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FDA’s Marks says time is now to start trials for vaccines against new COVID-19 variants as agency issues guidance

FDA issues guidance for vaccines, therapeutics and diagnostics 

Peter Marks urges companies to start trials of vaccines against new COVID-19 variants as the agency issues guidance for vaccines, therapeutics and diagnostics. 

Feb 23, 2021 | 2:25 AM GMT

FDA is outlining a streamlined clinical development path for COVID-19 vaccines against emerging variants based on clinical immunogenicity studies, and it’s time for manufacturers to start those trials, according to FDA’s Peter Marks. 

An update to the Oct. 20 EUA guidance on preventive COVID-19 vaccines allows manufacturers to seek amendments to existing emergency use authorizations for modified versions of COVID-19 vaccines that are made by the same process and manufacturer but designed to enhance efficacy against a variant.

It also allows companies to forgo the large clinical efficacy endpoint-driven trials required of the prototype vaccines, and instead, conduct smaller clinical immunogenicity studies that compare the neutralizing antibody response to the new variant with those generated by the prototype vaccine to the original strain.

The update guides sponsors to conduct two types of immunogenicity studies: one that compares neutralizing antibody titers from the vaccines in COVID-19 vaccine-naïve participants, and another that studies the variant vaccine as a booster in participants who previously received the prototype vaccine. 

The latter is particularly important for determining whether the modified vaccine can be safely given to people who have received other vaccines, and whether it can still generate adequate immune responses against the virus in those cases. 

The guidance also states that the immunogenicity trials can be run in a single age group, such as 18-55 year olds. 

For safety, the immunogenicity studies should follow patients for adverse events seven days after each dose, and expanded safety studies may be required if signals are detected. 

Clinical immunogenicity is a step that isn’t required for new influenza vaccines, Marks, who is director of FDA’s Center for Biologics Evaluation and Research (CBER), said on a media call Monday. It’s still necessary for COVID-19 though because it isn’t clear whether modified vaccines will remain effective against the old strain and whether they’ll retain safety and efficacy in people who have previously received a different COVID-19 vaccine. 

“After three or four times, if everything is consistent, we might move toward an influenza-type model,” he said.

Luciana Borio, former acting FDA chief scientist, told BioCentury that the new guidance “achieved a good balance. It also gives sponsors a lot of flexibility in how they go about developing the evidence-base.”

Threshold uncertainty

The updated guidance provides important clarity on how manufacturers of authorized vaccines can approach new variants, but it doesn’t address how to determine when to roll out a new vaccine for SARS-CoV-2 variants.

Acting FDA Commissioner Janet Woodcock previously said the timing for updates will depend on prevalence of escape variants and their degree of impact on the original product efficacy. 

At the moment, authorized vaccines have maintained efficacy against variants circulating in the U.S. Marks said it is not the time to roll out or even stockpile variant vaccines, but it is time to start the immunogenicity studies.

He noted that the clinical immunogenicity studies will require a few hundred patients and may take two-to-three months to complete. 

That’s in contrast to the large Phase III clinical efficacy endpoint-driven studies that have required tens of thousands of patients, depend on disease prevalence at trial locations and take many months to complete.

The guidance recommends that non-inferiority of a vaccine against new variants be defined as less than a 10% drop in serological response rates and a 1.5-fold drop in geometric mean titer (GMT). Marks said a margin of 10-15% in response rates is standard.

But variants can quickly spread through a community, so manufacturers need to monitor for the emergence of new variants and start trials before they become prevalent. 

Marks also said that a monovalent vaccine that replaces the prototype would be ideal, but that will only be possible if the variant vaccine retains efficacy against the original strain, so the data will drive that decision.

The guidance assumes that neutralizing antibodies may predict immune response to the vaccine, but it doesn’t address the need for harmonization in the measurement of antibody titers.

The problem with using neutralizing antibodies as a correlate of protection is that titers can vary widely depending on the assays used and even the protocols between labs. It’s less of an issue when a manufacturer is creating a modified version of its vaccine — the topic of the current guidance — because it involves a direct comparison between two products from the same manufacturer. 

It becomes more of an issue when immune correlates used across companies are used to accelerate development of new vaccines.

The guidance states that manufacturers need to inform regulators about the tests used, but also states that pseudovirus or wild-type virus assays are acceptable.

International consistency

New European regulatory requirements, released later in the week, are consistent with those in the U.S. The EMA guidance gives a few more details about how the immunogenicity studies should be structured, providing addition direction for manufacturers while at the same time somewhat limiting flexibility.

In a reflection paper issued on Thursday, EMA guided manufacturers to conduct the same two types of clinical immunogenicity studies, and stipulated more details than FDA on study requirements, assay harmonization and timing of variant vaccine release.

The paper suggests vaccine- and infection-naive participants in the first immunogenicity study be randomized to receive the variant or parent vaccine, but EMA will allow historical immunogenicity data if the parent vaccine cannot be used.

In the booster study, subjects should have participated in a clinical trial of the parent vaccine so that full immunogenicity data are available — a detail that limits flexibility in trial structure.

The paper also states that assay conditions should be consistent when comparing immunogenicity to that of the parent vaccine in a previous trial, or that “post-primary samples should be re-assayed for neutralizing antibody against the parent strain.”

Though the guidance does not define a trigger point for seeking authorization of variant vaccines, it requires justification for the variants selected based on disease surveillance and characterization of circulating strains. It also states that once a global forum is established to support SARS-CoV-2 strain selection for vaccines, those recommendations should be consulted by manufacturers when selecting variant strains.

Manufacturing progress

The immunogenicity studies will take a few months, but companies will also need time to create the modified vaccines.

In a written statement released ahead of tomorrow’s House Committee on Energy & Commerce hearing on expanding eligibility for COVID-19 vaccines, Ruud Dobber, EVP and president of the biopharmaceuticals business unit of AstraZeneca plc (LSE:AZN; NYSE:AZN), said that the company’s collaborators have started developing next generation adenoviral vector vaccines that incorporate genetic changes to the spike protein, but the process will take eight-to-nine months to complete.

“Given that we will have substantial safety data on the vaccine platform and there would be relatively small changes in the vaccine and its manufacturing, we are discussing a path forward with global regulators,” the statement said.

The mRNA and protein vaccine developers may be closer to clinical immunogenicity studies on variant vaccines.

BioNTech SE (NASDAQ:BNTX) previously said it could create an mRNA vaccine against a new variant in six weeks.

John Young, group president and CBO at Pfizer Inc. (NYSE:PFE), said in his statement that in vitro data and real-world evidence support efficacy of the partners’ original vaccine against circulating variants, but the company is also discussing clinical study designs with FDA “to investigate the safety and immunogenicity of an updated vaccine that involves a change to the mRNA construct to target an emerging variant.”

Moderna Therapeutics Inc. (NASDAQ:MRNA) is studying potential booster shots, “either of the existing vaccine or of a version that has been adjusted to address significant variants,” according to a statement from the company’s president, Stephen Hoge.

Novavax Inc. (NASDAQ:NVAX) initiated development of new protein constructs against emerging strains last month, and plans to begin clinical testing this half, John Trizzino, EVP, chief commercial officer and CBO, said in his statement for the hearing.

Diagnosing impact

Among the three guidance documents released by FDA Monday, the  guidance for COVID-19 test developers stood out for specifying a variant frequency that could indicate cause for concern. 

“FDA believes that when these types of mutations are observed in a sequence database at a significant frequency, such as greater than 5% (when considering at least 2000 sequences over a recent period of time, such as the past week, month, or quarter), this may signify that the mutation is present in an increasing proportion of infected individuals in the United States,” the document said.

FDA has been actively monitoring for variant-driven changes in the performance of molecular tests that detect viral genomic material, and issued safety alerts for the handful of tests it believed could  be affected by circulating variants.  

In the guidance, the agency recommended design strategies to minimize the impact of new variants on molecular tests, such as incorporating highly conserved target sequences, and targeting multiple sequences in the viral genome.

FDA recommended that companies conduct in silico studies to predict whether a variant alters the temperature at which the viral sequence unbinds from the test’s probes, which would disrupt the temperature-based amplification cycles that underlie polymerase chain reaction (PCR) tests.

The agency said variants flagged as concerning by these computational studies, or by clinical data suggesting a rise in false negative results, should be tested in wet lab experiments. If these experiments show a variant causes a ≥3-fold increase in a test’s limit of detection (LoD) compared with its LoD for the original strain, FDA recommends test developers pursue risk mitigation strategies, or present an analysis justifying why no mitigations are needed.

In contrast to its ongoing work assessing molecular tests, FDA is still “considering the best approach to monitoring the potential effects” of variants on antigen tests, which use antibodies to detect viral proteins, and serological tests, which measure patient antibodies against the virus.

The agency said companies with antigen and serological tests early in development should engage with FDA for up-to-date recommendations, and those with tests in circulation should monitor for new viral variants, assess the impact on their tests “as needed,” noting it plans to update its EUA templates for these tests as its knowledge progresses.

Across all test types, FDA said sponsors should “consider whether there is the potential for the aggregate of mutations to reduce performance of the test by 5% or more from the previously established performance, or to drop the test’s performance below the performance recommendations in the applicable EUA template.”

mAb about variants

FDA’s guidance on developing mAbs to target SARS-CoV-2, including emerging variants, encourages developers to create mAb combinations and suggests that manufacturers with complementary mAbs partner to create combination products.

The agency said it “strongly recommends that individual monoclonal antibody products be developed with the expectation that they will be combined with one or more monoclonal antibody products that bind to different epitopes to minimize the risk of losing activity against emergent variants.”

The guidance “encourages collaborations between sponsors of individual monoclonal antibody products to address this unmet medical need.” It also suggests that “sponsors, consortia, or other partnerships” should share information to expedite development of mAbs to address SARS-CoV-2 variants.

FDA is encouraging developers of mAbs to address variants to leverage experience from mAbs that are in development or that are already licensed, including by using existing manufacturing platforms. It is also encouraging “less-experienced manufacturers to partner with those with more experience to leverage all available development tools.”

Washington Editor Steve Usdin and Senior Editor Karen Tkach Tuzman contributed to this report.

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