Authorizations of Emergency Use of Certain Drugs and Biological Products During the COVID-19 Pandemic; Availability, 6578-6610 [2022-02359]

Download as PDF 6578 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices I. Background FDA is announcing the availability of a revised draft guidance for industry entitled ‘‘Assessment of Pressor Effects of Drugs.’’ This draft guidance is intended to advise sponsors on the premarketing assessment of a drug’s effect on blood pressure. Elevated blood pressure is known to increase the risk of stroke, heart attack, and death. The effect of a drug on blood pressure is, therefore, an important consideration in risk assessment and product labeling. This draft guidance revises the draft guidance entitled ‘‘Assessment of Pressor Effects of Drugs’’ issued on May 31, 2018 (83 FR 25013). Based on comments received to the docket, the draft guidance was updated to include recommendations on the design of an ambulatory blood pressure monitoring study; recommendations on the types of drugs that need an ambulatory blood pressure monitoring study; modification of Figure 1 in the draft guidance to show the relationship between the increase in 10-year atherosclerotic cardiovascular disease event risk with chronic increases in systolic blood pressure; inclusion in the guidance of Table 1, which summarizes landmark clinical trials showing the reduction of major adverse cardiac events with decreases in blood pressure with antihypertensives; and considerations for product labeling. In addition, editorial changes were made to improve clarity. This draft guidance is being issued consistent with FDA’s good guidance practices regulation (21 CFR 10.115). The draft guidance, when finalized, will represent the current thinking of FDA on ‘‘Assessment of Pressor Effects of Drugs.’’ It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. lotter on DSK11XQN23PROD with NOTICES1 II. Paperwork Reduction Act of 1995 While this draft guidance contains no collection of information, it does refer to previously approved FDA collections of information. Therefore, clearance by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501– 3521) is not required for this guidance. The previously approved collections of information are subject to review by OMB under the PRA. The collections of information in 21 CFR part 312 addressing investigational new drug applications have been approved under OMB control number 0910–0014 and the collections of information in 21 CFR part 314 addressing new drug VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 applications have been approved under OMB control number 0910–0001. III. Electronic Access Persons with access to the internet may obtain the draft guidance at https:// www.fda.gov/drugs/guidancecompliance-regulatory-information/ guidances-drugs, https://www.fda.gov/ regulatory-information/search-fdaguidance-documents, or https:// www.regulations.gov. Dated: January 31, 2022. Lauren K. Roth, Associate Commissioner for Policy. [FR Doc. 2022–02371 Filed 2–3–22; 8:45 am] BILLING CODE 4164–01–P DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2021–N–0335] Authorizations of Emergency Use of Certain Drugs and Biological Products During the COVID–19 Pandemic; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. The Food and Drug Administration (FDA) is announcing the issuance of three Emergency Use Authorizations (EUAs) (the Authorizations) under the Federal Food, Drug, and Cosmetic Act (FD&C Act), for use during the COVID–19 pandemic. FDA has issued one Authorization for a biological product as requested by AstraZeneca Pharmaceuticals LP (AZ), one Authorization for a drug product as requested by Pfizer, Inc. (Pfizer), and one Authorization for a drug product as requested by Merck Sharp & Dohme Corp. (Merck). The Authorizations contain, among other things, conditions on the emergency use of the authorized products. The Authorizations follow the February 4, 2020, determination by the Secretary of Health and Human Services (HHS) that there is a public health emergency that has a significant potential to affect national security or the health and security of U.S. citizens living abroad and that involves a novel (new) coronavirus. The virus, now named SARS–CoV–2, causes the illness COVID–19. On the basis of such determination, the Secretary of HHS declared on March 27, 2020, that circumstances exist justifying the authorization of emergency use of drugs and biological products during the COVID–19 pandemic, pursuant to the FD&C Act, subject to the terms of any SUMMARY: PO 00000 Frm 00096 Fmt 4703 Sfmt 4703 authorization issued under that section. The Authorizations, which include an explanation of the reasons for issuance, are reprinted in this document. DATES: The Authorization for AZ is effective as of December 8, 2021, the Authorization for Pfizer is effective as of December 22, 2021, and the Authorization for Merck is effective as of December 23, 2021. ADDRESSES: Submit written requests for single copies of the EUAs to the Office of Counterterrorism and Emerging Threats, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 1, Rm. 4338, Silver Spring, MD 20993– 0002. Send one self-addressed adhesive label to assist that office in processing your request or include a fax number to which the Authorizations may be sent. See the SUPPLEMENTARY INFORMATION section for electronic access to the Authorizations. FOR FURTHER INFORMATION CONTACT: Michael Mair, Office of Counterterrorism and Emerging Threats, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 1, Rm. 4340, Silver Spring, MD 20993–0002, 301–796–8510 (this is not a toll free number). SUPPLEMENTARY INFORMATION: I. Background Section 564 of the FD&C Act (21 U.S.C. 360bbb–3) allows FDA to strengthen public health protections against biological, chemical, nuclear, and radiological agents. Among other things, section 564 of the FD&C Act allows FDA to authorize the use of an unapproved medical product or an unapproved use of an approved medical product in certain situations. With this EUA authority, FDA can help ensure that medical countermeasures may be used in emergencies to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by biological, chemical, nuclear, or radiological agents when there are no adequate, approved, and available alternatives (among other criteria). II. Criteria for EUA Authorization Section 564(b)(1) of the FD&C Act provides that, before an EUA may be issued, the Secretary of HHS must declare that circumstances exist justifying the authorization based on one of the following grounds: (1) A determination by the Secretary of Homeland Security that there is a domestic emergency, or a significant potential for a domestic emergency, involving a heightened risk of attack with a biological, chemical, radiological, or nuclear agent or agents; (2) a E:\FR\FM\04FEN1.SGM 04FEN1 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices lotter on DSK11XQN23PROD with NOTICES1 determination by the Secretary of Defense that there is a military emergency, or a significant potential for a military emergency, involving a heightened risk to U.S. military forces, including personnel operating under the authority of title 10 or title 50, U.S. Code, of attack with (A) a biological, chemical, radiological, or nuclear agent or agents; or (B) an agent or agents that may cause, or are otherwise associated with, an imminently life-threatening and specific risk to U.S. military forces; 1 (3) a determination by the Secretary of HHS that there is a public health emergency, or a significant potential for a public health emergency, that affects, or has a significant potential to affect, national security or the health and security of U.S. citizens living abroad, and that involves a biological, chemical, radiological, or nuclear agent or agents, or a disease or condition that may be attributable to such agent or agents; or (4) the identification of a material threat by the Secretary of Homeland Security pursuant to section 319F–2 of the Public Health Service (PHS) Act (42 U.S.C. 247d–6b) sufficient to affect national security or the health and security of U.S. citizens living abroad. Once the Secretary of HHS has declared that circumstances exist justifying an authorization under section 564 of the FD&C Act, FDA may authorize the emergency use of a drug, device, or biological product if the Agency concludes that the statutory criteria are satisfied. Under section 564(h)(1) of the FD&C Act, FDA is required to publish in the Federal Register a notice of each authorization, and each termination or revocation of an authorization, and an explanation of the reasons for the action. Under section 564(h)(1) of the FD&C Act, revisions to an authorization shall be made available on the internet website of FDA. Section 564 of the FD&C Act permits FDA to authorize the introduction into interstate commerce of a drug, device, or biological product intended for use in an actual or potential emergency when the Secretary of HHS has declared that circumstances exist justifying the authorization of emergency use. Products appropriate for emergency use may include products and uses that are 1 In the case of a determination by the Secretary of Defense, the Secretary of HHS shall determine within 45 calendar days of such determination, whether to make a declaration under section 564(b)(1) of the FD&C Act, and, if appropriate, shall promptly make such a declaration. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 6579 not approved, cleared, or licensed under sections 505, 510(k), 512, or 515 of the FD&C Act (21 U.S.C. 355, 360(k), 360b, and 360e) or section 351 of the PHS Act (42 U.S.C. 262), or conditionally approved under section 571 of the FD&C Act (21 U.S.C. 360ccc). FDA may issue an EUA only if, after consultation with the HHS Assistant Secretary for Preparedness and Response, the Director of the National Institutes of Health, and the Director of the Centers for Disease Control and Prevention (to the extent feasible and appropriate given the applicable circumstances), FDA 2 concludes: (1) That an agent referred to in a declaration of emergency or threat can cause a serious or lifethreatening disease or condition; (2) that, based on the totality of scientific evidence available to FDA, including data from adequate and well-controlled clinical trials, if available, it is reasonable to believe that: (A) The product may be effective in diagnosing, treating, or preventing (i) such disease or condition; or (ii) a serious or lifethreatening disease or condition caused by a product authorized under section 564, approved or cleared under the FD&C Act, or licensed under section 351 of the PHS Act, for diagnosing, treating, or preventing such a disease or condition caused by such an agent; and (B) the known and potential benefits of the product, when used to diagnose, prevent, or treat such disease or condition, outweigh the known and potential risks of the product, taking into consideration the material threat posed by the agent or agents identified in a declaration under section 564(b)(1)(D) of the FD&C Act, if applicable; (3) that there is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating such disease or condition; (4) in the case of a determination described in section 564(b)(1)(B)(ii) of the FD&C Act, that the request for emergency use is made by the Secretary of Defense; and (5) that such other criteria as may be prescribed by regulation are satisfied. No other criteria for issuance have been prescribed by regulation under section 564(c)(4) of the FD&C Act. potential to affect national security or the health and security of U.S. citizens living abroad and that involves a novel (new) coronavirus. The virus, now named SARS–CoV–2, causes the illness COVID–19. Notice of the Secretary’s determination was provided in the Federal Register on February 7, 2020 (85 FR 7316). On the basis of such determination, the Secretary of HHS declared on March 27, 2020, that circumstances exist justifying the authorization of emergency use of drugs and biological products during the COVID–19 pandemic, pursuant to section 564 of the FD&C Act, subject to the terms of any authorization issued under that section. Notice of the Secretary’s declaration was provided in the Federal Register on April 1, 2020 (85 FR 18250). Having concluded that the criteria for issuance of the Authorizations under section 564(c) of the FD&C Act are met, FDA has issued three authorizations for the emergency use of drugs and biological products during the COVID–19 pandemic. On December 8, 2021, FDA issued an EUA to AZ for the biological product EVUSHELD (tixagevimab co-packaged with cilgavimab), subject to the terms of the Authorization. On December 22, 2021, FDA issued an EUA to Pfizer for the drug PAXLOVID (nirmatrelvir copackaged with ritonavir), subject to the terms of the Authorization. On December 23, 2021, FDA issued an EUA to Merck for the drug molnupiravir, subject to the terms of the Authorization. The initial Authorizations, which are included below in their entirety after section IV of this document (not including the authorized versions of the fact sheets and other written materials), provide an explanation of the reasons for issuance, as required by section 564(h)(1) of the FD&C Act. Any subsequent reissuances of these Authorizations can be found on FDA’s web page at: https:// www.fda.gov/emergency-preparednessand-response/mcm-legal-regulatoryand-policy-framework/emergency-useauthorization. III. The Authorizations An electronic version of this document and the full text of the Authorizations and are available on the internet at: https://www.fda.gov/ emergency-preparedness-and-response/ mcm-legal-regulatory-and-policyframework/emergency-useauthorization. The Authorizations follow the February 4, 2020, determination by the Secretary of HHS that there is a public health emergency that has a significant 2 The Secretary of HHS has delegated the authority to issue an EUA under section 564 of the FD&C Act to the Commissioner of Food and Drugs. PO 00000 Frm 00097 Fmt 4703 Sfmt 4703 IV. Electronic Access BILLING CODE 4164–01–P E:\FR\FM\04FEN1.SGM 04FEN1 6580 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Decemher8, 2021 Astra.Zen-eca Pharmaceuticals LP Attention; Stacey Cromer Ben:nai\ PhD SeniorRe:gulatory Affairs Director and team Lead OneMedlmmune W11,y Gaithersburg, MD 20878 RE: Em.etgency Use Authorization 104 Dear Dr: Cromer Berman: 'Ihl.s letter is in response to Astra.ZenecaPharm~euticals L:P's (AstraZeneca) request thatthe Food iil:ld Drug Adminisirafion (FDA or Agency) issue iil1 Emergency Use Autho'li,-,iliion (EUA) fortheemergency use ofEVUSHELDTM (tixagevimah co.-packagedwith cilgavimab) for the pre-exposure prophylaxis of coromvirus disease 2019 (CO\TlD- l 9)in certain adults and pediatric individuals (I 2 years of age and olderweighing at least 40 kg), as described in the Scope of Authorization (Section.JI)of this letter, pµtsuantto Section 564 Qftbe Federal Food, Drug, and Cosmetic Act(the Act) (21 U. S.C. §360hhlr3). On February 4, 2020, pursuant to Section 564(b)(I )(CJ of the Act; the Secretary of the Department ofHealth a1tdHuman Setvices (FIBS) determined thatthereis apublic health emergency that has a significantpptential to affectnationals:ecutity or the health an.dsecµruy.of United States citi7ens livingabroad, and thatinvolves the virus that causes corona,1rus disease 2019 (COVID-19). 1 On the basis of such determination, the Secretary of HHS onMarch 27, 202b, declared that circumstances exist justifying the authorization of emergency :use ofdrugs and biological producis during.the COVID-19 pandemic, pursuant to Sec.tion 564 of the Act (21 U.S.C; 360hbb-3),subjectto terms of any authorization issued under that section. 2 tixagevimab and cilgavimab, the active components ofEVtJSHELD, are neutralizinglgGl monoclonal aniibodies that bind to distinct, non-overlappingepilopes within the receptor binding domain of the spike protein ofSARS--CoV-2. EVUSHELD tiian investigational drug and is not approved.for any µses,includinguse a;&pre-e.xposureprophylaxis ofCOVID'-J 9, Based on theteview of the data from the PROVENT elm.foal ttia.1. (NCT04G25725),a PhaselII randomize4, double-blind, placehq-controlled clinic-al trial, itis reaspnable to believe that EVUSHELD may he effective foruse !LS pre-exposure prophylaxis of COVID-19i:n certain adults and pediatric :individuals (12 years of age and older weighrni atleast40 kg), .as described r tJ$.JJep.artm(lf)t qfffeiilth: !ind HUl'.liafl Sm.ices; tJete.rminatianofaPublir:FfeµJth Emergency and ~r:lamtiO/i lhal Circ,umstam:esExist.Justi;/yingAuJhorizciiiansPr(l'SUtUJJ to&CtiM 564(q) oftheFederalFomt Drug, mid VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00098 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.011</GPH> lotter on DSK11XQN23PROD with NOTICES1 CasmeticAc:!, 21 U.S.C . § 36Ql,bb-3•.Fcbmll.y4.,W20. 2 U.R Department ofH¢alth and HU!llan Setv.ic~Declwaaottih@Crrcittnstaiices Ex4't.J~sti.fyiiigAuthorizd/toti$ Pursuant to Seoiion J64(:b) ofiheFederalFood, Drug. andCoS111eticAct,21 U.S.-C § 360bb/{.3, 85I'R 18250 (April L,2020). Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices 6581 Page 2 ---AstraZeneca Pharmaceuticals LP in the Scope of Authorization (Section II), and when used underthe conditions described in this authorization, the known and potential benefits of EVUSHELD outweigh the known and potential risks of such product. Having concluded thatthe criteriaforissuance of this authorization under Section 564(c) ofthe Act are met,I am authorizing the emergency use.ofEVUSHELD for use as pre-exposure prophylaxis of COVID-19, as described in the Scope of Authorization section ofthis letter (Section II) a:nd subjectto the terms of this authorization. I. Criteria for .Issuance of Authorization I have concludedthatthe emergency use ofEVUSHELD for pre-exposure prophylaxis of COVID-19 when administered as described in the Scope of Authorization (Section II) meet$ the criteria for issuance of an authorization underSection 564(c) ofthe Act; because: L SARS-C-0V-2 can cause a serious or life-threatening disease or condition; including severe respiratory illness, to humans infected bythis vims; 2. Based on ihe totality of scientific evidence available to FDA, itis reasonable to believe that EVUSHELD may be- effective foruse as pre-exposure prophylaxis of COVID-19 in certain adults and pediatric individuals (12 years of age and older weighingat least 40kg), as described in the Scope of Authorization(sectionII), a:nd that, when¥sed under the conditions described in this authorization, the known and potential benefits of EVUSHELD outweigh the known and potential risks of such product; and :( TI1ere is no adequate. approved; and available alternative to the emergency use of EVUSHELD as pre-exposure prophylaxis ofCOVID-19 as further described in.the Scope of Authorization (section II), 3 II. Scope of Authorization I have concluded, pursuant to Sect10n 564(d){ i) oft.he Act, thatthe scope of this authorization is limited as follows: 3 4 • Distribution oft11e authorized EVUSHELDwill be controlled by the United States (U.S.) Government for use consistent with the tenns and conditions of this. EUA. AstraZeneca willsupplyEVUSHELDto authorized distributor(s)4,who will distribute to healthcare facilities or healthcare providers as directed by the U.S.. Government, in c-0llabor.atio11 witll state and local government authorities as needed; • EVDSHELD may only be used in adults and pedian-ic individuals (12 years ofage and o Ider weighing at least 40 kg): No other criteria ofissuancehavebeenprescribedbytegulationundcr ~ction564(cX4)oftheAct. ".AuthorizedDistributor{s)" are identified by AstraZeneca asanentity or entities allowed to distribute authorized VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00099 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.012</GPH> lotter on DSK11XQN23PROD with NOTICES1 EVUSHELD. 6582 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 3 - AstraZeneca Pharmaceuticals LP • Who are not curren1ly infected with SARS-Co V-2 and who have not had a known recent exposure to an individual infected with SARS-Co V-2 and o Who have moderate to severe immune compromise due to a medical condition or receipt of immunosuppressive medica1ions or treatments and may not mount an adequate immune response to COVID-19 vaccinations or o For whom vaccination wi1h any available COVID-19 vaccine, accordingto the approved or authorized schedule, is notrecotmnended due to a history of severe adverse reaction ( e.g., severe allergic re.action) to a COVID-19 vaccine(s)and/or COVII).19 vaccine component(s). Limitations on Authorized Use • Evusheld is not authorized for the following uses in individuals: • • FortreatmentofCOVID-19,or For post-eJq)()sure prophylaxis of COVID-19 in individuals who have been exposed to someone infected with SARS-CoV-2. • Pre-exposure prophylaxis with EVUSHELD i'l not a substitute for vaccination .in individuals for whom COVID-19 vaccination is recommended. Individuals for whom COVID-19 vaccination is recommended, including individuals with moderate to severe immune compromise who may derive benefit from COVID-19 vaccination, should receive COVID-19 vaccination. • For individuals who have received a CO VID-19 vaccine, EVUSHELD should be administered at least two weeks after vaccination. • The use of EVUSHELD covered by this authorization must be in accordance with the authorized Fact Sheets. Product Description EVUSHELD is supplied as a single carton (NDC 0310-7442-02) containing 1 single-dose vial of tixagevimab injection and 1 single-dose vial of cilgavimab injection. Tixagevimab injection (NDC 0310-8895-01) is a sterile, preservative-free, clear to opalescent and colorless to sligl1tly yellow solution supplied in a single-dose vial for intramuscular use. TI1e vial stoppers are not made with natural rubber latex. Each 1. 5 mL contains 150 mg tixagevimab, L- histidine (2.4 mg), L- histidine hydrochloride monohydrate (3. 0 mg), polysorbate 80 (0.6 mg), sucrose (123.2 mg), and Water for Injection, USP. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00100 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.013</GPH> lotter on DSK11XQN23PROD with NOTICES1 5 For additional information please see https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19vaccines-us.httnl Healthcare providers should considerthe benefit-risk for an individual patient. Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 4 6583 AstraZeneca Pharmaceuticals LP Cilgavimab injection (NDC 0310-1061-01) is a sterile, preservative-free, clear to opalescent and colorless to slightly yellow solution supplied in a single-dose vial for intramuscular use. The vial stoppers are not made with natural mbber latex. Each 1.5 mL contains 150 mg cilgavimab, Lhistidine (2.4 mg), L- histidine hydrochloride monohydrate (3.0mg), polysorbate 80 (0.6 mg), sucrose (123.2 mg), and Water for Injection, USP. Unopened vials oftixagevimab and cilgavimab must be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Vials must not be frozen or shaken. Unused portions must be discarded. EVUSHELD is authorized for emergency use with the following product-specific information required to be made available to healthcare providers and to patients, parents, and caregivers, respectively, through AstraZeneca's website www.EVUSHELD.com (referred to as the "authorized labeling"): • • Fact Sheet for Healthcare Providers: Emergency Use Authorization (EUA) for EVUSHELD Fact Sheet for Patients, Parents and Caregivers: Emergency Use Authorization (EUA) of EVUSHELD forCoronavims Disease 2019 (COVID-19) I have concluded, pursuant to Section 564(d)(2) of the Act, that it is reasonable to believe that the known and potential benefits ofEVUSHELD, when used for pre-exposure prophylaxis of COVID-19 in certain adults and pediatric individuals (12 years of age and older weighing at least 40 kg) and used in accordance with this Scope of Authorization (Section II), outweigh the known and potential risks. I have concluded, pursuant to Section 564(d)(3) of the Act, based on the totality of scientific evidence available to FDA, that it is reasonable to believe that EVUSHELDmay be effective for pre-exl)osure prophylaxis of COVID-19 in certain adults and pediatric individuals ( 12 years of age and o lderweiglring at least 40 kg)when used in accordance with this Scope of Authorization (Section II), pursuantto Section 564(cX2)(A) of the Act. Having reviewed the scientific information available to FDA, including the infommtion supporting the conclusions described in Section I above, I have concluded that EVUSHELD (as described in this Scope of Authorization (Section II)) meets the criteria set forth in Section 564(c) of the Act concerning safety and potential effectiveness. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00101 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.014</GPH> lotter on DSK11XQN23PROD with NOTICES1 The emergency use of your product under an EU A must be consistent with, and may not exceed, the terms of the Authorization, including the Scope of Authorization (Section II) and the Conditions of Authorization (Section III) Subject to the terms of this EUA and underthe circumstances set fot1h in the Secretaiy ofHHS's detennination under Section 564(b)(1XC)described above and the Secretaiy of HHS' s corresponding declaration under Section 564(b X1), EVUSHELD is authorized for use as pre-exposure prophylaxis of COVID-19 as described in tins Scope of Authorization (Section II) under this EUA, despite the fact that it does not meet certain requirements otherwise required by applicable federallaw. 6584 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 5 --- AstraZeneca Phannaceuticals LP III. Conditions of Authorization Pursuant to Section 564 ofthe Act, I am establishingthe following conditions on this authorization: AstraZeneca and Authorized Dist:ributors6 A. AstraZeneca and authorized distributor(s) will ensure that EVUSHELD is distributed with the authorized labeling (i.e., Fact Sheets )will be made available to healthcare facilities and/or heal1hcare providers as described in Section II of this Letter of Aulhorization. B. AstraZeneca and authorized distributor(s)will enstu:e thatappropriatl:l storage and cold chain is maintained until the product. is delivered to healthcare facilities and/or heal1hcare providers. C. AstraZeneca and airthorized distributor(s) will ensure that the tem1s of this EUA are made available to all relevant stakeholders (e.g., U.S. go.vemment agencies, state and .local government authorities, authorized.distributors, heal1hcare facilities, healthcare providers) involved in distributing or receiving EVUSHELD. AstraZeneca will provide to all relevant stakeholders a copy of this Letter of Authorization and commU11icate any subsequent amendments that might be made to this Letter of Authorization and its authorized accompanying materials (i.e., Fa"'t Sheets). D. AstraZeneca may request changes to this authorization, including to the authorized Fact Sheets for EVU SHELD. Any reque,.'t for changes to this EU A must be. submitted to the Office oflnfectious Diseases/Office ofNew Drugs/Center for Drug Evaluation and Research. Such changes reqtrire appropriate authorization priorto implementation. 7 E. AstraZeneca may develop and disseminate instructional and educational materials (e.g., materials providing information on product administration ru1d/orpatientmonitoring) that ·are consistent with the authorized emergency use ofEVUSHELD as described in this Letter of Authorization and authorized labeling, without FDA 's review and concurrence, when necessary to meet public health needs. Any instructional and educational materials that are inconsistent with the authorized labeling for EVUSHELD are prohibited. Ifthe Agency notifies AstraZeneca that any instructional and educational materials are VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00102 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.015</GPH> lotter on DSK11XQN23PROD with NOTICES1 6 "AuthorizedDistributor(s)" are identified by Astraieneca as ah entity or entities allowed to distribute EVUSHFLD for the use authorized in this letter. 7 The followingtypesofrevisions may be authorized withoutreissuing this letter: (1) changes to.the authorized. labeling; (2) non-substantive editorialcorrec.tions to this letter; (3) new types of authorized labeling, including new fact sheets; (4 )new carton/container label~; (5)expira tiondating extensions; (6)changes to manufacturing processes, including tests or other authorized components ofinanlifacturing; (7)new conditions of authorization to require data collNtion or study; (8 )new strengths of the authorized product, new product sources (e.g., of active pharmaceuticalingredient)or of product components. For changes to the authorization, including the authorized labeling, of the type listed in (3 ), (6), (7), or (8 ), review and concurrence is required from the Counter.Terrorism and Emergency Coordination StaIDOffice ofthe CenterDirector/CDER. andtheOffice ofCounterterrorism and Emerging Threats/Office of theChiefScientist. 6585 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices faconsisteritwithfli.e auihorizedfabeling,AstraZenecamustcease,distributionof such ,-insttuciioruilande:db.<iatfonal rrtaterials._'F'ut1hennore,.11$J>.ut{)f'itS.notffi¢ation.:the•Agency •ma}t alsqre~.A.sttl!Ze~io:fasue:-c~i::t'ive!!Qifittiqlµ¢!ITTP.11{S): R. ,AstraZenecawillrepoitto FDA.serious adverseevenisandallmedicatfonerrorsassociated •withthe use,;ttEVUSHELDfor;its~dusetlurt:arereportedto AstraZeneca.using eithet·ofth¢.f'QlloWing~ptionsi ··- •~~e1t~=~l'.eP9tP:th:rou.~me $:¢'etyRel!Orim~J>o,W(SlU>)'liSd~gi~.®Ji.e:J\DA, ·~!~~-==~~~f:!1~1:!hf$~~=~~ufmtissions GaumraytFSct)·$ Submittedreports-underboth-optionsshould.sfute:-'!EVUSHELD,use for:COVIO-l9°\111der Emergency,Use Authorization.(EUA)/1 Forrep.ortuubmitted-umlerl)ption 1. include.this •:~:t:i~~=i:t::a\~:~:::::.~~=th~:.;~, fiel& - H; -AstraZenecaWillsubniitinfonnafionto the.Agency•within'threewotkihgdaysofreceiptof -:l;=:g:=!r!::i=:~~~!:l:!:!;::1 ,.. llif'(')nrtlitioncqooei:1iihganyinddentthatc:iWsesihe:dtugprodl)ct()t·it& illbe:iiig to he niistakenfor,orappliedto,.anotherarlicle, or · · •• Infol11lafion conc~g llDymi~objologica1 cQrttlimll)afj(m -tit aey $igtufi;ci.urt cherrtical;.physical~or<>i:herchangeordeteriorationinthe distributeddrug prod~ or any failure-ofone onnore-disuibutedbatches ofthe productto meet the esciblishedspeciticatioos. lf:{l:slgn_ifi®tq~-pr9&lem:Ji.tf¢cl$11i1tele~ed-prodµcl-anil•-•~YalsQ'tro:p®tprodµci($) •previouslyreleased.and•distributed;then-informationshouldhe·subniittedfor•all:potentially ,impacted fots. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00103 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.016</GPH> lotter on DSK11XQN23PROD with NOTICES1 Ifnot included in its initialnotification, AstraZeneca must-submit information c9ntinningthat &tra:Zenecahas i4en:tifie4the·roQt cause-ofthe: i;ign;ificant qµi!iity pf!>:bl~s,Wcen c◊ttectiv:e ai>ti()ll, and,pro.yid'e: ajusiiffoation-coni1m1ingthafthe · correctiveaclion is appropriate and ·effceciive. Astrazenecamustsubmi1this 6586 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 7 -AstraZeneca PhannaceuticalsLP information as.soonaspossible.butno laterthan 45 calendar daysfromthe initial notification~ l. .~~rtecawiUmlitfii:(®ture.:EVDSfi£11)Jorttei!fal1.qi.Ul1itysfundar~and·perthe ··manu:facturingprocess,and·contrcil:straiegy.as detailed.inAstraZ.eneca~sEUArequest. ·:S!~=:;::.;::;a:::::::.:::1:':::~f!e:~:~control ;:;~~~::;;::;e!':1'~8!~:!;:t!::~==·wi~ut. t ~~~=~-==~ K. ..Asfr.aZenecawillestablish·aprocess:foi:monitoring;genomicdatabase(s)forthee~ce of.global viral variants of SARS--CoV~2.A summaryofAstraZeneca'sprocessshould be }!!:!:!fth1:i:::::~:l=::~~utoi::;::~~:~~!!:!:ess. . AstraZeneca:willprovide.reporlstotheAgency·ona:·monlhlybasis·suminariiing:an:y·· •findingsas·.aresult.:of•its monitoring.activities·•and..·asneeded,any.follow-up assessments ·p.lannedorconducted. :L .FDAlllay·reqµir<1.ASfr.aZenecatoassess the aciivityofthea:µthorizeifEVUS:HELJJagli~ .lltly glol:>al$AM~CoV~2:yariati.t(s}oflllWf~t(i:);g_ Viµilltlisthatareprev:menfofbecotning ;preva:lentthathatborsubstiftitions.in.thetatgetproteinor:inprotein(s)thatinteractWiththe. ~=£~~=~ adetailedstudyreportwithin30calendardaysofstudy·completion, AstraZenecawill · .$1:ibmit•an:y:re.levan:tptoposal(s}torevise theatrlhorizedlabelingl>~edontheresultsot'its .assessment;..a:srt1aybe ne·ces·sa.ry•or•4pPtopriatebagedonthe·foregomgassllSSrttent fyl. AsitaZene~i;!JaU ptovi~ 1I1iitipl~sa~ r~qe~ o.f:ii1!'.ll~al:l ~IJ(>f()ilgt!:vittlm,joth:e ·us. DepartmentofHealth.and.HumanServices(HHS)forevaJuationofactivityaga:inst :;:ut:~~irt~:;:~~!!1:~::1;:::::~=h~;:substituticms ===~==~== a:ssays,celt culture va:riantassa:ys (pseudotyped·V1tUS.Jike·particfosand/or.a:uthentic mus), -1111d ifl wweff':icacy:as$8cY& · N: AstraZenecamustprovidirthe folfowiitginformationfo the Agency: VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00104 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.017</GPH> lotter on DSK11XQN23PROD with NOTICES1 •• All anti-drug antibody (ADA). assessments that have nofbeen colllpleted at the time of this authotiiationfor subjects fromthe)'.!RQVENTclm.ie4lttial Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 8 6587 AstraZeneca Pharmaceuticals LP • • • • • • for days 1, 29, 5 8, and 183 by April 22, 2022. Interim analysis results through Day 28 for the first 50 subjects to receive a second dose from the PROVENT repeat-dose sub-study by April 22, 2022. AstraZeneca must conduct an additional study attempting to select for SARS-Co V-2 with reduced susceptibility to tixagevimab in culture. Such study must employ alternative strategies as agreed upon between AstraZeneca and the Agency. AstraZeneca must provide the Agency with a proposed protocol by January 7, 2022. AstraZeneca must submit a report of summary findings as soon as available, but no later than June 30, 2022. Report from AstraZeneca's study evaluating the potential fortixagevimab and cilgavimab to mediate antibody-dependent enhancen1ent of infection using sub-saturating concentrations of each monoclonal antibody by June 30, 2022. Final results from PROVENT and STORM CHASER by December 30, 2022. Results, to include baseline and all subsequent study visits, of the following biomarkers from the PROVENT repeat-dose sub-study: d-dimer, P-selectin, thrombin, and Factor VIII. Topline data, to include safety, phannacokinetic, ADA, and biomarker results for thrombotic events from the first 9 months of the PROVENT repeat-dose sub-study by January 31, 2023. Monthly aggregate reports for serious adverse events in the Cardiac Disorder System Order Class (SOC) and other non-cardiac thrombotic serious adverse events. 0. AstraZeneca and authorized distributor(s) will make available to FDA upon request any records maintained in connection with this EUA. Healthcare Facilities to Whom EVUSHELD Is Distributed and Healthcare Providers Administering EVUSHELD P. Healthcare facilities and healthcare providers will ensure that they are aware ofthe Letter of Authorization, and the terms herein, and thatthe authorized Fact Sheets are made available to healthcare providers and to patients, parents, and caregivers, respectively, through appropriate means, priorto administration ofEVUSHELD. Q. Healthcare facilities and healthcare providers receiving EVUSHELD will track all serious VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00105 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.018</GPH> lotter on DSK11XQN23PROD with NOTICES1 medication etTors and adverse events that are considered to be poten1ially attributable to E\11JSHELD use and nrnst report these to FDA in accordance with the Fact Sheet for Healthcare Providers. Complete and submit a MedW atch form (www.fda.gov/medwatch/report.htm), or complete and submit FDA Form 3500 (health professional) by fax (1-800-FDA-0178) (these forms can be found via link above} Calll: 800-FDA-1088 for questions. Submitted reports should state, "EVUSHELD use for COVID-19 under Emergency Use Authorization" at the beginning of the question "Describe Event" forfurtheranalysis. A copy of the completed FDA Form 3500 should also be provided to AstraZeneca per the instructions in the authorized labeling. 6588 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 9 -AstraZeneca Pharmaceutical1,,LP R Healthcarefacilities andhealthcare.provilers·will.ensure.thatappropriate.storageandcold chain istnaintaineduntil:theproductis adnrinisteredconsistentwiththetertns.of'thidetter and.tlie anth,<»izedla.beling, S,. ·Torough.aprocessofinvenforycontrot.healthcare•facilitieswillma:intainrecordsre!Jllding 1he dispensingand adtnihistrationofEVUSHELDforthe useauthorizedinthis lettet(Le., lotnunibers, (lWUltity, recei\7nl.!ts~ receipt date), produ¢tstor~e. an:dmaintaitipatient · ·in:f'o~on (e..g;, patientnam:e; age. 4iseli$e milliifestatiQii,n:uinh¢1' ofdQsesadinmisttited. ·per patient; other drugs administered). t.. Heaithcarefaci11ties Will ensure.that·any:recordsassociat«l.wfrhthis•EUAa:remaititained. untilMtified by.AstraZene¢aand/or FDA. Sucliteoordswiltbemad¢ avaitabteto As:tr:aZ.e~~.J:tas•.·:iuuI•:E1lAfQtinspection::ttpo,1 rectue$t; :U: .Healthcare••facilities and•providers-willreporttherapeutics•infonnafion.andutilizafiondata as directed. by1h.e U.S. Department ofHealth andHumanServices. Cc)nditions l{efatecH<>Printe:dMatter; Advertising. and Promotion V'. All descriptive printed matter; advertising.and promotionalma.terialsrelatingtothe use of EVUSHELDunderthisauthorizafionshall beconsistentwiththeauthorizedlabeling, .as we1Lasthe tenns setforthm this EUA.andmeetthe requitetrtents setforthfo·Section 5Q2(1i)an,d(n)()fthe Acf; lll, applicable~ imd FDA implementing ~gulalion:s, Refer~Ctl!l to •"appfQVed llill<:ling'\''perajittl3dlalleiing:'orsitnilart~nnsintbes~re.quitementsshall ~. understoodforeferto:theauthorizedlabelingfortheuse•ofEVUSHELDunder•this authorizatmti Inaddi'tion;suchmaterials shall: • Betailt>tedtotheintt:ndec.bmdi~ce. • Nottake the formo:t'tetnmdetadvertisemertts; asth!lttemlis descii):,ed ffi 21 CFR202.1(e)(2X:i), 2.1 cFR20(f2Q0ili1d 21 CFR20l. toO(f} Presentthe same·risk infotmationrelatingto the:tnaJotside effects and c.onttaindications concurrently in the audio and visual parts-0fthe prtl!lenta:tfon foradvertisingand promotionalmatetia.lsin.audio-visual fonnat ••• Beaccompanied.bythe authorizedlabe~ ifthepromotionalmlii:enals arenot subjectto Section 502(n}oftheAct. •• Be:submittedto FDA accompanied by FonnFDA•2253 atthetime of initial dissemination ot:fust use, ·• ttilie.Agencynotities Ali'ffllZertecathat any descriptive printed matter; advettismlfQt VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00106 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.019</GPH> lotter on DSK11XQN23PROD with NOTICES1 pro:ni9ticmalllla,ierialsd.on:Qtmeetthetennilsetfeilthin:~nditions V-X oftbis EU!\; AstraZenecamustcease.distribution ofsuchdescriptive·printedma1tei; advertising. or promotional materials in accordance with. the Agency>s notification. Furthennore; as part ofits fio'tification.,. theAgenc.ymayalso requite Asmtl.enec:ato issue corrective communication(s);. Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices 6589 Page 10- AstraZen~ca Pharmaceuticals LP W. No descriptive printed matter, adveruiing., orpromotionalmaterials rela1ingto the use of EVUSHELD undetthis llli1horization may represent orsuggestthat EVUSHELDis safe·or effectivewhenw;edaspre;.expo$U.tt!prophylaxisofCO-VID-19 asnescribedinthe·Scope of AuthorizatiQn (Section It). x All descriptive pnntednfatter, advertising".aridpromotiomilniaterialt relatingto.the use of EVUSHElDunderthis authotization clearly and conspicuously shalls1ate that: • EVUSHELb hasnot beenapproved,but haS been authot'izea for.emergency .QSe by FDAunderanEOA;forpn:'-exposureprophylaxis ofCOVID-1? in certaiti.adul~ ~pedi~iric indivi~ (12 y¢al'S ofage in.id olderweighingat 1east40 kg); and • the. emergertcyuseofEVUSHEtb is otuy authorizedforthe duratiOn ofthe declaration that cnt1utnslances existjustifyingthe ituthonz.ation ofthe emer:gencyuseofdrugs and biologicalproducts during the COVID0 19 pand.emi,c underSection 5-64(t,)(l)()fthe {\ct 21 US,C. § 360bbb-:3(bXl); unlessthedeclaration.istenninated or authorization revoked sooner. TiiisEUA willbeeffoctiveuntilthe.declarationthat.circumstances existjustifyihgthe authorizationofthe emergencyuseofdrugsand biologfoalproductsduringtheCOVID-19 pandemicistenninatedunderSection 5'64(b)(2) oftheActorthe EUAis revoked unde:rSection .564(g) 9fthe A.ct Sincerely; Isl Jacquelint: A. O'Shaughnessy. Ph.D. Acting Chief ·scientist VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00107 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.020</GPH> lotter on DSK11XQN23PROD with NOTICES1 Food and DrugAdministration 6590 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices December 22, 2021 Pfizer, Inc. Aiten:tfon:; .Ka:renJlake:r Dttector; Global Regulatory Affairs: 235 Eas:t42 nd Street New York, NY 10017-5755 RE: Emergency Use Authorization l05 Dear Ms. Baker: This letteris: in response to Pfiter; foci's. (Pfit.et) tequestthanhe Food and t>tugAdministration (FDA orAgency)issue an :Emergency Use Authorization (EUA)for the emergency use of PAXLOVID (ninnatrelvir co-packaged with ritonavir) for the treatmentofniild-to-moderate coronavirus disease.2019 (COVID-19) in certain adults.and pediatric patients pursuant to Section 564 of the Federal Food, Drug, and.Cosmetic Act (th:e Act) (21 OAtC. §360hbb-3). On Februiuy 4, 2020, ptl!'$uantto Section 564(b)(1 )(C) ofthe Act, the Secretary ofthe Department of Health and HumanS:etvices (HHS) determined that.th.ere is a public health emergency that has a significant potential to affectnathmalsecuri'ly orthehealth :and security of United States citizens: living abroad, and that.involves the virus that causes corona:,iws disease 2019 (COVID-19}. 1 On the basis of such determination, the Secretary of:aHS on Mat(;.lh 27, 2020; declared thatcircumstances existjusJifying the authorization of emergency use of drugs and biologicalprcrducts:duringthe COVID-19 pandemic,p.ursuantto $ection564 of the Act(21 Li.KC. 360.bbb-3),subject to cerms of any authorization issued undetihat section. 2 PAXLOVlDis comprised. of.nirmatrelvir, a SARS°CoV •2 main protease (Mpro: also referredto as 3CLpro ornsp5 protease) inhibitor, co-packaged with ritqnavir, an HlV-1 proteas1dnhil:>iior and CYP3Ainhibitor: Ritonavir, which has no activity against SARS-CoV-2 on its own, is included to inhibit the CYP3A-mediatedmetabolism 6f nirmatrelvit nnd consequently increas.e ninruttrelvir piasma concentrations to levels anticipated to inhibit SAR:$-'CoV-2 replication.. PAXLOVIO is not approved for any use, includftl:g for use:for the treattnen.t of COVID~W Based on the .totality of scientific evidence available t◊ FDA, including data from the clinical trial EP{CsHR (NCT04960ZQ2), a Phase 2/3 randomized, double bhnd, placebo-ecmtrolled clinical trial, it is reasonable to believe that PAXLOVTD may· be effectiveforthe treatment of mild-to-moderate COVTD-l 9 in adults and pediatric patients (12 years ot'age and older weighing VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00108 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.021</GPH> lotter on DSK11XQN23PROD with NOTICES1 l U.Sibepa.i:Lmertt, qllleaHh ®d il(imittr Servic~;Determinatiano/aPub/ic.Heq/t/JEmergem;y andDe.cla1rittan ihatCircumsJances-ExtsiJustijyingAuthortzattonsPursuant toSection564(t/)aftheFede,;al.Forxi; Drug, and Cosmerfo;1ct, 21 U.S;C. §360bblr3. February4.,W20. 2 US. bcp~1tmcr1t.ofHcalth anq Human Sctvicc.•,;Di(diilY//iaiithqtl"tre1i11i;slalr~s HiczytJit§ti}jlingAtithdiiiiiti6tts Purww:inti<~Sedum 564(b) oftheF:ederafFmrd, Drug, andCr1.~metfo Ac.l,21 U:.'{G.§ 360bf!1,:.J, 85 FR 18250 (April 1,2020); Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices 6591 Pagi) 2 -- Pfiz<)r, Inc. at least 40 kg) with positive results of direct SARS-Co V-2 viral testing, and who are at high risk for progression to severe COVID~ 19, including hospitalization or death, as described in the Scope of Authorization (Section II), and when used under the conditions desctibed in this authotization, the known and potential benefits of PAXLOVID outweigh the known and potential risks of such product. Having concluded thatthe criteria for issuance of this authorization under Section 564(c) of the Act are met, I am authorizing the emergency use of PA,,"'i'.:LOVID for the treatment of mild-tomoderate COVID-19 in certain adults and pediattic patients, as described in the Scope of Authorization section of this letter (Section II) and subjectto the terms of this authotization. I. Criteiia for Issuance of Authorization I have concluded that the emergency use of PA,,"\'.LOVID for the treatment of COVID-19, when administered as described in the Scope of Authorization (Section II), meets the ctitetia for issuance-of an authorization under Section 564(c) of the Act, because: 1. SAR.S-Co V-2 can cause a serious or life-threatening disease or condition, including severe respiratory illness, to humans infected bythis vims; 2. Based on the totality of scientific evidence available to FDA, it is reasonable to believe that PA,,-XLOVID may be effective for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-Co V-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, as described in the Scope of Authorization (section II), and that, when used underthe conditions described in.this authorization, the known and potential benefits of PAXLOVID outweigh the known and potential risks of such product; and 3. There is no adequate, approved, and available alternative to the emergency use of PA.XLOVID for the treatment of mild-to-moderate. COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-Co V-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. 3 II. Scope ofAuthorization I have concluded, pursua11t to Section 564(d)( 1) of the Act, that the scope of this. authorization is limited as follows: • Distribution of the authorized PAXLOVID will be controlled by the United States (U.S.) Government for use consistent with the terms and conditions of this EUA. Pfizer will supply PAXLOVIDto authotized distributor(s)4, who will distribute to 3 No othercriteria ofissuance have been prescribed by regulation under Section564(cX4)oftheAct. "AuthorizedDistributor(s)" are identified by Pfizer-as an entity or entities allowedto distributeauthorized PAl{LOVID. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00109 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.022</GPH> lotter on DSK11XQN23PROD with NOTICES1 4 6592 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 3 -- Pfizer, Inc. healthcare facilities or healthcare providers as directed by the U.S. Government, in collaboration with state and local government authorities as needed; • PAXLOVID may only be used by healthcare providers to treat mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-Co V-2 viral testing, and who are at high risk 5 for progression to severe COVID-19, including hospitalization or death; Limitations on Authorized Use • • • PAXLOVID is not authorizedforinitiationoftreatment in patients requiring hospitalization due tq severe or critical COVID-19. 6 PAXLOVID is not au1horizedforuse as pre-exposure or as post~exposure prophylaxis forprevention of COVID-19. PAXLOVID is not au1horized foruse for longer than .5 consecutive days. • PA){LOVID may only be prescribed for an individual patient by physicians, advanced practice registered nurses, and physician assistants that are licensed or authorized under state. law to prescribe drugs in the therapeutic class to which PA.XLOVID belongs (i.e., anti-infectives). 7 • The use of PAXL◊VID covered by this authorization must.be in accordance with the authorized Fact Sheets. Product Description PAX.LOVID consists of two 150111gtablets ofnit111atrelvirthat are co-package<! with one 100 mg tab let ritonavir. Nit1natrelvir is supplied as an oval, pink, iriunediate-release, film-coated tablet de bossed with "PFE" on one side and "3CL" on the other side. Ritonavir is supplied as a white, film-coated, ovaloid tablet de bossed wi1h the "a" logo and the codeNK. The authorized storage and handling infor111ation for PAXLOVID is ii.1cluded in the authorized Fact Sheetfor Healthcare Providers. For information on medical conditions andfactorsassociated'With increased risk forprogression to severe COVID 19, see the Centers forDisea seControl and Prevwtion.(CDC)website: https;//www.cdc.gov/coronavirus/2019ncov/need-extra-precautions/pegple-wit.h-medical-conditions.h1ml. 6 Pa tients.requiringhospitalizationdue to severe or critical COVID• l 9afterstarting treatment with PAXLOVID may complete the full 5-da y treatment course per the healthcare provider's discretion. 7 The term "State" includes any State or Territory ofthe United States,.theDistrictofColumbia, and the Commonwealth of Puerto Rico. See section20l(aXl )oftheAct. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00110 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.023</GPH> lotter on DSK11XQN23PROD with NOTICES1 5 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices 6593 Page 4 - Pfizer, Inc. PA.c"'CT,OVID is authorized for emergency use with the following product-specific information required to be made available to healthcare providers and to patients, parents,and caregivers, respectively, through Pfizer's website www.COVID19ora1RX.com (refertedto as the "authorized labeling''): • • Fact SheetforHealthcare Providers: EmergencyUseAuthorization(EUA)for PA.cXLOVID Fact Sheet for Patients, Parents and Caregivers: Emergency Use Authorization (EU A)of PAXLOVIDfor Coronavirus Disease 2019 (COVID-19) Ihave 'Concluded, pursuantto Section 564( d )(2) ofthe Act, that it is reasonable to believe that the knownandpotential benefits of PAXLOVIT>, when u$ed forthetreatment 9fCOVID-19 and used in accordance with this Scope of Authorization(Section II), outweigh the known and potential risks. I have concluded, pursuant to Section 564(dX3)ofthe Act, based on the totality of scientific evidence available to FDA, that it is reasonable to believe that PA.XLO VID may be e:ll'ective for the treatmentofCOVIl)..19 when used in accordance with this Scope of Authorization (Section II), pursuant to Section 564{cX2XA) of the Act Havingreviewedthescientific information available to FDA, including the informati01i supportingtheconclusions described in Section I above,lhaveconcluded thatPAXLOVID(as described in this Scope ofAuthorization (Section II)) meets the criteria setforth in Section 564(c) of the Act: concerning safety and potential effectiveness. 1lie emergency use of PAXLOVIDunderthisEUAmust be consistentwith, and maynotexceed; the terms ofthe Autlmrizi¢i.on, including the Scope of Authorization(Section II) and the Conditions of Authorization (Section III} Subject to the terms of this EUAand under the circumstances set forth in the Secretary ofHHS's detertnit1ation under Section 564(bXl)(C) described above and the SecretaryofHHS's corresponding declaration under Section 564(bXl), PAXLOVIbis authorized for-thetreatmentofruikUo-moderate CO'Vll)..19 in.adults andpediatricpatients (12 years of age and o lderweighing at least 40 kg)withposi1ive results of direct SARS-CoV•2 viral testing, and wbo are at high risk for progression to severeCOVlI).19, including hospitalization otdeath, as described in the ScopeofAuthorization(Section II) under this EUA, despitethefactthatit doesrtot meet certain requirements othetwise required by applicable federal law. III. ConditionsofAuthorlzation Pursuantto:Section 564 of the Act, I am establishing thefollowing:Con<litions on thisimthorization: Pfizer and Authorized Distnbutors 8 A. Pfizer and authorized distributo:r(s) will ensure that PAXIDVID is distributed and the authorized labeling (i.e., Fact Sheets )will be made available to healthcare facilities and/or healthcare providers as described in Sectiot1 II of this Le.tuir of Authorization. VerDate Sep<11>2014 SupraatNote4. 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00111 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.024</GPH> lotter on DSK11XQN23PROD with NOTICES1 8 6594 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 5 -- Pfizer, Inc. B. Ffizet and authorized distributot( s) will ensure that appropriate storage is maintained .until the product is delivered to healthcare facilities and/or healthcare pl'OViders. C. Ffizer and authorizeddistributot(s) will ensure that the terms of this EUA are made available to all relevant stakehokiers (e.g., U.S. government agencies, state and local. government authorities, authorized distributors, healthcare facilities, healthcare providers) involved in distributing or receiving PAXLOVID. Pfizer will provide to all relevant stakeholders a copy of this_ Letter of Authorization and communicate any subsequent amendments that might be made to this Letter of Authorization and its authorized accompanying materials (i.e., Fact Sheets). I); pfizer may request changes to this authorization, it1cluding to the authorized Fact Sheets for PAXL0Vm. Anyrequestforchangesto this EUAmust be submitted to the Office of Infectious Diseases/Office ofN ew Drugs/Center for Drug Evaluation and Research. Such changes require appropriate authorizati011 prior to implementation. 9 E.. Pfizer may develop and disseminate instructional and educational materials (e.g., materials providing infonnation on product administration and/or patient monitoring) that are consistent with the authorized emergency use of PAXL0VID as described in this Letter of Authorizati0t1 and authorized labeling, without FD A's review and concurrence, when necessary to meet public health needs. Any instructional and educational materials that are inclmsistent withtlte au1horized labeling for PAXL0VID are prohibited. If the Agency notifies Pfizer that any instructional and educational materials are inconsistent with the authorized labeling, Pfizermust cease distribution of such instructional and educati011al materials. Furthermore, as part of its notificati0t1, the Agency may also require Pfizer to issue corrective communication(s). F. Ffizer willrepmt to FDA serious adverse events a:nd all medicati011 errors associated with the use. of PAXL0VID for its authorized use that are reported to. Pfizer using either of the following opti011s. Option 1: Submit reports through the Safety ReportingPortal(SRP) as del3Cribedon the FDA SRPweb page. Option 2: Submit reports directly through the Electronic Submissions Gateway (ESG) as described on the FAERS electronic submissions web page. The following types ofrevisionsmaybe authorized withoutreissuing this letter: (l) changes fo the authorized labeling; (2)non-substantive editorial corrections to this letter; (3)newtypes of authorized labeling, including new fact sheets; (4)new carton/cootainer labels; (5)expirationdating extensions:, (6)changes to manufacturing processes, including tests or other a u1horized components ofmanufacturing; (7) new conditions of authorization to require data collection or study; (8 )new strengt~ of the authorized J.'lroduct, new product sources (e.g., of active phannaceutical ingredient) or ofproduct components. Forchanges to the authorization, including the authorized labeling, of the type listed in (3), (6), (7), or(8), review and concurrence is required from the Counter-Terrorism and Emergency Coordination Staff/O±lice ofthe Center Director/CDER: and theOffice ofCounterterrorism and Emerging Threats/Office of the ChiefScientist. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00112 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.025</GPH> lotter on DSK11XQN23PROD with NOTICES1 9 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices 6595 Page 6 - Pfizer, Inc. Submitted reports under both options must state: '"PA,XLOVID use forCOVID-19 under Emergency Use Authorization(EUA)." For reports submitted underOption 1, includelhis language at the beginning ofthe question"Describe Event" forfurther anaJysis. Forreporls submitted under Option 2, include this language at the beginning of the "Case Narralive" field. n All manufacturing, packaging, and tes1ingsites for both drug substance and drug product will comply with current good manufacturing practice requirements ofSection 50 I ( a X2)(B) of the Act. H. Pfizer will submit information to the Agency within three working days ofreceipt ofany infonnation concerning significant qualify problems with dru_g product distributed under this emergency useatithorization for P AXLOVID that indudes the following: • Infonnation concerning any incident that causes the drug product or its labeling to be mistaken for, or applie.dto,anotherarticle; or • lnfonnation concerning any microbiological contamination, or any significant chemical,physical, orotherchange or deterioration in the distnbuteddrug product, or any failure of one or more distributed batches ofthe productto meet the established specifications. If a significantqualityprobiem affects unreleased product and may aJso impact product(s) previously released and distributed, then information must be submitted for all potentially impacted lots. Pfizer will include in its notification tothe Agency whether the batch, or batches, in ·question will be recalled If not included in its initial notification, Pfizer must submit infonnation conflflllingthat f'fizer has identified the root cause ofthe significant quality problems,taken corrective action, and provide a justification confmningthat the corrective action is appropriate .and effective. Pfizer must submit this information as soon as possible but no lateithan 45 calendardaysfromthe initial notification. I. Pfizer will manufacture PA.XLOVIThomeet all quality standards and perthe manufacturing process and control strategy as detailed inPfizer'sEUArequest Pfizer will not implement any changes to the description of the product, manufacturing process, facilities and.equipment, and elements of the associated control strategy that assure process performance and quality of the au1horized product, without notification to and concurrence by the Agency as described under condition D. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00113 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.026</GPH> lotter on DSK11XQN23PROD with NOTICES1 J. Through a process of inventory control, Pfizer and authorizeddistribirtor(s) willmaintaiii records regarding distnbution of PAXLOVID (i.e., lot numbers, quantity, receiving site, receipt date). 6596 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 7 -Pfizer, Inc. K .Pfizerwill establish a process,formoni1Dringgenomicdatabase(s}forthe.emergence of glohalvital\latia.trtS.QfSARS-Cov~::bmd willprt>,vide~repot1S to the Age:ncyonamonthly basis stifillilariiinganyfmdingitas a resriftof:iis moriitoringactivities and,.as nee4ed, any. fijlfow-up il$Sess:tn¢ilts planntid or conl.bzjed Updated da1aJistin~ summariziiig;aniino · .acidvariabilityshotildbe:providedatleastmomhlYfor Mpro-ammo acld·sequences; and at ~~?.:?'SSf:;t==r L. FDAmay·require:Pfizerfo assesstheaclivityoftheauthorizedPAXLOVIUagainstany· gfobalsARS~Co:Y~2Vmant(:s)-0fitttetest(e,g;,viiriant$thatareptevalentorheoomihg:. •=:==~s~~::i::::~1:s0:!::1&:~:::::in:the agreed upon by Pfizer and the.Agency, ffizer:will submitt<>'FDAa prelii:niharysummar:y ·.report immediatelyuponcomplettonofits,assessmentfollowed. bya de1ailed study.report ·withih30calendar days of study completion. Pftzerwillsubmit anyrelevantproposal(s)to tev'isetheJ1uth:orizedlab¢Iln:gbased 01i:-theresults ofitsi assessme.rtt;.asmaybenecesS$)''6r .approprj$ ~d.QnihefqregofugllS~ssmen{ · · · XL Pfizer shallprovidesamples asrequestedoftheautho:rizednmnatretvirfo the U.S. DepartmerrtofHealth andHumattServic:es(HHS)forevahiation•of-activityagamst ·emerginggloblil.vii'alva:riants ofSA,:RSaCoy;;z.mcludingspecinc:•~o.•acid :substitution(s) llfinterest (e,lh variants that.are1iigblyprew:le~llortha(ham·Ol'.su1l!!tittitio11S ··iu thetal;get-prote~s}ortargeh:il~vagesit~!i)·withinSb11Sitiess'days··Qfanyreqi;iest·tt1a(fe 0 ··by HHS. Analysesperfonned•with.thesuppliedquantityofauthorizedniimatrelvir·may·· •.~~:~:::n◊t limitedt(I, cel.J.ctil1ilieJlotehc):'assays,biQChelllicalassays,andin.vi'vo .N: •Pfizermust:providethe:foBQwmginfonn:ation:fothe·Agency:• L :Pfizermust c6tiductcell culture phenotypic::anaiyses-ofrec6111binarttSARSQoV~2:vim-ses•orteplicons;c:lltJ.'Ying·spec·ifi¢amirt.o acid·changes.potentially lt!IS◊c:iated with~duc~nintr~Jyjr~ptipiJityin n:9ru,:(~cal ot¢linwlil: studies,,orpolymotphismsemerging.in,novel,SARS-CoV-,2variarits, Specific amino acid changes thatsfuutd'be c;hatac~rized includethefoUowing: o f::O°c:!~~J::;:Soci~withtediicedniimattel\iirsuscf!Ptibilliy :==1:===::=ll,o, ;::::~:~cr::::::rorprolongedvir<>logicshe~ot o· .·ammo ·acidpolymorphismsideritifiedii1resi:stance:su1Veillance·• analyses. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00114 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.027</GPH> lotter on DSK11XQN23PROD with NOTICES1 Ammo acid changes ili bothMpto andMpto cleaVage.sitessfouldbe consit.leredmthese_an.ilY$es. $p.ecffic ~o acidci@.ges:ofinterestfor 6597 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 8 -- Pfizer, Inc. 2. 3. 4. 5. 6. 7. phenotypic characterization in cell culture assays currently include Mpro substitutions Y54A,E55L, Fl40A,S144A,E166A, H172Y,Q189K, and A260V. When warrnnted due to technical challenges, alter11ative approaches to the requested cell culture assays will be co11Sidered 011 a case-by-case basis. Pfizer must submit a preliminary summary report no laterthan February 28, 2022 for any currently ongoing studies, and at least every 6 months thereafter as additional data accumulate. Pfizer must evaluate the cell culture antiviral activity ofoirmatrelvit against an a.uthenticSARS-CoV~2 isolate representative of the Omicron variant Pfizer must submit a summary report no later than February 28, 2022. Pfizer must cooduct studies characterizing potential nirtnatrelvirresistimce mechan.iS!lls in SARS-CoV-2 in cell culture, including selection and genotypic and phenotypic characterization ofllim1atrelvir-resista11t virus. Pfizer must submit a briefmoothly progress report on these studies; a preliminary summary report no laterthanApril 30, 2022, and a final reportwithin30 days of study completion. Pfizer must complete analyses ofSARS-CoV-2 shedding and nucleotide sequencing from the EPIC-HRclinical trial. Viral sequencing analyses should be conducted for all clinical samples with sufficient viral RNA levels, including samples collected at baseline, on-treatment and post-treatment, to identify and characterize the pote.ntial emergence or persistence of amino acid changes associated with PAXLOVID treatment. Pfizer must submit a summary of available data (including analysis-ready datasets) no later than February 28, 2022, and a final report and associated datasets (including analysis-ready datasets and raw fastq NGS data) no later than April 30, 2022. Pfizer will submit the clinical study report containing data from all enrolled subjects in the EPIC-HR clinical trial no later than January 15, 2022. Pfizer will provide results from a safety and pharmacokinetic study evaluating PAXLOVID as treatment of mild-to-moderate COVID-19 in patients with severe renal impairment (for both patients requiring and not requfringhemodialysis), withthe studyprotocol submitted 110 late.tthru1. March 31, 2022. Pfizer will provide the audited final report of the rat PPND study, An Oral (Gavage) Study ofthe l{tfects ofPF~0732 J33 2on Pre- and Postnatal De1,elopment Including Maternal Function in Rats, 110 later tha11 April 30, 1 . 2022. 0. Pfizer and authorized distributor(s) will make available to FDA upon request any records maintained in c01111ection with this EU A Healthcare Facilities to Whom PAXLOVID Is Distributed artd Ilealthcare Providers Administering PAXLOVID VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00115 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.028</GPH> lotter on DSK11XQN23PROD with NOTICES1 P. Healthcare facilities and healthcare providers will ensure that they are aware of the Letter of Authorization, and the terms herein, a11d that the authorized Fact Sheets are.made 6598 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices P,age 9 - P,fizer,Jnc. •availabletohealthcare providers. andtopatients,parents, and.oaregivera,.respectively, tht◊1:t$h·.amiropda~means, priortoadtttiriisW1t)fuof:PA:XLOV1b: Q, · Uea1th~facilrues @dh:el3lthcai'eptQVi\etSt¢'c¢i\fihgPJ\XLQV10willitc®k:all serious medicalion. errorsand adverse evettfsthatare considered to bepotetiti:a.lly:attributaole to ·PAXLOVID tlse•an:dtnustreporttheset() FDAin.·atcotdance·withtheFact•Sheetfor llelllth¢attJ>mvi~ts.·G~leye~d stibniita M:edWat!)hfott:r) .cwww~fda:go:v!med\\laWbite@ft.111lnl or cW'fiJilete~sJJbmitFOA Fotn:t 35do @~1th ·prof:essiqn!tl.)l>yfax(l~8®'-F:PA-Ol~}(tlteSt1 fonnscanllef:QU11d'1ialirik1:1.bove); C:all.b ·soO•FDA-10S:8'forquesfionKStibmittedreportsmuststat~f!PAXLOVIDuseforCOVID:- . 19 undetEmerge~tlseA:tltn<>.nzation"atthe beginmn~<>f'theguestion''Descnoe E'venf' forfuriher aniU)'Sis, A copy of'ih.¢ c~l~edFDAFotm3500 must also.lter,rovidedto l>f'.izetp~theirt~QnSlll.t®llutb:orizedl~l~; . R. .Healthcare•facilities andhealthcareprovii:lerswill ensurethat:appropriatestorageis ·maintained.untiUhe productisadministeredconsistentwith.thetenns,ofthis:letterandthe authorized labeling. S. Through.ap::rocessofinventorycontrot:.:heaithcarefacilities·willmaintainrecordsrefJl!ding the di!!pensiilgandadministrationofPAX I.OVID for theuse.authorized inthis. le'lter(ie.,, 101.numl>ers,q)iantityj receivingsit~ receipt datelproductstorage, andmaintainpati'ent infotmatiot1(e.,g;,.patientnatt1e;age,•disease mllnifestatio~.rtUtlil:!~·ofdoses;1dmifiistered Ptlf Pati~t; giherdrugs ll~bni~d). T. Healthcarefacilities willensurethatanyrecordi!:associatedwiththis.EUAaremairitained ·untilrtotified by Pf"izerand/otFDA Si:it:hrecotdswill be madeavailablet0:l>.tizer,HHS, and fDAJqrin!!f!ecti,on upot1request · U: Healthcarefacilities andproviderswillreporttherapeuticsinfonnationandutilizationd'ata as dfre¢ted.byHHS; .c:Ondnfons Refatedt-0 Printed.Matter., Advertising, artd Promotion V'. All descriptive printed matter; advertising, and promotionaJmaterialsrelatingtotheuse of PAXLOVID underth:isauthorizationshall be consisten.twiththe auth:ori&edlitbeli11g. as wen as the terms setforth.inthis EDA. andmeetthe teqwrerru:rtts setfottli.irt:Sectiim 5()2(a)and(rt)-0fthe Aci,as ~pplicabfo; ~ IDA iinplementingregulatiorts: R.efetenc\es to ••a,pproved la!Jellng'1,/'pen:nitted·Iallel41:g''9r·similwteilJl$in·theserequirerrrents~lillll be understoodtorefertotheauthorized.labelingfortheuse-0fPAXLOVIDunderthis authorization Inaddition, such materials shall:. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00116 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.029</GPH> lotter on DSK11XQN23PROD with NOTICES1 •• l3etailoredtQtheintertdedaudience. •• Not take.the fonnofreminderadvertisements, asthattermis descrioedin2l CFR.202. l(e)(ZXQ, Zl CFR200,200and2i CFR20i.lQ()(f} Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices 6599 Page 10 - }>fizer, Inc. • •• Presentthe same risk. information relating to the major side-effect!:! and contraindications concurrently in the audio and visual parts ofthepresenta1ion foradvertisingandpromotionalmaterialsinaudio-visualformat Beaccornplllliedbythe authorizedlabeling; ifthepromotioruilmaterials-arenot subject to Section 502(n}oftheAct • Besubmi:ttedtQFDA a®mpaniedhyFottnFDA•2253.att:hetime.ofmitla1 dissemination ()f fttst\i!le. Ifihe·.Agencynotifies Prizerihatany descriptiveprintedmatteriadveriisingorpromotional mateiialsdon:otmeetthetermssetforthin.ooru:litionsV~XofthisEUA, Pfizermustcease distributimofstichtlesctiptivepririredfuattet,.advertising,.orpromotiotlilmaterlals in accotdat'lcewith.theAgency'snotiftcation. Furthermore,.aspattofitS ttotification,. the A,gel)cyw.aya.tso·.teqµke·l:'flzertQ•is~e.cQttectiYec:omm:lllU<:atiQi1@, W: •No de.scriptiveprintedmafter1 advertising;or·promotionalmaterials.relatingtotheuseof PAXLOVtt> underthis.auth~on•rnat~reserttor·suggestthat:PA.XLO'\III)issafeor effective whenu~dfotthe :treatment ofCOVID 19. 0 }(: .All descriptiveptjtttedmafter; ~dve~mg.Mcl promotiQmi!lllliteri1U,r¢laungtotlleuse of PAXLOVlD underthisauthorizafionclearly andconspicuouslyshall state that: • PAXLOVUlhas notbeet11tpP!OVedtbuthas1'een lllithonzedf<>r: emersency use by Fl>A under lii1 EUJ\, forthetreatm.eot Qftnild-tomQderate .CO\TIQ-l?inadults andvediatricpatients(l2years of age: and older weighing af Ieast40 kg)withposi1iveresul1s of direct SARS~ Cov..2 viraltestitlg,andwho are athigh0 riskforprogression to.severe COVID-19,inclUdinghospitalization<>fdeath;and • The emer~cyuseof RAXit()Vl'fiisonlyiu,1t11Qtized.f«thedurati9n Qfthedecllitat:t'Qnthat.citctJmStancesexistjustifyingtheauthorizajionQf the emergency use of drugs andbiohgical products during the COVID19 pandemic under Section$64(bXl)oftheAct, 21URC. § 360bbtr. 3{b)(1),urt~$the decfatiltionis terminated otauthorizatiortrevoked SMn.et. IV. Durationof.Authorizd.on ThisEUA wiltbeeffectiveun1ilthededaratfon thatcircumstances e-xistjustifyfu~llfo authorization of the emetgenqyuse.ofd~ andbiologicalproductsiduringtheCOVID~t9 PMdemic isJerminatedunclerSecti.Qn 564(b)(2) Qfthei\.ctQtthe EtJAi!:! revoked µni,ler.Sec.tion 564(g)ofthe Act Sincerely. !.'age Tl -.I>fizer, Inc. Isl VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00117 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.030</GPH> EN04FE22.031</GPH> lotter on DSK11XQN23PROD with NOTICES1 hcq11elµ1e A O'Sha11ghness5', Ph.D. Acting Chief .Scientist Food and DrugAdminisfratiou 6600 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices December23, 2021 Merck Sharp & Oofrme Corp. AttennQll: Sushma Xumar, PhD; Pl\11? Senior Director, Global Regulatory Affai.rs andClirticl'\lSafety 1 MerckDriye · ·· · POBoxlOO Whit¢b:(ruse Stati◊n,NJ 0&&&9"0100 RE; Emergency Use All.ihoriz-1:ttim:r mi near iJ1-: Kumar: This letteris in respo1,1s.etoMerck:Sharp & Oohme C◊rp, 's(Mecrck) reqµE$tthatfh.e.l'ood and Drug Administration (FDAor Agency )issue: an Emergency Use AU1horization (EUA)forthe emergency use of moJnupiravirfor the tteatmerttofmild,to--mo:derate corortavirus, disease 2019 (COVlD•l9) in c.ertaiintdults who ate athigh--risk forp:togressiMto severe COVlD•l9. irrcludingho.spitalization ordeatll, p.ursuantto Sec:tiofl $64 ofthe: Federal food, Dxug. afld Cosmetic Act (the Act) (2 l lJ;RC. §3601,l,h-3). On February 4, 2020, pursuantto Section 56.4(b)(l )(C) ot'the Act the Secretary of the Department offlealth afltUlumaflServ:ices (lU{S) determined .thattherefs atrublic health emergenpy thatJ.uisasigoificafltpotel'.),tial to affectnationalsecurity orthehealih afldsecurityof United St11tes citizens living abroad, and thatinvolves the virus th:atcauses coronavirus disease 2019 (COVID-19), 1 On the basis .of such determination, the Secretary of HHS on March 27, 2020, declared i.lHlLcircumstances existjustifyingthe authorization ofemetgency us:e ofd:tu~ afld biOlogicalprodu<:1$ d4rirtg.(he COVID..J '1 pal'l(l.~c. pursuan.tto Section564 ofthe !\ct (21 U.S. C. 36:0bbb-3),.subjectio terms of any authorizaaon issued underthatsection.:i Moinupiravids a nucleoside analogue that inhibits SARS~CoV -2 repli:cati011by viral mutagen.esis. M◊lnUpiravitis notFDa~app.t-0Yed fOtaflY uses, ihcludinguse. as trea11nentfot COVID-19, . Based onthe review of the dataftomtlre MOYe 0UT cllirlcaitrfai (NCT04575597)~ a Phase 1ll rafldo:mized, double-blind, placebo-controlled clihical trial studyihgmohtupiravirfot the :treatmwt ofnon-h◊spitatized patients \'\'ith rnild-to-moderate: COVlD-19whu are athigh ris:kfor progression to severe COVID•l9; ihclu4in8 hospitalization or dea~ it is: reasonable .to believe 0 tlratmolnupiravirmay be effective for the treatment ofmild-to~moderate COVID~l 9 in adults 1 t1,S,Depi\iim¢!ito1'.1Ieahh ®d 1lt®;m $erv,~t:s,De.termi11auonofaPu6l1p'/1ealth'll,,w:rgenqyam.i.beclamiion ihaiCircumstancesExtstJ11siijyingAulhorlzat1011JPursuani toSectianS64'(q)oftheFedera1Forxi, Drug, and Cosmettc;fo( 21 U:S:C.§360bblr3.Februmy4,2020, i 1J. S, Department ot'Bciilth at\4 H::utni!!i Smiccs; JJec.iartiJirmJhiilCtftiifns)i:!li&s Ettst.h{St.tjy/ng,4iirhotfiti1fijf!S. Pu.r.mantf(JSeptkm 564(b) oft~FederatFood;Drtrg,andCo.t1t11:ltcAet,2l fZS.C:§360hhh-3, 85 FR 18250 VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00118 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.032</GPH> lotter on DSK11XQN23PROD with NOTICES1 (April 1,2020); Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices 6601 Page 2 -- Merck Sharp & Dohme Corp. who are at high-risk for progression to severe COVID-19, including hospitalization or death, and for whom attemative COVID-19treatment options authorized by FDA are not accessible.or clinically appropriate, as described in the Scope of Authorization (Section II), and when used under the conditions described in this allthorization, the known and potential benefits of molnupiravir outweigh the known and potential risks of such product. Having concluded that the critetia for issuance of this authorization under Section 564(c) of the Act are met, I am authorizing the emergency use of molnupiravir for the treatment of mild-tomoderate COVID-19 in adults who are athigh-riskforprogressionto severe COVID-19, including hospitalization or death, as described in the Scope of Authorization section of this letter (Section II) and subject to the tenns of this authorization. I. Criteria for Issuance of Authorization I have concluded that the emergency use of molnupiravir for treatment of mild-to-moderate COVID-19, when administered as described in the Scope of Authorization (Section II), meets 1he criteria for issuance of an authorization under Section 564(c) of the Act, because: 1. SARS-Co V-2 can cause a serious or life-threatening disease or condition, including severe respiratory illness, to humans infected bythis virus; 2. Based on the totality of scientific evidence available to FDA, it is reasonable to believe that molnupiravir may be effective for the treatment of mild-to-moderate COVID-19 in adults who are at high-risk for progression to severe COVID-19, including hospitalization or death, as described in the Scope of Authorization (section II), and that, when used under the conditions described in this authorization, the known and potential benefits of molnupiravir outweigh the known and potential risks of such product and 3. TI1ere is no adequate, approved, and available altemative to the emergency use of molllllpiravir for the treat1nent of mild-to-moderate COVID-19 in adults as further described in the Scope of Authorization (section II). 3 II. Scope of Authorization I have concluded, pursuant to Section 564(d)( 1) of the Act, that the scope of this authorization is limited as follows: • Distribution of the authorized molnupiravit will be contro lied by the United States (U.S.) Govemment foruse consistent with the terms and conditions of this EU A. Merck will supply molnupiravirto authorized distributor(s)4, who will distribute to healthcare facilities or healthcare providers as directed by the U.S. Government, in collaboration with state and local government authorities as needed; No other criteria ofissuance have been prescriboo by regulation under Section564(cX4)of the Act. "Authorized Distribu1m(s)" a re identified by Merck as an entity or entities a llo woo to distribute au1horized molnupiravir. 3 VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00119 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.033</GPH> lotter on DSK11XQN23PROD with NOTICES1 4 6602 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 3 -- Merck Sharp & Dohme Corp. • Molnupiravir may only be usedfor the treatment of mild-to-moderate C0VID-19 in adults: • • • With positive results of direct SARS-CoV-2 viral testing, and Who are at high-risk5 for progression to severe C0VID, including hospitalization or death, and For whom alternative C0VID-19treatment options authorized by FDA are not accessible ot clinically appropriate. Limitations on Authorized Use • • • • Molnupiravir is not authorized foruse in patients who are less than 18 years of age. Molnupiraviris not authorized for initiation of treatment in patients requiring hospitalization due to CO VID-19. 6 Benefit of treatment with moln upiravir has not been observed in subjects whe11 treatment was initiated after hospitalization due to COVID-19. Molirnpiraviris rtot authorizedforuse for1ongetthan 5 cortsecutivedays. Molnupiravir is not authorized for use as pre-exposure or as post-exposure prophylaxisforpreventionofC0VID-19. • Molnupiravir may only be prescribed for an individual patient by physicians, advanced prac.,1ice registered nurses, and physician assistants that are licensed or authorized under state 7 Jaw to prescribe drugs in the therapeutic class to which molnupiravir belongs (i.e., anti-infectives). • 'The use of molnupiravii: covered by this authorization must be i11 accordance with the authorized Fact Sheets. Product Description The authorized molnupfravir is supplied as a bottle (NDC~0006-505S-06, NDC-0006-5055-07) cot1taining a.sufficient quantity ofmolnupiravir 200 mg capsules to complete a fulltreatmetlt course (i.e., 40 capsules). Molnupiravir is manufactured as a Swedish Orange, opaque capsule co11tai11ingthe Merck corporate logo at1d "82" print.ed in white ink. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00120 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.034</GPH> lotter on DSK11XQN23PROD with NOTICES1 s For information on medical conditions and factors associated with .increased ri.<ik forprogression to severe COVID 19, seethe Centers for Disease Control and Preverition(CDC)website: https://www.gdc.gov/corgnayirus/2019.ncov/need-extr<H;n;ecautigns/pegple-with,medical-cgndition5,html ~ Patients requiring hospitalizationafter starting treatment with molnupiravirmay completethefull 5 day treatment course per the healthcare provider's discretion. 7 The term "State"includes any State or Territory ofthe United States, theDistrictofCo!umbia, and the Commonwealth of Puerto Rico. See section201 (aXl) oftheAct. Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices 6603 Page 4 -- Merck Sharp & Dohme Corp. Tue authorized sto~ and handling infonnation is included in the authorized Fact Sheet for Healthcare Providers. Mohmpiravir is authorizedfor emergency use with the following product-specific information required to be made available to healthcare providers and to patients and caregivers, respectively, through Merck's website www.molnupiravir.com (referred to as the. "authorized labeling"): • • Fact Sheet for Healthcare Providers: Emergency Use Authorization (EU A) for molnupiravir Fact Sheet for Patients and Caregivers: Emergency Use Authorization (EUA) of molnupiravir for Coronavin1s Disease 2019 (COVID-19) I have concluded, pursuant to Section .564(d)(2) of the Act, that it is reasonable to believe that the known and potential benefits of molnupiravir, when used for the treatment of COVID-19 and used in accordance with this Scope of Authorization (Section II), outweigh the known and potential risks. I have concluded, pursuant to Section 564(d)(3) of the Act, based on the totality ofscientific evidence available to FDA, that it is reasonable to believe that moltmpiravir may be effective for the treatment ofCOV1D-19 when used in accordance with this Scope of Authorization (Section II), pursuant to Section 564(c)(2)(A) of the Act. Having reviewed the scientific information available to FbA, including the information supportingthe conclusions described in Section I above, I have concluded that molnupiravir(as described in this Scope of Authorization (Section II)) meets the criteria set forth in Section 564(c) of the Act conceming safety and potential effectiveness. The emergency use of mo lmtpiravir product under this. EUA mu<;t be consistent v.ith, and may not exceed, thetem1s of the Authorization, including the Scope of Authorization (Section II) and the Conditions of Authoriza1ion (Section III). Subjectto. the terms ofthis EUA and under the circumstances set forth in the Secretary of HHS's determination under Section 564(b)(1 XC) described above and the Secretary of HHS ·s cottesponding declaration mider Section 564(b XI), molnupiravir is authorized for the treatment of CO VID-19 as described in this Scope of Authorization (Section II) under this EUA, despite the fact that it does not meet certain requirements otherwise required by applicable federal law. III. Conditions of Authorization Pursuant to Section 564 of the Act, I am establishing the following conditions on this authorization: Merck and Authorized Distributors 8 A. Merck and authorized distributor(s) will ensure that mo lnupiravir is distributed and the authorized labeling (i.e., Fact Sheets )will be made available to healthcare facilities and/or healthc,u·e providers as described in Section II of this Letter of Authorization. VerDate Sep<11>2014 Supra at Note 4. 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00121 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.035</GPH> lotter on DSK11XQN23PROD with NOTICES1 8 6604 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 5 -- Merck Sharp & D.ohme Corp. B. Merck and authorized distributor(s) will ensure that appropriate storage is maintained until the product is delivered to healthcare facilities and/or healthcare providers. C. Merck and authorized distributor(s) will ensure that the terms ofthis EUA are made available to all relevant stakeholders (e.g., U.S. government agencies, state and local government authorities, authorized distributors, healthcare facilities, healthcare providers) involved in distributing or receiving molnupiravir. Merck will provide to.all relevant stakeholders a copy of this Letter of Authorization and commtmicate any subsequent amendments that might be made to this Letter of Authorization and its authorized accompanying materials (i.e., Fact Sheets). D. Merck may request changes to this authotization, including to the authorized Fact Sheets for molnupiravir. Any request for changes to this EU A must be submitted to the Office of Infectious Diseases/Office ofNew Dmgs/Centerfor Drug Evaluation and Research. Such changes require appropriate authorizati011 prior to implementation. 9 E. Merck may develop and dissemin.ate instn1ctional and educational. materi.als (e.g., materials providing infommtion on product administration and/or patient monitoring) that are consistent with the authorized emergency use ofmolnupiravit as described in thisLetfer of Authorization and authorized labeling, without FD A's review and concurrence, when necessaryto meet public health. needs. Any instructional and educational materials that are inconsistent with the au1horized labeling f ormolnupiravir are prohibited. Ifthe Agency notifies Merci( that any instructional and educational materials are inc011siste1rt with the. authorized labeling, Merck must cease distribution ofsuch instructional and educational materials. Furthermore, as part of its notificatioo, the Agency may also require Merck to issue corrective communicatioo(s). F. Merck will report to FDA serious adverse events and.all medication errorsassociatedwith the use of molnupiravir for its authorized use that are reported to Merck using either of the following options. Option 1:. Submitreportsthroughthe SafetyReportingPortal(SRP) as described on the ,IDA SltP web page. Option 2: Submit reports directly through the ElectronicSubmissions Gateway (ESG) as described on the FAERS electronic submissions web page. 11le following types ofrevisions may be authorized withoutreissuing this letter: (1) changes fo the authorized labeling; (2)non-substantive editorialcottections to this letter;.(3)newtypes of authorized labeling, including new fact sheets:, (4 )new carton/container labels; (5 )expira tiondating extensions; (6)changesto manufacturing processes, including tests or other authorized components ofmanufacturing; (7) new conditions of authorization to require data coJle.ction or study; (8 )new strengths of the authorized product, newpro<;luct sourc<"S (e.g., of active phannaceutical ingredient) or of product domponents. For changes to the authorization, including the authorized labeling, of the type listed.in (3), (6), (7), or(8), review and concurrence is required from the Counter-Terrorism and Emergency Coordination Staff/Otlice oftheCenterDirector/CDBR and the Office of'Counterterrorism and Emerging Threats/Office of the ChiefScientist. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00122 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.036</GPH> lotter on DSK11XQN23PROD with NOTICES1 9 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices 6605 !>age 6 -,MerckSharp & Pohme Corp. Submittedreporls underbothoptionsmuststate;''Molnupiraviruse forCOVID-19 under Etnetgenqt.Tse Autho~ (EUA)t Fottepotts submitted undetOption 1, inc'iude1his language attheheginiilitgofthe question ''Descme Event''fotfurthetanafysis, Fotreports suQmitte4 under Option 2, im.:lu.dethis langµage:atthe beginning of the "Case 1-l'a:mrtive'' field. . G, .Allnfantifacttirlrig,packa:gm:g,andtestirigsitesforboth.dfugsubstance.anddfugprod'.uct ·wm complywitlicuttentgoodtttanuracturlngpractice·requifetnertt$ ofSectioo 5Ql(a)(2}(13)-0ftheA<;t ·· · R Merckwill submit informafionto theAgencywithinthreeworldngdays ofreceipf. ofany ·infoi:'mlltion.concerning.sigttificant•quality pml:!lems·with dtugprod:ttct~istributedutidet this•.EPAf9r·t11olnupira,mtl:m:findudesthefol1oWirig: •• 1nf()ni1a«dn C'Oficertifug anyinciderttthai causes the di-ugprodootor ·its ~1mg to be mistakenfo1\ or appliedto,.anotherarticle; or •• In:fonnano1:rconc~gany111i'Cf<>biologiclll contan::iinafion, or anysigajfi~t <.hemJct,tl,.physiplll,Otothercltangeordeteriorationiti:the 4i~uted<irug product,oranyfailureofoneormoredistributedbatchesofthe•producttomeet the esta6Ji$hed ~peclficafions. 'I(i1:significan.iquality·prohlemmfecls unreleasedprodllcl.ancl•maY•·a~oimpactproduct(s.) previouslyreleasedanddistributed,theninformationmustbe.submit1edfurallpoteritially impacted lots. M~t~kwill in.ch::u:hdnits. notificatioot<>athe Agen~ywhe1het the batch, or batches, in questi;onwill berecaUed · · · ttrH>tlftcluded 1n its1nitiafnotificati◊n, Merck mustsubm1tilifQtmatit>ncoriftin11ng thatMerckhMidentiftedthe toott:auseof:the ~ignificantquality problems, taken corret:tive action~ and provide aju$fificati0rt CQtifirmingJh:atthec c.on-ectiveaction is approp~ateandeffective, Merckmuststibmitthis infortnafionas soon as possible but M laterthan45 calendar days fromtheinitialnotification 1 Mer¢kwillmllliuf'a~emohi.upltavirto.tt1e1:1ta:11 quafity stimdat~ i!iidpetthe manufacturingprqce~ amlconfrolsirategyas detailed.inMetck'sEUA request Mmk. will also•testthe.active·phannaceuficalingredient(APl)startingmalerial·foradditional qualityattributes agreeduponbyMerck andtheAgency.Merckwillnotimplementany changestothe descriptiortofilieptdduct,.manufllciilringptoce~,facilmes andequipm• and.elet11t1rtts..·offfi:e.as.<iociated•t:ontrolstmtegythatas.<iµrep~~sperfonnll!lce.a,ndquality of theauthoriz:ed product. \Yilhoutnotificaticmtd and t:oncurrence by th:e.Agency as · · VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00123 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.037</GPH> lotter on DSK11XQN23PROD with NOTICES1 •describedunderconditfonDi 6606 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 7 -.Merck.Sharp & I)ohme Corp. J, 'Through a processof inyentorycontrol,Merckandauthorized.distributor(s)will maintain records regardingdistributionofmolnupiravir(i;e., lotnumbers, quantify, receivingsite, receipt date). K. tvlerckwiIIestablishaprocessformorutoringgenomicda~se(s)fortheemergenc.,of globalvitalvariantsofSARS-CoV~2.. AsummaryofMerck'sprocessshouldbe.submitted to the Agencyas soonaspracticab1e, butno laterthlll130 calendar days ofthe issuance of this letter, and within30 calendar days Qfanymaterial changes to sucfrprocess. Merck will provideteportstotheAgenccyonamonthlybasissummarizing11J1Yfindings.as aresultof itsmonitoring1tcti'vitiesand;asneeded,anyfollowaup~essn1entsplannedorcooducted; L. FDA may require.Merck to assess the activity of the authorizedmolnupiraviragainst any global SARSaCoV;.2variant(s)of:interest(e,g:, variant'i that are prevalentorhecoming prevalent:thathaworsubstifutions in the target protein odnpro'teih(s)that interactwiththe target protein).. Merckwil1pe1fonntherequired assessment in a.manner and timeframe agreed upon by Merckandthe Agency; Merok.will submifto FDAapreliminazy summa:iy rep?rt immediately upon completion ofits assessment followed by a detailed study report within 30calendar days ofstudy compktion, Merck.will submit any relevant propooal(sJtO revise the autlwrizedla®ling based on the.results ofits ~~ment, ;is1nay b~1'eces~ or appropriate bllSed onilleforeg()Ulgasse!!Sment M. Merck·shaii provide samples as requestedofmolnupifavifto.iheU.R Department of' Health and Human Services (HHS) for evalua1:ion. ofacli'vityagainst emergingglobalviral varian1s ofSARSs0:>V~2: including specific amino ac.id.substit.Ution(s) <'!finterest (1tg., varianistbatlll'e.highlyprevalentorthatharllors1Jbstitutionsinthetatgetprofei11)within5 businessdays ofanyrequestmade by HHS. Analysesperfonnedwiththesuppliedquantify ofmolnupiravirmayinclude, hut are notiimitedto, ceil.Ptlhure.potency assays, biochemical assays, and in vivo i:.ifficacyassays: N: Merck musfprovidethe following information to the Agency: VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00124 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.038</GPH> lotter on DSK11XQN23PROD with NOTICES1 L Merck will conduct a thorough investtgation info the differences ili efficacy observe.cl in the firstand seconclhalfofl>art2.◊ftrial MK-44&2-002. This assessmentsh<>1Jld inv()lve the synthesis ofdjttll, including, 1:mtnot limited to; additional. baseline serology testing, a.detailed comparison ofbaseline. characteristics (including demographic, clinical disease, and virologic characteristics), and an exploration ofpoterttialdifferences in standard of care byregfon and overtime. Merckwillsnbmit a report ofitsfindingstothe Agt:ncy. Merclcwillsub111ita prelirninlµ'Y report no laterth.tt1Mllrch 31, 2022and afinalreportincQrporating.available serologyresultsnolaterthan septembet30,2022. 2. Merck wm su!Jmitthe completevh:a1sheddingtestdtsandfu1fgenome SARs~CoV-2 nnc.teotide sequencingresultsfromihefuU randomized population:in si:udy MK-4482~()().2 ~art 2. Viral sequ.encins analysessh◊t:i.14 include allBaseline andEnd~of•Treatinent (DaySJsamples with sufficient RNA levels for analysis1as well as allPost-Tteatnrentsamples with viral Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices Page 8 6607 Merck Sharp & Dohme Corp. RNA levels 2'.100,000 copies/mL. Cell culture infectivity assessments should be conducted for any clinical specimens in which amino acid changes were detected in the SARS-Co V-2 spike protein. Submissions should include summary report( s) and associated datasets (including analysis-ready datasets and raw fastq NGS data). A separate summary should be provided describing the results of the viral shedding and sequencing analyses specifically from immunocompromised patients. Merck will submit a preliminary report and associated datasets for the viral shedding and Baseline/Day 5 sequencing analyses no later than March 31, 2022,and a final report and datasets including the remaining analyses no later than June 30,2022. 3. Merck will evaluate the cell culture antiviral activity ofmolnupiravir against an authentic SARS-Co V-2 isolate representative of the Omicron variant. Merck must submit a study report no later than February 28, 2022. 4. Merck will conduct a pharmacokinetic (PK) study in wild type Fisher 344 rats to establish if NHC or NHC-TP is detected in testes. Ib.e study should include plasma exposure levels that meet/exceed the human exposure for NHC. Merck will submitthe results of the PK study no later than March 31, 2022. o If the results of the PK study demonstrate NHC or NHC-TP distribution to testes, Merck will also conduct a male germ cell mutation assay in the Big Blue rat model. Merck must submit a protocol for the Big Blue rat assay no later than 30 days after the PK results are submitted to FDA, or by April 30, 2022. Results from the Big Blue rat assay will be submitted no later than July 31, 2023. 0. Merck must maintain a pregnancy surveillance program to collect information through telephone and online repo1ting of pregnancies and collect outcomes for individuals who are exposed to molnupiravirduring pregnancy. Merck must submit to the Agency reports detailing any available exposure information and outcome(s) data on a monthly basis unless othenvise notified by FDA P. Merck and authorized distributor(s) will make available to FDA upon request any records maintained in conne<.1:ion with this EUA. Healthcare Facilities to Whom Molnupiravir Is Distributed and Healthcare Providers Administering Molnupiravir Q. Healthcare facilities and healthcare providers will ensure that they are aware of the Letter of Authorization, and the tem1s herein. Healthcare providers must provide and document that a copy of the authorized Fact Sheet for Patients and Caregivers has been provided, either through electronic means or hardcopy, to the patient or caregiver prior to prescribing molnupiravir. VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00125 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.039</GPH> lotter on DSK11XQN23PROD with NOTICES1 R. Healthcare providers must infom1 patients or caregivers of the information detailed in the sectionMandatory Requirements for Administration ofMolnupiravir Under Emergency Use Authorization in the Fact Sheet for Healthcare Providers. 6608 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices P~e 9 -MerckSharp & Dohme Col:}). S:. MoJnupiravinnayonly-beprescribedto a pre.gnantindividualafter the prescribing •fidlthcate.prov:idet'has•completed·fhemandatoeyrequfrements·<>ripatie:ntass.es!lfflent, patierttcottn.selirtg, artd doomnentation a!/ desttibedinthe FactSheetfor Healthcare · ·Pro-vi<l.ers. SeeMani,fatotJtRequirerrurntsfQrA.drnin:istraJidn. of}yf;olnuwravir U.n.d.et -Emergency UseAuthorizati'oninthe FactSheet.forHealthcareProviders,. T. Healtb~pr1wl.dersntustinforrn afid-doctmtentthatpregnant individualswho:are •::=~~=~~!8;!~1::::;~a;a:::~:::i:~J:i!ai::to- participateinthepregnancy-surveillanceprogramandallowstheprescribinghealthcare •providerto disclosepatientspecificinformationtoMerck,theprescribinghelilthcare.pro.videtrnust provide the pa1ient's ~ and.contact infonnatfon.to Merclc at 1-877-888- 4'.Z~J Qrpte8,1Wtcytepotfing:tll$d.CQQL U: Healthcare:faciliti1,s an.dhealthcareproyilersieceivingmohtupiqwirwill trackall :medication errors and serious adverse. e.ven1s thatareconsidered to bepoterrtially -attributable tomohiupiraviruse•andn.ru$treportthesetoFDAin accordance with the Fact --=~;J~::~::~:=l~~=t==~:~~t:rm ;!S()Q.·(h~lth professional} byfax(l~80!FFDA:.;Ol7&}(these fonns c-an·be,.found vialinkabove} Call 1• 80~FDA-J088forquestioos.-SUbmittedrq,orts.muststate,. "MoJnupiraviruse.fotCOVID·19tirtdetEmergency OseAuihorizatron"•atthe beginning ofthe question··•oescnbe Event'' for further anlilysi's;.Ac.Opy ofthe c001pletedFPAFotm3SOOmustlilso be provided to Merel<: perth.e. itlsnucitiOllS il:tth.e atd;Jlorizeil J.$e ling, ·· v: Heait:hcitreJ'acffities an,.fl:teatfhca:teptovKierswU1 erisW'e fh•at appropriate stotiige:is maintainedtillfilthe productisadministe:redci:lnsi'$teirtwiththetertnii ofthislettetand1he 0 authorizedlabeling. W'. :r:!1!t:=::a°l~~~~t:c:::::£:::t!:ot~r:~!e lot n.umbel!I; quantity, rec:eivingsi~ r!aleeipt date), productst0rase, andmaintaitrpa1ient ·- in:formati.011(e:g,,patien.tl:i~1;,i~, d.i~ase manifestatio~ n.unwet of d.osesadJ:µiniitered p:erpati~ otberdrugs administered}- X: ltealthcarefacitl.iies wttt ensure.iha1:anyrec0rcJgassoclated·wltinitlsEDAaremattitaiii:ed -u11tiln.otified J;y:Merckand/oi:FDA Sucltr:ecorcfu.will·t,em-ade•avaihibleto:Merck, 'flliS, .an.d FPAfor,:i.n.specliOJ1uponre.quest ·y; •Healthcare.facilities afidproviderswillr1,POrltherapeuticsinformationand:titilizatfond'ata_ VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PO 00000 Frm 00126 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.040</GPH> lotter on DSK11XQN23PROD with NOTICES1 as directedJ-,:yHHS. Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices 6609 Page 10 - MerckSharp & Dohme Corp. Conditions Relatedt-0 Printed Matter; Advertising, and Promotion Z. All descriptive printed matter, advertising,and promotional materials relating to the use of molnupiravitunderthis authorization shall be consistentwith the authorized labeling, as well as the terms set forth in this EDA, and meet the requirements set forth in Section 502(a)and(n)ofthe Act,as applicable, andFDAimplementingregulations. References to "approved labeling", "pennitted labeling" or similar terms in these. requirements shall be understood to referto the authorized labeling forthe use of molrtupiravit under this authorization Inaddi:t:ion, such materials shall: • • • • • Betailotedtotheintended audience, Not take the form.of reminder advertisements, as thatterm is described in 21 CFR202.l(e)(2Xi),2J CFR200.200and21 CFR20l.IOO(f} Presentthe same risk information relating to the major side effects and contraindications concurrently in the audio and visual parts of the presenta1ion for advertising and promotional materials in. audio-visual fonnat Be accompanied by the authorized labeling, if the promotional materials are not subject to Section 502(n) of the Act. Be submitted to FDA accompanied by FormFDA-2253 atthetiine of initial dissemination or first use. If the Agency notifies Merck that any descriptive printedm:atter, advertising or promotional materials do not meet the terms set forth in conditions Z through BB ofthis EDA, Merck mustcease distribution of such descriptive printed matter, advertising, orpromotional materials in accordance with the Agency's notification. Furthermore, as part of its notification, the Agency may also require Merck to issue. corrective communication(s) AA No descriptive printed matter, advertising, or promotional materialsrela1ingto the use of mohrupiravitunderthis authorization may represent or suggestthatmolnupiravir is safe or effective when used for the treatment of COVID-19. VerDate Sep<11>2014 18:50 Feb 03, 2022 • Molnupitavit has not been approved, but bas been authorized for emergency use by FDAunder an EU A,forthe trea1ment of mild-to-moderate COVH)-19 in adults who are at high-risk for progression to severe COVID-19, in.eluding hospitaliza1ioo or death, and for whom alternative CO\711). 19treafment options authorized by FDA are.not11ccessible or clinically appropriate; and • The emergencyuseofmolnupitavirisoruy authorizedforthe dura1ion ofthe declaration that circums1ances existjustifying the authorization ofthe emergencyuse of dru~ and biological products duringthe COVID-19 pandemicunderSeciion564(b)(l)oftheAct, 21 U.S.C. §360bbb-3(bX1), unless the declaration is tenninated or authorization revoked sooner. Jkt 256001 PO 00000 Frm 00127 Fmt 4703 Sfmt 4725 E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.041</GPH> lotter on DSK11XQN23PROD with NOTICES1 BB. All descriptive printed matter, advertising, andpromotional material, relatingtothe use.ofmohrupiravirunder.this authorizationclearly and conspicuously shall state that 6610 Federal Register / Vol. 87, No. 24 / Friday, February 4, 2022 / Notices 'Ibis Et)A will:be~ffec:tive Ufitilthe 1.lec}$.tation, that circu~es existjustifyingthe authorization•ofthe emergencyuseofd~andbiolo:gicalproduclsduringtheCOV:IDsl9 plWdemicmtemrinated undcetSectio:tt 564(b}(2) ofthe Act or the EUA is revoked under Stction 564(g).oftheAa. Jacqueline A O'Shaµghnessy, J>li;D; i\c~gCnief ~ci¢ritist Dated: January 28, 2022. Lauren K. Roth, Associate Commissioner for Policy. [FR Doc. 2022–02359 Filed 2–3–22; 8:45 am] BILLING CODE 4164–01–C DEPARTMENT OF HEALTH AND HUMAN SERVICES Health Resources and Services Administration Agency Information Collection Activities: Submission to OMB for Review and Approval; Public Comment Request; The Stem Cell Therapeutic Outcomes Database, OMB No. 0915– 0310—Extension Health Resources and Services Administration (HRSA), Department of Health and Human Services. ACTION: Notice. AGENCY: In compliance with of the Paperwork Reduction Act of 1995, HRSA has submitted an Information Collection Request (ICR) to the Office of Management and Budget (OMB) for review and approval. Comments submitted during the first public review of this ICR will be provided to OMB. OMB will accept further comments from the public during the review and approval period. OMB may act on HRSA’s ICR only after the 30 day comment period for this Notice has closed. DATES: Comments on this ICR should be received no later than March 7, 2022. ADDRESSES: Written comments and recommendations for the proposed information collection should be sent within 30 days of publication of this notice to www.reginfo.gov/public/do/ lotter on DSK11XQN23PROD with NOTICES1 SUMMARY: VerDate Sep<11>2014 18:50 Feb 03, 2022 Jkt 256001 PRAMain. Find this particular information collection by selecting ‘‘Currently under Review—Open for Public Comments’’ or by using the search function. FOR FURTHER INFORMATION CONTACT: To request a copy of the clearance requests submitted to OMB for review, email Samantha Miller, the acting HRSA Information Collection Clearance Officer at paperwork@hrsa.gov or call (301) 443–9094. SUPPLEMENTARY INFORMATION: Information Collection Request Title: The Stem Cell Therapeutic Outcomes Database OMB No. 0915–0310— Extension. Abstract: Given the rapid evolution of COVID–19 and its impact on those with compromised immune systems, it is imperative for the transplant community to continue collecting COVID–19 related data. Having access to COVID–19 vaccination status on blood stem cell recipients and understanding immune responses will assist with making informed decisions regarding direct clinical care. This will also inform critical policy decisions. The Stem Cell Therapeutic and Research Act of 2005, Public Law (Pub. L.) 109–129, as amended, provides for the collection and maintenance of human blood stem cells for the treatment of patients and research. It also maintains a scientific database of information relating to patients who have been recipients of a stem cell therapeutics product (e.g., bone marrow, cord blood, or other such product) from a donor. Given the rapid evolution of the COVID–19 public health emergency and its impact on immunocompromised patients, availability of new vaccines, PO 00000 Frm 00128 Fmt 4703 Sfmt 4703 and continual changes in vaccination recommendations, HRSA wants to leverage the required data collection platform of the Stem Cell Therapeutic Outcomes Database to obtain vaccine information for all US allogeneic hematopoietic stem cell transplant recipients. A 60-day notice published in the Federal Register, 86 FR 67478 (November 26, 2021). There were no public comments. Need and Proposed Use of the Information: To collect COVID–19 vaccine data, HRSA is requesting an extension of OMB’s approval of both the Pre-Transplant Essential Data (Pre-TED) Form 2400 and Post-Transplant Essential Data (Post-TED) Form 2450. Collecting these data will help clinicians and policymakers to understand the landscape of vaccination among immunocompromised patients before and after a blood stem cell transplant. This information will be used to analyze outcomes based on vaccine manufacturer/type, doses received (including potential boosters), timing, and inform future vaccination strategies. Information currently collected regarding COVID–19 infections has already been used in research studies. Data collected prior to a patient receiving a blood stem cell transplant will be used to characterize frequencies of vaccination, and the level of protection afforded during and after transplant based on the incidence of COVID infection. Post-transplant, this information can be used to assess vaccination rates and timing in blood stem cell recipients, characterize emerging vaccination strategies (which may include ‘‘boosters’’), describe possible short and long-term side effects E:\FR\FM\04FEN1.SGM 04FEN1 EN04FE22.042</GPH> Food.and Drug.Administration

Agencies

[Federal Register Volume 87, Number 24 (Friday, February 4, 2022)]
[Notices]
[Pages 6578-6610]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-02359]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2021-N-0335]


Authorizations of Emergency Use of Certain Drugs and Biological 
Products During the COVID-19 Pandemic; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
issuance of three Emergency Use Authorizations (EUAs) (the 
Authorizations) under the Federal Food, Drug, and Cosmetic Act (FD&C 
Act), for use during the COVID-19 pandemic. FDA has issued one 
Authorization for a biological product as requested by AstraZeneca 
Pharmaceuticals LP (AZ), one Authorization for a drug product as 
requested by Pfizer, Inc. (Pfizer), and one Authorization for a drug 
product as requested by Merck Sharp & Dohme Corp. (Merck). The 
Authorizations contain, among other things, conditions on the emergency 
use of the authorized products. The Authorizations follow the February 
4, 2020, determination by the Secretary of Health and Human Services 
(HHS) that there is a public health emergency that has a significant 
potential to affect national security or the health and security of 
U.S. citizens living abroad and that involves a novel (new) 
coronavirus. The virus, now named SARS-CoV-2, causes the illness COVID-
19. On the basis of such determination, the Secretary of HHS declared 
on March 27, 2020, that circumstances exist justifying the 
authorization of emergency use of drugs and biological products during 
the COVID-19 pandemic, pursuant to the FD&C Act, subject to the terms 
of any authorization issued under that section. The Authorizations, 
which include an explanation of the reasons for issuance, are reprinted 
in this document.

DATES: The Authorization for AZ is effective as of December 8, 2021, 
the Authorization for Pfizer is effective as of December 22, 2021, and 
the Authorization for Merck is effective as of December 23, 2021.

ADDRESSES: Submit written requests for single copies of the EUAs to the 
Office of Counterterrorism and Emerging Threats, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 1, Rm. 4338, Silver 
Spring, MD 20993-0002. Send one self-addressed adhesive label to assist 
that office in processing your request or include a fax number to which 
the Authorizations may be sent. See the SUPPLEMENTARY INFORMATION 
section for electronic access to the Authorizations.

FOR FURTHER INFORMATION CONTACT: Michael Mair, Office of 
Counterterrorism and Emerging Threats, Food and Drug Administration, 
10903 New Hampshire Ave., Bldg. 1, Rm. 4340, Silver Spring, MD 20993-
0002, 301-796-8510 (this is not a toll free number).

SUPPLEMENTARY INFORMATION:

I. Background

    Section 564 of the FD&C Act (21 U.S.C. 360bbb-3) allows FDA to 
strengthen public health protections against biological, chemical, 
nuclear, and radiological agents. Among other things, section 564 of 
the FD&C Act allows FDA to authorize the use of an unapproved medical 
product or an unapproved use of an approved medical product in certain 
situations. With this EUA authority, FDA can help ensure that medical 
countermeasures may be used in emergencies to diagnose, treat, or 
prevent serious or life-threatening diseases or conditions caused by 
biological, chemical, nuclear, or radiological agents when there are no 
adequate, approved, and available alternatives (among other criteria).

II. Criteria for EUA Authorization

    Section 564(b)(1) of the FD&C Act provides that, before an EUA may 
be issued, the Secretary of HHS must declare that circumstances exist 
justifying the authorization based on one of the following grounds: (1) 
A determination by the Secretary of Homeland Security that there is a 
domestic emergency, or a significant potential for a domestic 
emergency, involving a heightened risk of attack with a biological, 
chemical, radiological, or nuclear agent or agents; (2) a

[[Page 6579]]

determination by the Secretary of Defense that there is a military 
emergency, or a significant potential for a military emergency, 
involving a heightened risk to U.S. military forces, including 
personnel operating under the authority of title 10 or title 50, U.S. 
Code, of attack with (A) a biological, chemical, radiological, or 
nuclear agent or agents; or (B) an agent or agents that may cause, or 
are otherwise associated with, an imminently life-threatening and 
specific risk to U.S. military forces; \1\ (3) a determination by the 
Secretary of HHS that there is a public health emergency, or a 
significant potential for a public health emergency, that affects, or 
has a significant potential to affect, national security or the health 
and security of U.S. citizens living abroad, and that involves a 
biological, chemical, radiological, or nuclear agent or agents, or a 
disease or condition that may be attributable to such agent or agents; 
or (4) the identification of a material threat by the Secretary of 
Homeland Security pursuant to section 319F-2 of the Public Health 
Service (PHS) Act (42 U.S.C. 247d-6b) sufficient to affect national 
security or the health and security of U.S. citizens living abroad.
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    \1\ In the case of a determination by the Secretary of Defense, 
the Secretary of HHS shall determine within 45 calendar days of such 
determination, whether to make a declaration under section 564(b)(1) 
of the FD&C Act, and, if appropriate, shall promptly make such a 
declaration.
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    Once the Secretary of HHS has declared that circumstances exist 
justifying an authorization under section 564 of the FD&C Act, FDA may 
authorize the emergency use of a drug, device, or biological product if 
the Agency concludes that the statutory criteria are satisfied. Under 
section 564(h)(1) of the FD&C Act, FDA is required to publish in the 
Federal Register a notice of each authorization, and each termination 
or revocation of an authorization, and an explanation of the reasons 
for the action. Under section 564(h)(1) of the FD&C Act, revisions to 
an authorization shall be made available on the internet website of 
FDA. Section 564 of the FD&C Act permits FDA to authorize the 
introduction into interstate commerce of a drug, device, or biological 
product intended for use in an actual or potential emergency when the 
Secretary of HHS has declared that circumstances exist justifying the 
authorization of emergency use. Products appropriate for emergency use 
may include products and uses that are not approved, cleared, or 
licensed under sections 505, 510(k), 512, or 515 of the FD&C Act (21 
U.S.C. 355, 360(k), 360b, and 360e) or section 351 of the PHS Act (42 
U.S.C. 262), or conditionally approved under section 571 of the FD&C 
Act (21 U.S.C. 360ccc). FDA may issue an EUA only if, after 
consultation with the HHS Assistant Secretary for Preparedness and 
Response, the Director of the National Institutes of Health, and the 
Director of the Centers for Disease Control and Prevention (to the 
extent feasible and appropriate given the applicable circumstances), 
FDA \2\ concludes: (1) That an agent referred to in a declaration of 
emergency or threat can cause a serious or life-threatening disease or 
condition; (2) that, based on the totality of scientific evidence 
available to FDA, including data from adequate and well-controlled 
clinical trials, if available, it is reasonable to believe that: (A) 
The product may be effective in diagnosing, treating, or preventing (i) 
such disease or condition; or (ii) a serious or life-threatening 
disease or condition caused by a product authorized under section 564, 
approved or cleared under the FD&C Act, or licensed under section 351 
of the PHS Act, for diagnosing, treating, or preventing such a disease 
or condition caused by such an agent; and (B) the known and potential 
benefits of the product, when used to diagnose, prevent, or treat such 
disease or condition, outweigh the known and potential risks of the 
product, taking into consideration the material threat posed by the 
agent or agents identified in a declaration under section 564(b)(1)(D) 
of the FD&C Act, if applicable; (3) that there is no adequate, 
approved, and available alternative to the product for diagnosing, 
preventing, or treating such disease or condition; (4) in the case of a 
determination described in section 564(b)(1)(B)(ii) of the FD&C Act, 
that the request for emergency use is made by the Secretary of Defense; 
and (5) that such other criteria as may be prescribed by regulation are 
satisfied.
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    \2\ The Secretary of HHS has delegated the authority to issue an 
EUA under section 564 of the FD&C Act to the Commissioner of Food 
and Drugs.
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    No other criteria for issuance have been prescribed by regulation 
under section 564(c)(4) of the FD&C Act.

III. The Authorizations

    The Authorizations follow the February 4, 2020, determination by 
the Secretary of HHS that there is a public health emergency that has a 
significant potential to affect national security or the health and 
security of U.S. citizens living abroad and that involves a novel (new) 
coronavirus. The virus, now named SARS-CoV-2, causes the illness COVID-
19. Notice of the Secretary's determination was provided in the Federal 
Register on February 7, 2020 (85 FR 7316). On the basis of such 
determination, the Secretary of HHS declared on March 27, 2020, that 
circumstances exist justifying the authorization of emergency use of 
drugs and biological products during the COVID-19 pandemic, pursuant to 
section 564 of the FD&C Act, subject to the terms of any authorization 
issued under that section. Notice of the Secretary's declaration was 
provided in the Federal Register on April 1, 2020 (85 FR 18250). Having 
concluded that the criteria for issuance of the Authorizations under 
section 564(c) of the FD&C Act are met, FDA has issued three 
authorizations for the emergency use of drugs and biological products 
during the COVID-19 pandemic. On December 8, 2021, FDA issued an EUA to 
AZ for the biological product EVUSHELD (tixagevimab co-packaged with 
cilgavimab), subject to the terms of the Authorization. On December 22, 
2021, FDA issued an EUA to Pfizer for the drug PAXLOVID (nirmatrelvir 
co-packaged with ritonavir), subject to the terms of the Authorization. 
On December 23, 2021, FDA issued an EUA to Merck for the drug 
molnupiravir, subject to the terms of the Authorization. The initial 
Authorizations, which are included below in their entirety after 
section IV of this document (not including the authorized versions of 
the fact sheets and other written materials), provide an explanation of 
the reasons for issuance, as required by section 564(h)(1) of the FD&C 
Act. Any subsequent reissuances of these Authorizations can be found on 
FDA's web page at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization.

IV. Electronic Access

    An electronic version of this document and the full text of the 
Authorizations and are available on the internet at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization.
BILLING CODE 4164-01-P

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    Dated: January 28, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-02359 Filed 2-3-22; 8:45 am]
BILLING CODE 4164-01-C

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