FDA outlines new regulatory approach for convalescent plasma to treat COVID-19

A new policy from the FDA aims to expedite the use of “convalescent plasma” to help treat patients affected by COVID-19. But as AgencyIQ explains, there are still rigorous requirements that could limit the use of the therapy for large numbers of patients.

To contact the author of this analysis, please email Laura DiAngelo.
To contact the editor of this analysis, please email Alec Gaffney.

Executive IQ Brief

  • How Things Work Now: “Convalescent plasma,” or plasma derived from donors who were previously infected with the virus but have recovered, has been seen by researchers as a potential treatment for viral outbreaks. Researchers have previously considered or studied the use of convalescent plasma to treat Ebola, SARS, MERS, and sever flu outbreaks.
  • What’s New: The FDA issued a new policy outlining instances in which it will grant emergency, single-patient access to convalescent plasma in response to the COVID-19 outbreak. However, the requirements are strict—even more so than the regular regulatory requirements on the US blood supply and donor eligibility—and the scope of the policy is limited.
  • What’s Next: The FDA has already granted the New York Department of Health approval to begin studying the use of convalescent plasma in individuals with life-threatening COVID-19. However, it’s unlikely that the product is a option for widespread treatment based on limitations, which include repeated testing and getting patients to plasma collection sites.

Regulatory Background

Under section 351 of the Public Health Services (PHS) Act, blood and plasma products are regulated by the FDA as biologic products. However, the collection, processing, manufacturing, and distribution of blood products often includes more facilities, establishments, and personnel than are involved in traditional drug—or even biologic—manufacturing.

That process includes licensed manufacturers, unlicensed blood establishments, transfusion services, contract organizations and individual donors themselves. Further, under the Federal Food, Drug and Cosmetic (FD&C) Act, the FDA is directed to oversee various aspects of blood and blood components that are intended for transfusion or other manufacturing use (21 CFR 630). Under this authority, the FDA sets standards for the eligibility of blood donors, including “deferring” or prohibiting certain populations from donating blood.

Blood products, like other types of biologics, are required to submit evidence to the FDA for review and approval before coming to market in the form of a Biologic License Application. Additionally, researchers studying new blood products for therapeutic effect are required to submit an Investigational New Drug (IND) application (which, when approved, permits the initiation of clinical study) and adhere to FDA clinical trial requirements.

Regulatory Context

The FDA is extremely risk-averse when it comes to regulating blood products, and takes what it calls a “conservative approach to ensure the safety of the Nation’s blood supply.”

The regulation of the blood supply, including who may or may not donate blood and licensure and registration of the facilities and entities involved, is complex, burdensome, and geared towards preventing potential contamination through exclusion. In general, the agency would rather turn away donors that may be eligible than allow for the possibility of contamination. It has acknowledged that its regulations “may result in the deferral of otherwise acceptable donors.”

FDA authority over the US blood supply and blood-derived products is a function of the HIV/AIDS epidemic in the 1980s and 1990s, as well as public health crises associated with contamination of hepatitis C and “Mad Cow” disease, all of which are transmitted in part through the US blood supply. In 1988, the Presidential Commission on HIV highlighted the FDA’s lack of oversight over the blood industry as a key issue, while the spread of hepatitis C via blood products before the 1990s raised significant public health concerns for lawmakers.

In 1996, all lots of the plasma product called albumin were recalled industry-wide by the Centers for Disease Control and Prevention (CDC) and the FDA due to a manufacturing issue that had rendered them unsterile. At the time, it was the largest recall in US history and prompted significant blowback from federal policymakers. The FDA’s handling of the recall was widely questioned by both lawmakers and the US Department of Health and Human Services (HHS), the parent department of the agency. A 1997 reportfrom HHS’ Office of the Inspector General investigating the recall found significant gaps in the FDA’s oversight. Another report from HHS, commissioned by Congress, stated that “if FDA had been more aggressive about responding to its earlier inspections and if those earlier inspections were more encompassing, the incident probably would not have occurred.”

In response to the outbreaks, public concern, and those concerns from both lawmakers and HHS, the FDA issued a proposed rule in 1997 to alter reporting requirements for blood products. That rule was finalized in 2001. In addition to altering the reporting requirements for licensed blood establishments, it expanded these reporting requirements to all entities engaged in the manufacture of blood and blood components by amending the current good manufacturing practice requirements (CGMP) requirements. These included all licensed and unlicensed registered establishments, manufacturers, and transfusion services.

Convalescent Plasma: An Opportunity in the Case of Outbreak

Upon infection with a virus, white blood cells will produce proteins, called antibodies, to counteract the antigen. If the individual recovers from the virus, the immune response can be stored, potentially granting the person “immunity” from becoming seriously ill with the virus again.

“Convalescent plasma,” or plasma derived from donors who were previously infected with the virus but have recovered, has been seen by researchers as a potential treatment for viral outbreaks. While therapeutics and vaccines to treat a novel disease might take years to develop, convalescent plasma is available quickly and, depending on the scope of the outbreak, readily.

The use of convalescent plasma is well documented, even if its effects aren’t always evident. Regulators around the world have historically allowed certain individuals to access convalescent plasma in absence of another treatment option. Convalescent plasma has been used as an emergency response treatment for several viral outbreaks over the last few decades, including severe acute respiratory treatment (SARS), the H1N1 influenza virus pandemic, and, most recently, Ebola.

There are significant limitations to relying on convalescent plasma, however. First, the distribution of blood products—especially plasma, which is typically not refrigerated, but instead stored at room temperatures—is notoriously difficult, including a significant number of entities. Second, the virus itself must be confirmed not be spread by blood to blood contact, such as hepatitis C or HIV, the spread of which in the blood supply was the impetus for the establishment of a typically risk-averse blood product regulatory framework. Third, and perhaps most significantly, the supply of convalescent plasma is completely dependent on a qualified donor’s willingness and eligibility to give their plasma.

During the Ebola outbreak, the World Health Organization (WHO) issued best practices for convalescent plasma collection programs, outlining the several steps required to successfully—and ethically—collect and distribute convalescent plasma, including:

  • Identifying the recovered patients who could be potential donors;
  • Providing these patients with informed consent, and selecting donors from the pool of survivors;
  • Blood grouping and screening for transfusion transmissible infections (e.g., HIV);
  • Blood collection and donor care;
  • Labeling, storage, and data collection through the transfusion service;
  • Informed consent of patients;
  • Patient blood grouping and compatibility testing;
  • Storage and transportation of the plasma product to the transfusion site;
  • Identifying patients for transfusion;
  • Transfusion;
  • Data collection; and
  • Empirical efficacy assessments.

Following the WHO’s recommendations, the FDA also issued guidance on assessing blood donor eligibility for convalescent plasma to treat Ebola in 2017. As the FDA noted, there were no approved treatments for Ebola, and the standard of care at the time was limited to supportive care (e.g., pain control, intravenous fluids). While the agency stated that “the effectiveness of convalescent plasma or immune globulin concentrates made from convalescent plasma remains biologically plausible,” it also wrote that further study would be needed in a controlled study to determine its safety and efficacy. Only one studyregistered on ClinicalTrials.gov on the use of convalescent plasma to treat Ebola was completed. According to the results of that study, the transfusion of convalescent plasma “was not associated with a significant improvement in survival.”

To date, the FDA has not approved convalescent plasma as a therapy for any disease.

What’s New

With the recent outbreak of COVID-19, the FDA is under significant pressure to identify treatments for the disease and to make them available to patients.

On March 24, 2020, the FDA issued guidance on the use of convalescent plasma for treating COVID-19. While the FDA maintains that investigators seeking to study the efficacy and safety of using these products for COVID-19 should follow the regular procedure for submitting an IND, it also stated that it will allow for single patient emergency INDs, or eINDs.

Those eIND requests are submitted by an individual practitioner to the FDA. If granted, the request permits the patient to receive Expanded Access to a drug or biological product under investigation (as long as the producer of the product consents).

As the FDA’s policy currently stands, it will only consider eIND requests for the treatment of COVID-19 for individual patients, not prevention.

The guidance outlines specific requirements that should be in place for convalescent plasma to be used in patients with COVID-19, including specific donor eligibility requirements. In addition to the standard eligibility requirements and standard testing procedures for the suitability of donor blood, the FDA included several new considerations.

In order to donate plasma to be used as a treatment, an individual must:

  • Have a documented diagnosis of COVID-19 with confirmatory results from laboratory tests;
  • Have experienced a resolution of symptoms of at least 14 days prior to donation;
  • Be male, or a female donor negative for human leukocyte antigen (HLA) antibodies (these antibodies can interfere with the success of a platelet transfusion, and are more common after a pregnancy or organ transplant);
  • Test negative for COVID-19 through more than one nasopharyngeal swab or one molecular diagnostic test from blood;
  • If testing can be conducted, have defined levels of the COVID-19 associated virus (i.e., SARS-CoV-2 represented at, optimally, a concentration greater than 1:320).

Any blood establishment that collects or packages convalescent plasma must use the following label: “Caution: New Drug—Limited by Federal (or United States) law to investigational use.”

Patients eligible for an eIND to receive convalescent plasma would be those with laboratory confirmed COVID-19 with “severe or immediately life-threatening” symptoms. The patients must also provide informed consent.

Clinicians would need to submit an eIND to the agency using form 3926 and email to the FDA. The form should include patient information, including the applicability of the regulatory requirements of a single-patient emergency IND.

Further, clinicians would need to identify where they would obtain the convalescent plasma. The FDA would not provide the treatment, and it’s not clear how the agency would consider an eIND request from a clinician who is not connected to a blood establishment that is working to identify potential donors, screen them for eligibility, collect a sample, test it, package it, and provide it to that clinician.

What’s Next

In the new policy, the FDA states that it is “important to determine through clinical trials, before routinely administering convalescent plasma to patients with COVID-19, that it is safe and effective to do so.”

There is already movement from New York State to study the potential efficacy of convalescent plasma. NY’s Governor Andrew Cuomo (D) announced that the FDA had approved the state’s Department of Health to begin a study on convalescent plasma in his Monday address to the state, which has been particularly hard hit by the outbreak. Governor Cuomo wasn’t the first administrator to bring up the potential for convalescent plasma as a therapy—the President also mentioned it as an option in a Coronavirus Task Force briefing on March 19.

There is one other clinical trial, which is registered on ClinicalTrials.gov, to study the use of convalescent plasma in COVID-19, run through the Shanghai Public Health Clinical Center.

Because, by definition, the only donors eligible to give convalescent plasma would be those who had survived the initial infection, the donor pool is typically quite low. Additionally, these donors are still subject to regular donor eligibility standards, including certain health status indicators, lifestyle exclusions, and the presence of certain Relevant Transfusion-Transmitted Infections (RTTI).

There is, however, a potential larger donor pool: People who were infected by SARS-CoV-2 but failed to show symptoms. Early clinical reports indicate the number of persons in this category may be substantial. However, without additional testing capacity to identify these persons—and whether they produced sufficient antibodies—it could be difficult to increase the collection of plasma.

It may also be difficult for patients to access a plasma collection center, since most public transportation options are not available amid nationwide shutdowns to prevent the spread of COVID-19.

Testing capacity is likely to be a significant barrier in general. Already, two tests would be needed to confirm a person’s COVID-19 infection, and then at least one test (preferably two) would be needed to confirm that a patient no longer has COVID-19 before they could donate plasma. At a time when tests are already in low supply, a single patient requiring four tests could place additional strains on the supply chain.

The new policy for single-patient emergency INDs adds new barriers to the eligibility to donate convalescent plasma, including gender or antibody markers and potential titration and identification of antibodies that could further reduce the donor pool. The policy also requires increased testing for donors, even as the reported national lack of diagnostics continues. It seems unlikely that health care providers will use their limited tests to re-test individuals that have recovered from the virus for the potential to donate plasma unless testing capacity markedly increases.

Given these considerations, it’s unlikely that convalescent plasma is something that will be an immediate, viable, nationally-available treatment option for COVID-19.

To contact the author of this analysis, please email Laura DiAngelo.
To contact the editor of this analysis, please email Alec Gaffney.

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