the extent practicable given the circumstances of the emergency) to establish certain conditions on an EUA that the Commissioner finds necessary or appropriate to protect the public health, and permits the Commissioner to establish other conditions that the Commissioner finds necessary or appropriate to protect the public health. Such conditions may include a requirement to disseminate information to health care professionals or authorized dispensers and to prospective patients and other consumers regarding the EUA, the product’s significant known and potential benefits and risks, and the extent to which such benefits and risks are unknown; available alternatives and their benefits and risks; and, for prospective patients and consumers, the option to accept or refuse the product and any consequences of refusal. Other conditions may include adverse event reporting and monitoring, data collection and analysis, and recordkeeping and records access.

For unapproved uses of approved products, certain of these conditions and other conditions may be required in an EUA.

Use of a product under an authorization must be consistent with any conditions imposed on the EUA.

5.  Have any other EUAs been issued?

Yes. FDA has issued numerous EUAs since 2005. For example, many EUAs were issued in response to the 2009 H1N1 influenza pandemic. However, because the pandemic has ended, the H1N1 EUAs are no longer in effect. For additional information on the EUAs that FDA has issued, visit the FDA EUA Website. 1

6. Where can I find additional information about EUAs?

Additional information about FDA’s EUA authority, including EUA guidance and EUAs that have been issued, is available at FDA’s EUA website. 2

The PREP Act and EUAs

7. What is the PREP Act?

The Public Readiness and Emergency Preparedness (PREP) Act authorizes the HHS Secretary to issue a PREP Act declaration 3 that provides immunity from tort liability (except for willful misconduct) for claims of loss caused by, arising out of, relating to, or resulting from the administration or use of a countermeasure to a disease, threat, or condition determined by the Secretary to constitute a present or credible risk of a future public health emergency to entities and individuals involved in the development, manufacture, testing, distribution, administration, and use of the countermeasure. A PREP Act declaration is specifically for the purpose of providing immunity from tort liability, and is different from, and not dependent on, other emergency declarations.

The PREP Act also authorizes the establishment of an emergency fund in the United States Treasury to provide compensation for injuries directly caused by administration or use of a countermeasure covered by the HHS Secretary’s declaration. Compensation may be available under the Countermeasures Injury Compensation Program (CICP), which is administered by the Health Resources and Services Administration (HRSA), for medical benefits, lost wages, and death benefits to individuals for specified injuries.

Countermeasures covered under a PREP Act declaration can include products that are approved, cleared, or licensed under the FD&C Act or the PHS Act, authorized for investigational use under the FD&C Act, or authorized under an EUA. For example, if a person is given a countermeasure that is authorized for emergency use under an EUA in a declaration made by the HHS Secretary, then that person may be eligible under the PREP Act for compensation through the CICP if serious physical injury or death results from use of the countermeasure.

For more information on the PREP Act, visit HHS’s Public Readiness and Emergency Preparedness Act Questions and Answers. 4 Additional information on the PREP Act (including PREP Act declarations that have been issued) and on the CICP can be found on HRSA’s CICP website. 5

8. What happens if the drugs that are authorized for emergency use under an EUA (i.e., unapproved drugs or approved drugs for unapproved uses) are distributed outside the scope of, or inconsistent with, the conditions of the EUA once it has been issued?

If the FDA issues an EUA to allow for the lawful distribution or dispensing of products for emergency use under certain circumstances and if stakeholders do not distribute or dispense the countermeasures in accordance with the scope and conditions of the EUA, then liability protections afforded by the PREP Act may be affected.

Doxycycline EUA for Post-Exposure Prophylaxis (PEP) of Inhalational Anthrax

9.  Why is FDA issuing an EUA for doxycycline for PEP of inhalational anthrax now when there is no current or actual public health emergency involving anthrax in the United States?

This EUA 6 was issued to facilitate preparedness and response efforts, not in response to a current immediate threat or increased risk of exposure to Bacillus anthracis (B. anthracis), the agent that causes anthrax. CDC requested the EUA to support stakeholders’ pre-event planning and preparedness activities (e.g., pre-event stockpiling of doxycycline), which will enable responders to rapidly initiate antimicrobial therapy—in this case, oral formulations of doxycycline—for PEP for inhalational anthrax through various distribution and dispensing modalities should an actual anthrax emergency occur. In addition to supporting pre-event efforts, the EUA allows for the use of doxycycline without delay should an actual anthrax event occur. (The EUA also supports federal agency pre-event stockpiling and preparedness efforts that are occurring under Executive Order 13527. 7)

As discussed in additional detail below in Question 13, an EUA was needed because such preparedness and response activities may include elements that could otherwise violate provisions of the FD&C Act under FDA’s legal interpretations. For example, during an actual anthrax emergency, doxycycline may be dispensed without individual patient prescriptions, which would not be consistent with FDA’s legal interpretations of the FD&C Act.

10. Who are the stakeholders in the EUA?

For the purposes of this EUA, the term stakeholder means the public agency or its delegate that has the legal responsibility and authority to respond to an incident, based on political or geographical (e.g., city, county, tribal, State, or Federal boundary lines) or functional (e.g., law enforcement or public health) range or sphere of authority to prescribe, administer, deliver, distribute, or dispense doxycycline in an emergency situation.

11. How is this EUA different from previous EUAs?

This EUA differs from previously issued EUAs because it is intended to facilitate pre-event planning and preparedness activities for an anthrax emergency, as well as response efforts should an actual anthrax emergency occur. For example, the EUA allows for flexibility in developing some of the information materials for health care professionals and for recipients by providing a minimum set of elements that must be provided to them (see Question 19); previous EUAs required that specific fact sheets be used. This additional flexibility is intended to support stakeholders’ planning efforts so that they can best meet their preparedness and response needs.

In addition, stakeholders are authorized to dispense oral formulations of doxycycline in circumstances when they reasonably believe that there is a need for mass dispensing because their constituents have been, are suspected to have been, or are imminently likely to be exposed to B. anthracis spores.

12. What products does this EUA cover?

This EUA covers oral formulations of doxycycline products that have been approved by the FDA for PEP to reduce the incidence or progression of disease, including inhalational anthrax, following exposure to aerosolized B. anthracis. For purposes of illustration, such products include capsule, tablet, and liquid formulations of doxycycline, including: 8

  • Doxycycline hyclate 100 mg oral tablets, supplied in a unit-of-use (UoU) bottle containing 120 tablets for a 60-day treatment or containing 20 tablets for an initial 10-day supply
  • Doxycycline monohydrate 100 mg oral capsules, supplied in a UoU bottle containing 120 capsules for a 60-day treatment or containing 20 capsules for an initial 10-day supply
  • Doxycycline 25 mg/5 mL suspension, supplied as dry powder in a 60 mL bottle
  • Doxycycline (Vibramycin) 50 mg/5 mL syrup in a 473 mL bottle

During an emergency, this authorization would permit dispensing of FDA-approved drugs that are not supplied in a UoU container, if necessary.

13. Why is an EUA needed to distribute and dispense doxycycline for emergency use when the product is already FDA-approved?

Doxycycline is FDA-approved for PEP for inhalational anthrax. However, certain aspects of emergency distribution, dispensing, and use of oral formulations of doxycycline products are not approved by FDA (i.e., not covered by their FDA-approved applications). An EUA allows these drugs to be legally distributed, stockpiled, and dispensed for the unapproved uses for which they are being authorized.

For example, for preparedness and response purposes, stakeholders may need to distribute emergency use information (e.g., fact sheets) to recipients, dispense doxycycline without a prescription and without all of the required information on the prescription label, dispense a partial supply of the full 60-day dosage regimen (i.e., an initial start-up supply), or store and distribute doxycycline packaged or repackaged for emergency distribution. Or, stakeholders may not be able to comply with certain current good manufacturing practice (CGMP) requirements during an actual anthrax event. Without this EUA, these actions would otherwise violate FDA’s legal interpretations of provisions of the FD&C Act.

14. Was an EUA already in effect for doxycycline?

Yes, but the existing EUA for doxycline had a more limited application than the July 2011 EUA for oral formulations of doxycyline. In October 2008, FDA issued an EUA for doxycycline hyclate tablet emergency kits for eligible United States Postal Service (USPS) participants and their household members under a Cities Readiness Initiative (CRI) effort. The USPS EUA remains in effect. However, the USPS EUA is limited to allowing doxycycline hyclate tablet emergency kits to be distributed to and stored by eligible USPS/CRI participants and their household members so that the participants are ready at the outset of an emergency to distribute PEP to the affected population. For additional information on the USPS EUA, visit the FDA EUA Website. 9

The USPS EUA is different from the new EUA for oral formulations of doxycycline products.
The new EUA for oral formulations of doxycycline provides for preparedness activities and for mass dispensing to the affected population in response to an actual anthrax emergency, whether such dispensing occurs via the postal model, local points of dispensing (PODs), or any other distribution or dispensing approach authorized by stakeholders.

FDA also worked closely with CDC to prepare for mass dispensing of doxycycline should an anthrax event occur during the 2009 Presidential Inauguration in the D.C. metropolitan area. However, an EUA was not issued at that time.

15. Does the EUA cover doxycycline products that have had their shelf life extended under the federal Shelf-Life Extension Program (SLEP)?

Yes, doxycycline products covered by this EUA may include such products that are authorized to have their expiration date extended under SLEP. SLEP is a federal, fee-for-service program (administered by the Department of Defense) through which the labeled shelf life of certain federally stockpiled medical materiel can be extended after selected products undergo periodic, comprehensive testing by FDA.

16. Will the EUA cover doxycycline products that are not supplied by the Strategic National Stockpile (SNS)?

Yes. The EUA covers oral formulations of doxycycline products that are supplied by the SNS, as well as oral formulations of doxycycline products that are purchased and stockpiled by stakeholders (i.e., non-SNS products), if the terms and conditions of the EUA are met.

Some health agencies are responsible for dispensing PEP to USPS workers following a positive Biohazard Detection System (BDS) alert at a USPS facility (this is distinct from the USPS National Postal Model, which involves USPS employee volunteers delivering medication directly to homes in pre-determined ZIP codes following an anthrax attack and is described in Question 14). The EUA covers stakeholders’ preparedness and response efforts related to dispensing oral formulations of doxycycline following a positive BDS alert, if the terms and conditions of the EUA are met.

17. Is FDA planning to issue additional EUAs for preparedness purposes (e.g., for ciprofloxacin)?

While FDA does not independently initiate EUA requests, FDA works closely with its federal government partners (e.g., CDC) to provide technical assistance and regulatory feedback on preparedness issues related to EUAs and would favorably consider a request from CDC for a ciprofloxacin EUA. Although FDA currently has no plans to issue additional EUAs within a specific timeframe, the same legal preparedness issues apply to ciprofloxacin that apply to doxycycline. In other words, an EUA would also be needed for ciprofloxacin to facilitate preparedness and response activities for an anthrax emergency.

18.  Does this EUA preempt state law?

As stated in FDA’s EUA Guidance (VIII. Preemption), "FDA anticipates that preemption issues may arise when an EUA is issued to the extent that states have existing requirements governing the dispensing, administration, or labeling of unapproved medical products or approved medical products for unapproved uses." FDA believes that the terms and conditions of an EUA issued under section 564 of the Act preempt State laws (i.e., legislative requirements and common-law duties) that impose different or additional requirements on the medical product for which the EUA was issued in the context of the emergency declared under section 564. However, questions about whether specific State laws would be preempted by an EUA would need to be addressed on a case-by-case basis.

Information for Health Care Professionals and for Recipients

19.  Are stakeholders required to use the four fact sheets provided as exhibits in the EUA?

Stakeholders are not required to use the doxycycline fact sheets for health care professionals and recipients that are provided as examples in the EUA—they can develop their own fact sheets as long as the fact sheets they develop contain the minimum elements included in the Conditions of Authorization of the EUA. However, stakeholders are required under this EUA to use the home preparation instruction fact sheets that are provided as exhibits in the EUA and that are also available on FDA’s web site at http://www.fda.gov/doxyprepare.

Health care professionals and recipients. Fact sheets may be used to communicate important information about the EUA and doxycycline to health care professionals and recipients. Stakeholders may develop their own fact sheets for health care professionals and for recipients, but any such fact sheets must include the minimum elements set forth in the conditions of the EUA (Section IV. Conditions of Authorization). This approach was taken because it facilitates and adds flexibility to stakeholders’ preparedness efforts.

Exhibit 1 (Doxycycline EUA Fact Sheet for Health Care Professionals) and Exhibit 2 (Doxycycline EUA Fact Sheet for Recipients) are examples of fact sheets that include the minimum elements set forth in the EUA’s Conditions of Authorization for health care professionals and for recipients. Stakeholders may decide to use these fact sheets, or they may modify them (e.g., by including additional information, changing the format, etc.) or develop their own new fact sheets. However, if stakeholders modify the exhibit fact sheets or develop new fact sheets, then such emergency use information still must include each of the minimum elements set forth in the EUA’s Conditions of Authorization. Also, to the extent feasible, stakeholders are encouraged to ensure that recipient fact sheets provide information in such a way as to adequately inform individuals with lower literacy (e.g., at a 6th grade reading level).

Home preparation. For home preparation instructions for children and adults who cannot swallow pills, stakeholders must use one or both of the fact sheets provided in Exhibit 3 or Exhibit 4; if these exhibits are updated by FDA, stakeholders must use the revised versions provided on the FDA website at http://www.fda.gov/doxyprepare. In other words, stakeholders are authorized to use Exhibit 3 and Exhibit 4 (or FDA-updated versions of these exhibits), but they are not authorized to modify Exhibit 3 or Exhibit 4 or develop new fact sheets with home preparation instructions. It is important that all recipients who are unable to swallow pills receive the same information necessary to facilitate proper home preparation and administration of the medicine. This approach also facilitates the posting of any important updates to these fact sheets that FDA may make in the future.

20. What does it mean to makeavailable "through appropriate means" information provided to health care professionals and to recipients that includes the minimum elements listed in the EUA? Do stakeholders have to distribute paper copies of fact sheets to health care professionals and to recipients?

The EUA states that “[s]takeholders must make available through appropriate means information provided to health care professionals and to recipients…that includes the minimum elements set forth” in the Conditions of Authorization (Section IV) of this EUA. FDA's EUA Guidance 10 states that, ordinarily, FDA expects that some form of written information will be given to medical countermeasure recipients. The EUA authorizes stakeholder preparedness activities with the goal of increasing stakeholders’ ability to respond efficiently during an actual anthrax event.

One way to improve efficiency is to develop and reproduce fact sheets for health care professionals and recipients as a part of anthrax preparedness activities. Making written information available through appropriate means most typically means handing fact sheets directly to each health care professional involved in dispensing doxycycline and to each recipient with the doxycycline product at a POD, but could also include making the information available for reference at a POD through use of posters and/or through printed copies available for health care professional and recipient review.

However, because some emergency situations may present challenges in mass producing and providing written information to health care professionals and recipients, appropriate means for making the authorized information available may include other communications modalities such as through mass media public service announcements, websites, or DVDs. Additionally, these alternative communications methods may be used to provide supplemental information (e.g., information on how to contact public health authorities) that is consistent with the authorized information as described in Question 19. If electronic media (e.g., posting materials on a website) are used, then stakeholders should ensure that vulnerable populations and populations without access to electronic media can obtain the information. Accurate translations of any information provided also can be provided in foreign languages.

Finally, if FDA were to require that additional updated information for health care professionals and recipients be disseminated during an emergency response, and recognizing the difficulty of mass producing revised versions of information sheets during a response, the alternative communications approaches described above (e.g., poster displays, public service announcements) to disseminate the updated information would be acceptable.

21. Are volunteers and other non-health care professionals (e.g., certain public health officials) dispensing doxycycline at a POD the same as health care professionals under the EUA?

The EUA’s Conditions of Authorization require that recipients and health care professionals administering the doxycycline product be informed of the minimum elements of information (as exemplified in the fact sheets for recipients and health care professionals). A non-health care professional volunteer or responder handing out doxycycline product is not considered to be a health care professional under the EUA.

However, depending on stakeholders' applicable mass dispensing plans and state and local law, the EUA acknowledges that non-health care professionals might be involved in dispensing doxycycline to the public at PODs. Regardless of the dispensing modality, including the use of responders and volunteers who are not health care professionals to dispense doxycycline, it is expected that a health care professional will be available on-site at a POD or that information will be made available at a POD about how to reach a health care professional to respond to questions from recipients of doxycycline product. Additionally, stakeholders may choose to provide, for reference purposes, the health care professional and recipient fact sheets to their non-health care professional dispensers. 

22. Will the fact sheets be translated to Spanish and other languages and made available to stakeholders?

Translation of the fact sheets into Spanish or other languages is not a condition of the EUA and, therefore, is not required. At this time, FDA has not translated the four exhibits provided in the EUA. CDC or a stakeholder may provide accurate translations of the fact sheets in other languages. CDC is currently developing its version of the recipient fact sheet taking into account readability level; this fact sheet will then be translated into the top 50 languages and will be available for the stakeholders on a DVD for reproduction. Stakeholders are the most familiar with the language needs of their communities and should ensure that translated materials are prepared and made available as necessary.

23. Where can I access the package inserts for doxycycline products?

For more information about the benefits and risks of doxycycline, please see the FDA-approved package inserts for doxycycline products at www.dailymed.nlm.nih.gov.

24. Do stakeholders still need to comply with CGMPs?

This authorization covers only oral formulations of doxycycline products that have been manufactured, (re)packaged, and (re)labeled under CGMP requirements and were stored in compliance with the manufacturers’ labeled storage conditions for the products. For preparedness activities (e.g., pre-event stockpiling), stakeholders must still comply with CGMP requirements.

However, to facilitate rapid dispensing during an actual anthrax emergency and a decision on the part of the responsible stakeholder to mass dispense doxycycline under the terms and conditions of this EUA, doxycycline products may require transportation without the capacity to maintain labeled storage conditions in the midst of the response. In such circumstances, the products (i.e., doxycycline tablets, doxycycline delayed release tablets, doxycycline capsules, doxycycline powder for oral suspension, and doxycycline oral suspension) may be stored with temperature excursions from the labeled storage conditions of up to 40°C for a total period of up to 7 days.

PREP Act Coverage

25. Will the PREP Act cover doxycycline products under the EUA?

A PREP Act declaration for multiple types of anthrax countermeasures 11 was issued on October 1, 2008, and extends through December 15, 2015. Because this PREP Act declaration is in effect for anthrax countermeasures, including antimicrobials such as doxycycline, and because the PREP Act covers countermeasures authorized for emergency use under an EUA, the PREP Act covers doxycycline products authorized for emergency use under this EUA if the terms and conditions of the EUA and the PREP Act declaration are met.

Reporting Adverse Events

26. How should adverse events associated with using oral formulations of doxycycline >be reported?

Health care professionals and recipients who observe or experience adverse events (side effects) or medication errors are encouraged to report to MedWatch 12 by:

When reporting adverse events or medication errors related to this EUA to MedWatch, doxycycline should be identified as "doxycycline EUA" and the report should include that the product was used under an EUA by including in the description of the event section (Section B.5) of the MedWatch Form 3500 the abbreviations “EUA” or the words “Emergency Use Authorization.”

For Additional Information

27. Whom should I contact if I have additional questions regarding the EUA?

Additional information about EUAs can be found by:

(August 2011)

Footnotes

3. Pursuant to section 319F-3(b) of the PHS Act (42 U.S.C. 247d-6d).

6. HHS, Authorization of Emergency Use of Oral Formulations of Doxycycline; Availability, 76 Fed. Reg. 47,197 (Aug. 4, 2011).

8. FDA-approved drugs can be identified at the Drugs at FDA website at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.