[ACTUALIZADO] INVESTIGATIONAL COVID-19 CONVALESCENT PLASMA – EMERGENCY INVESTIGATIONAL NEW DRUG by Puerto Rico Medical Task Force Covid-19

INVESTIGATIONAL COVID-19 CONVALESCENT PLASMA – EMERGENCY INVESTIGATIONAL NEW DRUG Date April 7, 2020 BACKGROUND: At this moment, we are facing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) or COVID-19 pandemic without a proven effective treatment option. Several antivirals are under investigation, as well as other anti-malarial and antibiotic combinations without conclusive data. The use of convalescent plasma has been proposed as a treatment option in other viral outbreaks such as SARS-CoV, H5N1 avian influenza, Ebola Virus, and H1N1. In a small report of patients with COVID-19 the use of convalescent plasma was associated with improved clinical outcomes. The rationale for its use is that the plasma recovered from patients who have recovered from the disease contains antibodies against the virus that could be effective to fight the infection. Since only limited data exits at this moment regarding the effectiveness of this therapy, it cannot be routinely recommended or use as a proven treatment option. The Food and Drug Administration (FDA) has provided several pathways to administer or study the use of convalescent plasma in COVID-19 patients: • Clinical Trials: Investigators wishing to study the use of convalescent plasma need to submit a request to FDA for investigational use under the traditional IND regulatory pathway (21 CFR 312). • Expanded Access: FDA is working with multiple federal partners and academia to open an expanded access protocol to facilitate access to COVID-19 convalescent plasma. For patients with, or at risk of, severe or life-threatening COVID-19 disease who are not eligible or who are unable to participate in randomized clinical trials, access may be available through participation of acute care facilities in an investigational expanded access protocol under an IND already in place. • Single Patient Emergency IND: For patents who are not able to participate in a clinical trial or in an expanded access program, given the public health emergency FDA also is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of the patient’s physician requesting a single patient emergency Investigational New Drug Application (eINDs) for the individual patient under 21 CFR 312.310. This process allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization. This eIND process is not for the use of COVID-19 convalescent plasma for the prevention of infection. We understand that given the circumstances and the design of the healthcare system in Puerto Rico, the best pathway to follow to benefit more patients who could qualify for the use of convalescent plasma, is through the request of a of Single Patient Emergency IND.

WHO CAN DONATE CONVALESCENT PLASMA? According to the FDA, COVID-19 convalescent plasma must only be collected from recovered individuals if they are eligible to donate blood according to federal regulations. Potential donors must have: •

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Evidence of COVID-19 documented by a laboratory test either by: • A diagnostic test (e.g., nasopharyngeal swab) at the time of illness, OR • A positive serological test for SARS-CoV-2 antibodies after recovery, if prior diagnostic testing was not performed at the time COVID-19 was suspected. Either one of the following: • Complete resolution of symptoms at least 28 days prior to donation • Complete resolution of symptoms at least 14 days prior to donation, AND • Negative results for COVID-19 either from one or more nasopharyngeal swab specimens or by a molecular diagnostic test from blood. Male donors, female donors who have not been pregnant or female donors who have been tested since their most recent pregnancy and results interpreted as negative for HLA antibodies. Defined SARS-CoV-2 neutralizing antibody titers (e.g., greater than 1:80) • If neutralizing antibody titers cannot be obtained in advance, consider storing a retention sample from the convalescent plasma donation for determining antibody titers at a later date.

The FDA will not provide the convalescent plasma, thus the strategy of collecting plasma from recovered patients should be done through local Blood Banks (i.e. Banco de Sangre de ASEM, Servicios Mutuos, Cruz Roja de Puerto Rico) To our knowledge, Banco de Sangre de ASEM at the Medical Center is already in the process of establishing their institutional protocol with the guidance of the FDA in order to collect COVID-19 convalescent plasma. WHICH PATIENTS ARE ELIGIBLE TO RECEIVE COVID-19 CONVALESCENT PLASMA? • Laboratory confirmed COVID-19 • Severe or immediately life-threatening COVID-19, for example:1 • Severe disease is defined as: ✓ dyspnea, ✓ respiratory frequency ≥ 30/min, ✓ blood oxygen saturation ≤ 93%, ✓ partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300, and/or ✓ lung infiltrates > 50% within 24 to 48 hours • Life-threatening disease is defined as: ✓ respiratory failure, ✓ septic shock, and/or ✓ multiple organ dysfunction or failure • Provide informed consent

HOW TO OBTAIN AUTHORIZATION FOR USE OF COVID-19 CONVALESCENT PLASMA TO TREAT PATIENTS USING AN EMERGENCY IND? • For requests that are not highly time sensitive (response from FDA provided within 4 to 8 hours), the requesting physician may contact FDA by completing form 3926 (https://www.fda.gov/media/98616/download) (SEE APENDIX FOR THE COPY OF THE DOCUMENT) and submitting the form by email to CBER_eIND_Covid-19@FDA.HHS.gov. • In the event of an emergency that is highly time sensitive (response required in less than 4 hours) or where the provider is unable to complete and submit form 3926 due to extenuating circumstances, the provider may contact FDA’s Office of Emergency Operations at 1-866-3004374 to seek verbal authorization. o If verbal authorization is given, the requestor must agree to submit an expanded access application (e.g., form 3926) within 15 working days of FDA's authorization of the use. DOSING AND ADMINISTRATION OF COVID-19 CONVALESCENT PLASMA • Plasma handling, storage and accountability should follow local institutional guidelines for conventional plasma including ABO compatibility checks and thawing. • The volume of plasma to be transfused will be one full unit ABO compatible COVID-19 convalescent plasma, or at least 200 ml of plasma, based on the initial available data available that was used in similar patients and showed potential clinical benefit. • Plasma should be provided by a registered or licensed blood bank after obtaining informed consent. • IND number and the medical order. Medical order should include the IND number provided by the FDA. • The container label of COVID-19 convalescent plasma units must include the following statement, “Caution: New Drug--Limited by Federal (or United States) law to investigational use." (21 CFR 312.6 (a). • Individual institutional guidelines for the administration of plasma should be followed, including the use of any pre-medications, such as acetaminophen and diphenhydramine or steroids. The duration of infusion will usually take 1 to 2 hours (rate of 100 to 250 mL/hr). Provided by Dr. Noridza Rivera, Hematology Oncology Division Chair (Task Force Collaborator).

References 1. Duan K, Liu B, Cesheng Li et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. PNAS Latest Articles; March 2020. 2. Roback JD, Guarner J, Convalescent Plasma to Treat COVID-19: Possibilities and Challenges., JAMA. 2020 Mar 27. 3. Ko JH, Seok H, Cho SY, Ha YE, Baek JY, Kim SH, Kim YJ, Park JK, Chung CR, Kang ES, Cho D, Müller MA, Drosten C, Kang CI, Chung DR, Song JH, Peck KR, Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience., Antivir Ther. 2018;23(7):617- 622. 4.https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-deviceexemptionide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds

Relevo de responsabilidad: Este protocolo está basado en la información que se conoce a la fecha de su redacción. El mismo podrá sufrir modificaciones de acuerdo a la evolución de la pandemia y a nueva información que se vaya adquiriendo.

Consentimiento para Administración de Plasma Convaleciente en Pacientes con Enfermedad Severa por COVID-19 Nombre Paciente: ____________________________________

MR: ________________________

Fecha: __________________

ACLARACION: Si usted es un familiar o representante legalmente autorizado a firmar este documento a nombre de otra persona, tome nota que la palabra “usted” en este documento se refiere al paciente. Por favor lea atentamente este documento. Contiene información importante sobre el uso experimental de un tratamiento que su médico ha entendido podría resultar de beneficio para usted. Su médico podrá contestar cualquier duda o pregunta antes de firmar este documento. ¿Que es el plasma convaleciente? El plasma convaleciente es la parte líquida de la sangre que se recoge de los pacientes que se han recuperado de la nueva enfermedad del coronavirus, COVID-19, causada por el virus SARS-CoV-2. Los pacientes con el COVID-19 desarrollan anticuerpos en la sangre contra el virus. Los anticuerpos son proteínas que pueden ayudar a combatir la infección. ¿El plasma convaleciente, me podría ayudar? Se está investigando el plasma convaleciente para el tratamiento del COVID-19 porque no existe un tratamiento aprobado para esta enfermedad y hay cierta información que sugiere que podría ayudar a algunos pacientes a recuperarse del COVID-19. Todavía se necesitan hacer más investigaciones para determinar si el plasma convaleciente podría acortar la duración de la enfermedad, reducir la morbilidad o prevenir la muerte asociada con el COVID-19. ¿Cual es el procedimiento? La FDA ha regulado el uso del plasma convaleciente como un tratamiento bajo investigación y ha facilitado el acceso de este. Su médico solicitará una autorización de emergencia (denominada eIND), lo cual permitirá utilizar el plasma convaleciente en usted. Se le administrará una unidad de plasma de una persona que se recuperó de COVID-19. El plasma será compatible con su tipo de sangre. La administración del plasma se realiza por vena y recibirá un volumen aproximado de 200ml en 1 a 2 horas. ¿Cuales son los posibles riesgos o complicaciones? Las reacciones a la administración del plasma pueden ser similares a las de una transfusión de algún componente sanguíneo como sangre, o plaquetas. Algunas de estos incluyen las reacciones febriles, reacciones alérgicas, reacciones, hemolíticas, sobrecarga de volumen, y transmisión de enfermedades infecciosas. Esta ultima, aunque posible, es de baja probabilidad, debido al cernimiento estricto para evitar este tipo de complicaciones según los protocolos actuales de colección de productos sanguíneos de los bancos de sangre. Su médico determinará si debería recibir algún tipo de premedicacion para la prevención o el manejo de reacciones alérgicas. _________________________________________________________________________________________________ Al firmar este documento usted: 1. Certifica haber entendido los beneficios y los posibles riesgos del uso de plasma convaleciente 2. Autoriza la administración de este tratamiento experimental. 3. Certifica haber preguntado y aclarado con el personal médico cualquier duda o inquietud acerca del tratamiento antes explicado en este documento. Nombre del paciente en letra de molde: ______________________________________________________ Nombre Familiar o Representante Autorizado que Firma: __________________________________________ Firma (paciente o representante autorizado): _________________________________ Fecha : ____________Hora:________ Personal Médico que obtiene el consentimiento

Certifico que discutí el documento a cabalidad con el paciente y/o familiar o su representante autorizado Nombre del médico letra de molde: _______________________________________ Firma: _________________________________ Núm. Lic.: __________________ Fecha: ____________ Hora:________

PUERTO RICO MEDICAL SERVICES ADMINISTRATION Blood Bank/Transfusion Service P.O. Box 2129 San Juan, PR 00922-2129 Tel. (787) 777-3535 Ext. 6504, 6505, 6550, 6530 Effective Date: April 2020 Doc. Number: 1532

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Introduction One investigational treatment being explored for COVID-19 is the use of convalescent plasma collected from individuals who have recovered from COVID-19. It is possible that convalescent plasma that contains antibodies to SARS-CoV-2 (the virus that causes COVID-19) might be effective against the infection. Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV1 epidemic, and the 2012 MERS-CoV epidemic. Although the indications are very preliminary at this stage, it appears that COVID-19 convalescent plasma (CCP) may be safe and may have the potential to reduce the duration and severity of COVID-19. Convalescent plasma treatment works because plasma collected from individuals who have already recovered from COVID-19, contains antibodies that could provide passive immunity, which may help patients fight the infection. Further investigation is still necessary to determine if convalescent plasma will shorten the duration of illness, reduce morbidity, or prevent death associated with COVID-19. If this treatment is effective, a hyperimmune globulin pharmaceutical product will be the preferred delivery device for these antibodies. However, it could take several months to manufacture and produce this product. CCP will provide the bridge to future treatment with hyperimmune globulin. Given the public health emergency that the expanding COVID-19 outbreak presents, while clinical trials are being conducted and an expanded access protocol is available, FDA is facilitating access to CCP for use in patients with serious or immediately life-threatening COVID-19 infections through the process of the patientâ&#x20AC;&#x2122;s physician requesting a single patient emergency Investigational New Drug Application (eINDs) for the individual patient under 21 CFR 312.310. Objectives The objectives of this procedure is to provide plasma from COVID-19 convalescent donors that meets the minimum safety and quality criteria and ensure the safety of the donor, the safety of the personnel collecting and processing the component and the safety and quality of the product. This protocol is expected to change as FDA releases new information in response to the evolving pandemic.

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Donor Recruitment The ASEM Emergency Room, University Hospital, Municipal Hospital and other Health Care providers will partner with the ASEM Blood Bank to recruit as volunteer CCP donors to the recovered pCOVID-19 patients. The message CCP donation will be given by treating physicians or public health employees that will contact the patients already discharged from care or newly recovered patients as they are discharged from care. It is important to provide recovered patients of a hard copy documentation of bothhh the initial patientâ&#x20AC;&#x2122;s positive diagnostic test AND a negative test for SARS-CoV-2 at the time of recovery. This documentation must be provided to the ASEM Blood Bank. The local media also will be asked to deliver public service announcements requesting recovered COVID-19 patients to contact ASEM Blood Bank to discuss the requirements of donation and to make an appointment. Donor Eligibility Criteria and Documentation Documentation of SARS-CoV-2 infection (diagnosis) o Diagnostic test (nasopharyngeal swab) at the time of illness o Written documentation may be hand carried by the potential donor 2. Documentation of SARS-CoV-2 infection (recovery) o Complete resolution of symptoms at least 14 days prior to donation and negative results for COVID-19 from a nasopharyngeal swab specimen or by a molecular diagnostic test from blood. o Complete resolution of symptoms at least 28 days prior to donation and negative results for COVID-19 from a nasopharyngeal swab specimen or by a molecular diagnostic test from blood, if the patient has been hospitalized. 3. Age of donor: between 21 to 60 years. 4. Donor recovery from COVID-19 prior to donation based on testing and resolution of symptoms is necessary for: o The safety of other donors and staff o As evidence that the potential donor is healthy and well on the day of donation, as required by donor eligibility criteria. 1.

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Follow the protocol of the Blood Bank for all donors (temperature at arrival, face mask, hand sanitizer) when the donor arrives to the Blood Bank COVID-19 convalescent plasma must only be collected from recovered individuals if they are eligible to donate blood (SOP# 1503) Required testing must be performed and the donation must be found suitable. Donors must be males or female donors who have not been pregnant or female donors who have been tested since their most recent pregnancy and results interpreted as negative for HLA antibodies. Defined SARS-CoV-2 neutralizing antibody titers (greater than 1:160). A titer of 1:80 may be considered acceptable if no alternative is available. o Since, now, neutralizing antibody titers cannot be obtained in advance, a retention sample from the convalescent plasma donation will be stored for determining antibody titers later. The frequency of donation will be 28 days. If more frequent, the medical director approval is needed. o If collections are more frequent than 28 days, a total protein test and immunoglobulin quantification will be performed every 30 days. The donation will be performed by appointment o

CCP Collection 1. Prior to collection, donor consent will be obtained 2. CCP will be collected by apheresis and labeled as FFF or PF24h. No other collection types are permitted during the CCP during CCP collection. 3. The maximum volume to collect is 10% of donor volume, as average 400 ml and the maximum amount to be collected is 600 ml during each collection. 4. As anticoagulant ACD will be used. 5. Follow the safety precautions established by the ASEM Blood Bank, using PPE (mask, gloves, gown). 6. The current policies for retrieval and quarantine will be followed. CCP Processing and Labeling 1. The plasma will be prepared in units of approximately 200 ml and frozen at -18ยบC, following the current SOP for processing of FFP and PF24h.

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2. CCP is an allogenic collection for which all FDA regulations apply, including testing, processing, storage and traceability. 3. The container label of COVID-19 convalescent plasma units must include the following statement, “Caution: New Drug--Limited by Federal (or United States) law to investigational use." (21 CFR 312.6 (a) CCP Storage 1. The frozen units will be stored in the Transfusion Service, separated from other units of FFP for transfusion 2. The shelf life of the units stored at -18ºC is one year 3. When thawed, the shelf life is 24 hours stored at 1-6ºC 4. For requesting CCP Request 1. Before order a unit of CCP, a red top blood tube should be sent to the Transfusion Service for ABO grouping (if no ABO is available from the patient) 2. The request for a thawed unit of CCP will be in advance by phone providing the eIND number (call to Transfusion Service 6530/6340).. 3. To issue the unit a copy of the medical order, with the name of the attending physician, transfusion criteria and the eIND will be provided. CCP Recordkeeping Record will be maintained at the Transfusion Service for each CCP units administered to the COVID-19 patients. Record will include the ISBT donation number of the unit and the order from. How to obtain authorization for use of COVID-19 convalescent plasma 1. To facilitate requests for emergency INDs for use of COVID-19 convalescent plasma to treat patients, the eligibility criteria used for the National Expanded Access Treatment Protocol could be considered. These criteria include: • •

Laboratory confirmed COVID-19 Severe or immediately life-threatening COVID-19, for example:1

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Severe disease is defined as: § dyspnea, § respiratory frequency ≥ 30/min, § blood oxygen saturation ≤ 93%, § partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300, and/or § lung infiltrates > 50% within 24 to 48 hours o Life-threatening disease is defined as: § respiratory failure, § septic shock, and/or § multiple organ dysfunction or failure Provide informed consent o

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2. How to obtain authorization for use of COVID-19 convalescent plasma to treat patients using an emergency IND •

For requests that are not highly time sensitive (response from FDA provided within 4 to 8 hours), the requesting physician may contact FDA by completing form 3926 (https://www.fda.gov/media/98616/download) and submitting the form by email to CBER_eIND_Covid-19@FDA.HHS.gov. o If you have problems opening the PDF form in your browser, try downloading it instead: 1. Right-click the form link. 2. Click the Save option. (On most browsers, this is the Save Link As option.) You may also need to upgrade your version of Adobe ReaderExternal Link Disclaimer. o The completed form should include a brief clinical history of the patient, including: diagnosis, current therapy, and rationale for requesting the proposed investigational treatment in order to meet the expanded access use requirements of 21 CFR 312.305 and 312.310. o The form should include information regarding where the COVID-19 convalescent plasma will be obtained (Banco de Sangre ASEM, ca. 22 Bo. Monacillos, Rio Piedras, PR 00935). o Providers should complete the form to the extent possible, and FDA will work with the provider if additional information is required.

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FDA will review the request and, upon approval, FDA will send the requesting physician a confirmatory email that includes the emergency IND number. In the event of an emergency that is highly time sensitive (response required in less than 4 hours) or where the provider is unable to complete and submit form 3926 due to extenuating circumstances, the provider may contact FDA’s Office of Emergency Operations at 1-866-300-4374 to seek verbal authorization. o If verbal authorization is given, the requestor must agree to submit an expanded access application (e.g., form 3926) within 15 working days of FDA's authorization of the use. o

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References 1. FDA Investigational COVID-19 Convalescent Plasma - Emergency INDs April 3, 2020

2. Roback JD: Convalescent Plasma to Treat COVID-19. Possibilities and Challenges. JAMA March 27, 2020 3. Comité Científico para la Seguridad Transfusional . Ministerio de Sanidad España: Recomendaciones para la obtención de plasma de donantes convalecientes de COVID-19. 26 de marzo 2020. 4. Wu Z, McGoogan JM. Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. Published online February 24, 2020. doi:10.1001/jama.2020.2648 5. AABB: COVID-19 Convalescent Plasma Collection. April 4, 2020 6. FDA Investigational COVID-19 Convalescent Plasma - Emergency INDs April 8, 2020

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SOP HISTORICAL RECORD DATE

WRITTEN

REVIEWED

APPROVED

NEXT REVIEW

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Removed

SOP CONTENT REVISION REVISION DATE

REVISION DESCRIPTION

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SOP READING RECORD I have read the above procedure and understand its contents. I have been trained on this procedure and accept responsibility for its correct performance.

Staff Member

Initials

Date

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PLASMA DE PACIENTES CONVALECIENTES DE COVID-19 Que es el plasma convaleciente? Es la parte liquida de la sangre que se colecta de un paciente que se ha recuperado de una infeccion Los anticuerpos presentes en el plasma convaleciente son proteinas que pueden ayudar a combatir una infeccion Por que se estรก investigando el plasma convaleciente para tratar el COVID-19? Porque al momento no hay un tratamiento aprobado para esta enfermedad y hay informacion que sugiere que puede ayudar a algunos pacientes a recuperarse de COVID-19 Se necesitan investigaciones adicionales para determinar si el pasma convaleciente puede acortar la duracion de la enfermedad, reducir la severidad y prevenir la muestre asociada a COVID-19 Quien puede donar plasma convaleciente de COVID-19? El plasma convaleciente de COVID-19 solo se obtiene de personas que se hayan recobrado de la enfermedad y sean elegibles para donar sangre. La persona tiene que tener un diagnostico de COVID-19 documentado por una prueba de laboratorio La persona tiene que estar sin sintomas de COVID-19 por lo menos 14 dias antes de la donacion y tener una prueba de COVID-19 negativa Si esta interesado en donar puede llamar al 787-777-3844 para orientaciรณn y darle una cita.

Horario de servicio: lunes a domingo de 8:00am a 2:00pm Tel. 787-777-3844

COVID-19 CONVALESCENT PLASMA PHYSICIAN’S ORDER FORM DATE: ____________________.

TIME: _________________

HOSPITAL INFORMATION

PATIENT INFORMATION

INSTITUTION'S NAME :

NAME:

ADDRESS:

DOB:

TELEPHONE:

MR NUMBER:

CONTACT NAME:

ALLERGIES:

PHYSICIIAN'S NAME:

THE USE OF CONVALESCENT PLASMA IS RESTRICTED FOR PATIENTS WITH SEVERE OR LIFE TREATHENING DISEASE. PLEASE REVIEW THAT THE PATIENT MEETS THE FOLLOWING CRITERIA IN BOLD: Laboratory confirmed COVID-19 Signed Informed consent for COVID-19 Convalescent plasma use And One the following Severe disease defined as: o o o o o

Dyspnea Respiratory frequency ≥ 30/min Blood oxygen saturation ≤ 93% Partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300, and /or Lung infiltrates > 50% within 24 to 48 hours

Life threatening disease define as: o Respiratory failure o Septic shock, and/or • o Multiple organ dysfunction ____________________________________________________________________________________

REQUEST FOR 1 UNIT (200mL) of ABO Compatible COVID-19 Convalescent Plasma FDA eIND authorization number: _________________________________________________________

Physicians Name*:________________________________ Signature*:____________________________

License Num: _________________ NPI: _____________________ Date/Time : ____________________ *In academic institution, the orders should only be made by attending physicians. Orders from interns, residents or fellows will not be accepted.