Source FDA

Yesterday 08/23/2020 FDA has issued guidance to provide recommendations to health care providers and investigators on the administration and study of investigational convalescent plasma collected from individuals who have recovered from COVID-19 (COVID-19 convalescent plasma) during the public health emergency.

The guidance provides recommendations on the following:

• pathways for use of investigational COVID-19 convalescent plasma
• patient eligibility
• collection of COVID-19 convalescent plasma, including donor eligibility and donor qualifications
• labeling, and
• record keeping

In the document FDA clearly specifies that

1. COVID-19 convalescent plasma has not yet been approved for use by FDA and thus
2. is regulated as an investigational product,
3.  although promising, convalescent plasma has not yet been shown to be safe and effective as a treatment for COVID-19.
4. Therefore, it is important to study the safety and efficacy of COVID-19 convalescent plasma in clinical trials. 

A health care provider must participate in one of the pathways described below.  FDA does not collect COVID-19 convalescent plasma or provide COVID-19 convalescent plasma.  Health care providers or acute care facilities should instead obtain COVID-19 convalescent plasma from an FDA-registered blood establishment.

In another document called FACT SHEET FOR HEALTH CARE PROVIDERS the FDA confirms that the information in this Fact Sheet is the minimum information necessary to inform you of the significant known and potential risks and benefits of the emergency use of COVID-19 convalescent plasma.

As the health care provider administering COVID-19 convalescent plasma, you must provide recipients with the Fact Sheet for Patients/Caregivers and must communicate the following information to the recipients:

1. FDA has authorized emergency use of COVID-19 convalescent plasma, which is not an FDA-approved biological product
2. The patient or caregiver has the option to accept or refuse administration of COVID-19 convalescent plasma
3. The significant known and potential risks and benefits of COVID-19 convalescent plasma and the extent to which such risks and benefits are unknown
4. Information on available alternative treatments and the risks and benefits of those alternatives.
5. If providing this information will delay the administration of COVID-19 convalescent plasma to a degree that would endanger the lives of patients, the information must be provided to the patients as soon as practicable after convalescent plasma is administered.
6. For information on clinical trials that are testing the use of COVID-19 convalescent plasma for COVID-19, please see www.clinicaltrials.gov.

In the document the FDA specifies INTENDED USE also:
The EUA for COVID-19 convalescent plasma authorizes the use of COVID-19 convalescent plasma for the treatment of hospitalized patients with COVID-19. This EUA is based on historical evidence using convalescent plasma in prior outbreaks of respiratory viruses, certain preclinical evidence, results from small clinical trials of convalescent plasma conducted during the current outbreak, and data obtained from the ongoing National Expanded Access Treatment Protocol (EAP) sponsored by the Mayo Clinic.
Data suggest that use of COVID-19 convalescent plasma with high antibody titer may be effective in reducing mortality in hospitalized patients with COVID-19.

Health care providers can decide whether to use these units based on an
individualized determination of potential benefit:risk.

FDA will continue to evaluate this authorization based on additional data that become available. Current evidence also suggests that benefit is most likely in patients treated early in the course of the disease.
Given that the clinical evidence supporting this EUA was not obtained from prospective, well-controlled randomized clinical trials (RCTs), additional RCTs are needed.
Convalescent plasma should not be considered a new standard of care for the treatment of patients with COVID-19. Ongoing clinical trials of convalescent plasma should not be amended based on the issuance of the EUA. Providers are encouraged to enroll patients inthose ongoing clinical trials.

Pathways for Use of Investigational COVID-19 Convalescent Plasma

The following pathways are available for administering or studying the use of COVID-19 convalescent plasma:

 1. Clinical Trials

Investigators wishing to study the use of convalescent plasma in a clinical trial should submit requests to FDA for investigational use under the traditional IND regulatory pathway (21 CFR Part 312). CBER’s Office of Blood Research and Review is committed to engaging with sponsors and reviewing such requests expeditiously. During the COVID-19 pandemic, INDs may be submitted via email to CBERDCC_eMailSub@fda.hhs.gov.

2.  Expanded Access

An IND application for expanded access is an alternative for use of COVID-19 convalescent plasma for patients with serious or immediately life-threatening COVID-19 disease who are not eligible or who are unable to participate in randomized clinical trials (21 CFR 312.305). FDA has worked with multiple federal partners and academia to open an expanded access protocol to facilitate access to COVID-19 convalescent plasma across the nation. Access to this investigational product may be available through participation of acute care facilities in an investigational expanded access protocol under an IND that is already in place. 

Currently, the following protocol is in place: National Expanded Access Treatment ProtocolExternal Link Disclaimer

3. Single Patient Emergency IND

Although participation in clinical trials or an expanded access program are ways for patients to obtain access to convalescent plasma, for various reasons these may not be readily available to all patients in potential need. Therefore, given the public health emergency that the COVID-19 pandemic presents, and while clinical trials are being conducted and a national expanded access protocol is available, 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 IND (eIND) 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, if the applicable regulatory criteria are met.  Note, in such case, a licensed physician seeking to administer COVID-19 convalescent plasma to an individual patient must request the eIND (see 21 CFR 312.310(b)).

To Obtain a Single Patient Emergency IND  

The requesting physician may contact FDA by completing Form FDA 3926 (https://www.fda.gov/media/98616/download) and submitting the form by email to CBER_eIND_Covid-19@FDA.HHS.gov.

NOTE: To enable electronic completion of the form, download it from your internet browser, save locally, close and re-open. Do NOT ATTEMPT to fill out this form after opening it from your internet browser; the form will not be fillable until downloaded, saved and opened locally. Check either box 3a or 3b to enable form logic and the appropriate fields. For more detailed instructions see the FDA FORM 3926 Instructions (https://www.fda.gov/media/98627/download).

CBER requests that all forms be filled out electronically to facilitate rapid review. Hand written forms are often hard to read and may delay the processing of the request. Please pay special attention to the following:

• The completed form should include a brief clinical history of the patient, including: age, gender, diagnosis, current therapy, and rationale for requesting the proposed investigational treatment in order to meet the expanded access use requirements in 21 CFR 312.305 and 312.310.
• The form should include the name of the blood establishment collecting the COVID-19 convalescent plasma.
• Providers should complete the form to the extent possible, and FDA will work with the provider if additional information is required.

For requests between 8am ET and 8pm ET (Mon-Sun): FDA will respond within four hours. For requests between 8am ET and 8pm ET when the provider is unable to complete and submit Form FDA 3926 due to extenuating circumstances, the provider may contact FDA’s Office of Emergency Operations at 1-866-300-4374 to be routed to the appropriate clinical review staff for assistance with submitting the request.

For requests that are made overnight between 8pm ET and 8am ET (Mon-Sun):

• In case of a medical emergency, i.e., when authorization and issuance of an emergency IND number is needed before 8 am the next morning, the provider should contact FDA’s Office of Emergency Operations at 1-866-300-4374 to be routed to the appropriate clinical review staff for assistance with submitting the request and issuance of an emergency IND number.
• In case of a non-critical overnight request, the Form FDA 3926 should be submitted by email to CBER_eIND_Covid-19@FDA.HHS.gov for review, and the emergency IND number will be issued by 8 am the next morning.

In situations when the provider is unable to complete and submit Form FDA 3926 due to extenuating circumstances, the requestor must agree to submit an expanded access application (e.g., Form FDA 3926) within 15 working days of FDA’s authorization of the use (21 CFR 312.310(d)(2)). When submitting the expanded access application form the requestor is advised to indicate that the application is a follow-up to a previously granted emergency IND, and to provide the IND number.

Patient Eligibility

To facilitate requests for eINDs for use of COVID-19 convalescent plasma to treat patients, health care providers seeking an emergency IND may want to consider the eligibility criteria used for the National Expanded Access Treatment ProtocolExternal Link Disclaimer. These criteria include:

• Laboratory confirmed COVID-19
• Severe or immediately life-threatening COVID-19, for example,
  • Severe disease is defined as one or more of the following:
    • shortness of breath (dyspnea),
    • respiratory frequency ≥ 30/min,
    • blood oxygen saturation ≤ 93%,
    • partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300,
    • lung infiltrates > 50% within 24 to 48 hours
  • Life-threatening disease is defined as one or more of the following:
    • respiratory failure,
    • septic shock,
    • multiple organ dysfunction or failure
• Informed consent provided by the patient or healthcare proxy.

Collection of COVID-19 Convalescent Plasma

Health care providers or acute care facilities seeking to use COVID-19 convalescent plasma should include information in the IND submission that the COVID-19 convalescent plasma will be obtained from an FDA-registered blood establishment that follows the donor eligibility criteria and donor qualifications described below in collecting plasma from donors.

1. Donor Eligibility
   1. COVID-19 convalescent plasma must only be collected from individuals who meet all donor eligibility requirements (21 CFR 630.10, 21 CFR 630.15). Note the additional donor eligibility requirements for the collection of plasma by plasmapheresis in 21 CFR 630.15 (b). Donation testing for relevant transfusion-transmitted infections must be performed (21 CFR 610.40) and the donation must be found suitable (21 CFR 630.30).
   2. COVID-19 convalescent plasma is collected from individuals who meet the following qualifications:
      1. 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.
      2. Complete resolution of symptoms at least 14 days before the donation. A negative result for COVID-19 by a diagnostic test is not necessary to qualify the donor.
      3. Male donors, 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.
      4. SARS-CoV-2 neutralizing antibody titers, if available
         • When measurement of neutralizing antibody titers is available, we recommend neutralizing antibody titers of at least 1:160. A titer of 1:80 may be considered acceptable if an alternative matched unit is not available.
         • When measurement of neutralizing antibody titers is not available, consider storing a retention sample from the convalescent plasma donation for determining antibody titers at a later date. Although optional for all IND pathways, storing samples for single patient eINDs is not recommended.

Registered and licensed blood establishments that collect plasma intended for transfusion do not need to request a supplement to their license or obtain their own IND to collect and manufacture COVID-19 convalescent plasma for investigational use provided they 1) follow their standard operating procedures for plasma collection and all applicable regulations, and 2) collect plasma from individuals that meet the donor qualifications specified above, which would be included in the applicable IND(s) held by a health care provider or other sponsor.

Once manufactured, the COVID-19 convalescent plasma may be distributed for investigational use.

Blood establishments do not need to request an alternative procedure or exception under 21 CFR 640.120(a) to collect COVID-19 convalescent plasma.

2. Labeling
   1. 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)).
      
      In addition, the requirements in 21 CFR 606.121 for the container label apply, including the requirement to include a reference to the circular of information.
      1. FDA recognizes that the current circular of information does not contain specific information about COVID-19 convalescent plasma regarding indications for use, dosage information, contraindications or cautions, but it provides information on the use of plasma.
   2. We recommend the use of a uniform container label for COVID-19 convalescent plasma. In particular, we recommend the use of the International Society of Blood Transfusion (ISBT) format specified in the United States Industry Consensus Standard for the Uniform Labeling of Blood and Blood Components Using ISBT 128.
   3. The manufacturing process used and the expiration date on the label for COVID-19 convalescent plasma should be the same as for other plasma products that are of the same type. For example, COVID-19 Convalescent Plasma, Fresh Frozen, should be frozen within 8 hours after collection, stored at -18C or colder and have an expiration date one year from the date of collection.
3. Recordkeeping 

A health care provider who is participating in an IND, including an expanded access IND or eIND, must maintain records for the COVID-19 convalescent plasma unit(s) administered to the COVID-19 patient (21 CFR 312.62).  Such records should include the unique identification number(s) (e.g., the ISBT donation identification number(s)) of the unit(s).