FDA releases updated guidance on convalescent plasma

The U.S. Food and Drug Administration (FDA) released updated guidance on investigational COVID-19 convalescent plasma, which extends the period of enforcement discretion through the end of February 2021.

This extension will allow continued access to convalescent plasma for the treatment of hospitalized COVID-19 patients while blood establishments develop the necessary operating procedures to manufacture the plasma consistent with the emergency use authorization (EUA). The guidance also includes a new recommendation that authorized COVID-19 convalescent plasma not be collected from individuals who have received an investigational COVID-19 vaccine.

The guidance describes FDA’s interim compliance and enforcement policy regarding the IND requirements for the use of investigational convalescent plasma to facilitate the availability of convalescent plasma to treat hospitalized patients with COVID-19. The guidance supersedes the guidance of the same title issued in April 2020 and updated in May and September 2020.

The guidance provides recommendations on the following:

• pathways for use of investigational convalescent plasma
• collection of convalescent plasma
• record keeping
• compliance and enforcement policy regarding investigational new drug requirements for use of convalescent plasma

Because convalescent plasma for the treatment of COVID-19 has not yet been approved for use by the FDA, it is regulated as an investigational product. As such, its administration must be under the EUA or an IND. The FDA does not collect convalescent plasma or provide convalescent plasma. Healthcare providers or acute care facilities should obtain convalescent plasma from an FDA registered or licensed blood establishment.

Excerpts from the guidance document are provided below.

On August 23, 2020, the FDA issued an EUA for COVID-19 convalescent plasma for the treatment of hospitalized patients with COVID-19. However, adequate and well-controlled randomized trials remain necessary for a definitive demonstration of COVID-19 convalescent plasma efficacy and to determine the optimal product attributes and appropriate patient populations for its use. Additional data will be forthcoming from other analyses and ongoing, well-controlled clinical trials. The ongoing clinical trials of investigational convalescent plasma should not be amended based on the issuance of the EUA; health care providers are encouraged to enroll patients in those trials.

Because convalescent plasma for the treatment of COVID-19 has not yet been approved for use by FDA, it is regulated as an investigational product. As such, its administration must be under the EUA or an IND. The emergency use of COVID-19 convalescent plasma is not authorized under the EUA unless it is consistent with, and does not exceed, the terms of the Letter of Authorization, including the Scope of Authorization and Conditions of Authorization. Alternatively, investigational convalescent plasma may be administered under the traditional IND regulatory pathway, a single-patient IND for emergency use, or an intermediate-size population expanded access IND.

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

1. Emergency Use Authorization

Healthcare providers intending to administer COVID-19 convalescent plasma under the EUA are not required to report its use to FDA. Providers should refer to the Fact Sheet for Health Care Providers for information on the intended use and known and potential risks and benefits of COVID-19 convalescent plasma. The Fact Sheet also provides a description of the product, information on the dosage, administration and storage of COVID-19 convalescent plasma, use in specific populations, and instructions for communicating with recipients.

As described in the Fact Sheet, health care providers must maintain records and conduct a thorough investigation of adverse reactions after transfusion of COVID-19 convalescent plasma and must report fatalities to FDA as required in 21 CFR 606.170.  Refer to FDA’s guidance entitled, “Notifying FDA of Fatalities Related to Blood Collection or Transfusion” for recommendations on reporting fatalities related to blood transfusion to FDA.

2. Clinical Trials

The EUA is not intended to replace clinical trials that are critically important for the definitive demonstration of safety and efficacy of investigational convalescent plasma.  Ongoing clinical trials of investigational convalescent plasma should not be amended based on the issuance of the EUA.  Health care providers are encouraged to enroll patients in those trials and complete clinical trials to fully answer the questions about the effectiveness of convalescent plasma for the treatment of COVID-19.

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).  The Center for Biologics Evaluation and Research (CBER) Office of Blood Research and Review (OBRR) is committed to engaging with sponsors and reviewing such requests expeditiously.  During the COVID-19 pandemic, INDs may be submitted via email to [email protected].

3. Expanded Access

An IND application for expanded access is an alternative for use of investigational 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).  During the COVID-19 pandemic, INDs for expanded access, that are not single patient INDs, may be submitted via email to [email protected].

1. Single Patient IND for Emergency Use

Given the public health emergency that the COVID-19 pandemic presents, the FDA is continuing to facilitate access to investigational convalescent plasma through the process of a physician requesting a single patient IND for an individual patient with serious or life-threatening COVID-19 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 cases, a licensed physician seeking to administer investigational convalescent plasma to an individual patient must request the IND. 

Given that the intended use of COVID-19 convalescent plasma under the EUA is for treatment of hospitalized COVID-19 patients, FDA expects few requests for single patient INDs. The FDA recommends that physicians seeking to use convalescent plasma for hospitalized COVID-19 patients should do so under the EUA and not under single patient INDs. Other options for the use of investigational convalescent plasma are listed above.

Registered or licensed blood establishments collecting authorized COVID-19 convalescent plasma under the EUA or investigational convalescent plasma under an IND should refer to the guidance for recommendations on donor eligibility and qualification, testing plasma for anti-SARS-CoV2 antibodies, and labeling.

A healthcare provider who is participating in an IND, including an expanded access IND or single patient IND for emergency use, must maintain records for the investigational convalescent plasma unit(s) administered to the COVID-19 patient. Such records should include the unique identification number(s) (e.g., the ISBT donation identification number(s) of the unit(s)).

FDA has the release.  

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