Here’s how companies could get their treatments and vaccines for COVID-19 approved by FDA

Companies are racing to develop treatments and vaccines for COVID. But first, they’ll need to figure out how to test the safety and efficacy of these drugs. Here’s what they might be thinking about in the weeks ahead.

 

To contact the author of this piece, please email Kedest Tadesse (ktadesse@agencyiq.com).
To contact the editor of this piece, please email Alec Gaffney (agaffney@agencyiq.com).

 

Executive IQ Brief

  • How things work now: Under ordinary circumstances, vaccines and antiviral treatments go through a series of nonclinical testing in animals before entering clinical trials. Among the key challenges that sponsors of these studies face is determining whether the products are safe and effective. Those tests require companies to think about which outcomes to study.
  • What’s New: According to a review by AgencyIQ, there are 65 vaccine and therapeutic candidates in the pipeline to treat, cure or prevent COVID-19. As clinical testing begins on these products, there are multiple challenges companies trying to eventually obtain approval for their products. While the FDA does not currently have any established guidance for how companies can evaluate the safety and efficacy of products for COVID-19, there are other guidance documents applicable to viral conditions which could provide a roadmap for potential study.
  • Impact: The FDA has said it recognizes that the conduct of clinical trials during a pandemic comes with challenges: Quarantined patients, supply chain interruptions, shortages of products and clinical protocols that can be put at risk. In guidance released on March 18, 2020, the FDA offered general considerations to assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic. Companies may also wish to leverage data from outside of the US, which is permitted.

Regulatory Background

The discovery and development of new vaccines and antiviral treatments is of the utmost importance as the US and other countries try to limit the spread and control the effects of COVID-19, the medical condition caused by SARS-CoV-2.

Under normal circumstances, clinical development takes years, even decades to complete, and the vast majority of products that enter clinical testing are never approved by the FDA. According to an analysis conducted by BIO from 2006-2015, just 9.6% of drugs that enter Phase 1 clinical testing go on to receive FDA approval, while 85.3% of drugs that are submitted to the FDA for approval (typically following Phase 3 research) are approved.

 

For vaccines, the likelihood of approval is 16.2%. For infectious disease therapies, it’s 19.1%. (Other studies have found the success rates to be somewhat higher: 26.7% for infectious diseases and 31.6% for vaccines).

 

Despite improved scientific understanding of how the immune system responds to infection, there are multiple factors that make it difficult to predict clinical success. It remains challenging to predict which pre-clinical data will indicate future efficacy and safety in humans. It’s not always clear which clinical endpoint will demonstrate the effects of a drug or vaccine. Some patients may respond to a product differently, for example by metabolizing a drug poorly (thereby minimizing its effectiveness) or having an adverse immune reaction (thereby reducing its safety). Viruses are also naturally challenging to target, since many can hide from immune responses through antigenic variation, the process through which surface proteins are altered.

 

While the benefits of approved vaccines vastly outweigh their risks, no medical product is without some degree of risk. Some vaccine products have historically raised pointed safety concerns, including those developed in response to public health crises. For example, in 1955, the first Polio vaccine developed was abandoned after initial vaccinations led to paralysis in children, caused 40,000 cases of Polio and killed 10 patients. This event is commonly referred to as the “Cutter Incident.” In 1976, a vaccine developed to treat Swine Flu resulted in 450 people developing Guillain-Barre Syndrome, a condition in which the immune system attacks the body’s nerves.

As such, while public health efforts may necessitate the development of a vaccine, regulators must weigh the benefits and risks of accelerating access to a medical treatment with its potential to cause adverse effects in treated patients.

 

The FDA’s Center for Biologics Evaluation and Research (CBER) is responsible for regulating vaccines and follows a multi-step approval process which typically includes submission of an investigational new drug application (IND) to begin a clinical trial, pre-licensure clinical trials to test the vaccine, the submission of a Biologics License Application (BLA) to seek approval, inspection of a product’s manufacturing facility to ensure it meets good manufacturing practices, an Advisory Committee meeting to address lingering concerns, and the review of the product’s labeling to ensure its safe use after approval. The Agency also monitors adverse events post approval using its Vaccine Adverse Event Reporting System (VAERS).

 

Vaccines have saved millions of lives and reduced rates of disability and suffering for countless others. In a study published by Proceedings of the National Academy of Sciences of the United States of America, an analysis of vaccines to protect against 13 diseases estimated that a for a single birth cohort nearly 20 million cases of diseases were prevented, including over 40,000 deaths. In addition to saving lives, vaccination also have resulted in net economic benefits to society by reducing cost of illness. Vaccines not only provide individual protection, but also provide community protection by reducing spread of disease.

 

 

Regulatory Context

In recent years, the world has seen several notable epidemics, pandemics and other pathogens of public health concern, including the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome (SARS), Ebola Virus Disease, and Swine Flu (H1N1).

 

In some of these cases, drug development efforts have been able to rapidly help alleviate the threat to public health. In other cases, development efforts took years to come to fruition. For example, the H1N1 pandemic started in April of 2009 and a vaccine was approved by the FDA in mid-September of 2009. The most outbreak of Ebola Virus Disease in 2014 resulted in development of a vaccine, Ervebo, which was submitted for review in July 2019 and approved on December 20, 2019.

 

Based on the type of virus strain causing the outbreak and resources available, it is difficult to predict when treatments or vaccines will be available for COVID-19.

According to a review by AgencyIQ, there are 65 vaccine and therapeutic candidates in the pipeline to treat, cure or prevent COVID-19. About 10 of these are currently approved products and 16 products that are in clinical development for other indications that are that are being tested for efficacy in COVID-19. Currently there are multiple drugs that are in the process of starting or have started clinical testing at different phases.

 

But as clinical testing begins on these products, there are multiple challenges companies trying to eventually obtain approval for their products. Those challenges including the adequate design of the trials, recruiting patients who might be sick or under quarantine, determining appropriate outcomes measures for the trial (i.e.: How do you determine if a drug was effective? What would it improve?), and the safety of clinical trial workers.

 

 

What’s New

The FDA currently does not provide clinical development guidance with regards to endpoints or outcomes applicable to COVID-19, specifically, or Severe Acute Respiratory Syndromes in general.

 

However, it does have existing guidance documents that may indicate how it will ask for companies to assess their products intended for use in patients with COVID-19.

Based on a review by AgencyIQ of existing FDA guidance documents applicable to vaccine and antiviral drug development, we can predict what the FDA might require of COVID-19 studies in a future guidance document for vaccines and antiviral therapies.

 

Nonclinical studies

Before a drug can be tested in humans, it should undergo testing using established scientific methods, including in certain animals.

 

For nonclinical virology studies, sponsors are asked to identify the mechanism of action of the investigational vaccine (how it works), help establish a specific antiviral activity of the product in a model and system (that it works), and provide data on the development of viral resistance of the investigational product (that it will continue to work).

 

All of this must take place prior to the initiation of testing in humans (Phase 1 clinical trials).

 

In its June 2006 guidance document on Antiviral Product Development, the FDA encouraged sponsors to use approved assays that are characterized and validated. Assays are used to detect either the presence of the virus, or an immune response to the presence of the virus, which would indicate the potential effects of the drug. If an investigational assay is used, sponsors should provide information about the performance of the assay, the source of virus, the storage and stability of the assay, and cell culture procedures.

 

If the investigational drug being studied has a different mechanism other than a direct antiviral effect, sponsors should conduct cell culture, biochemical and genetic studies to support animal toxicity studies. Candidate drugs should also be assessed for antiviral activity in cell culture assays, in vivo activity in appropriate animal models, and for their potential to enhance replication of other pathogens.

 

In cases where an investigational antiviral product is co-administered with another approved product (such as a second antiviral drug) to treat the viral infection, a sponsor should conduct in vitro combination activity studies to identify possible negative interactions. In addition, due to cross-resistance, it is important to determine the antiviral activity of investigational and approved products against relevant viruses resistant to other products with the same target molecule. The FDA’s guidance document strongly recommends comprehensive resistance testing be undertaken during all phases of product development and encourages sponsors to address this topic during meetings before the filing of a clinical trial application (known as a Pre-IND meeting).

 

Data from animal studies can provide supporting information for human clinical trial design as well information for early regulatory decisions. However, in rare circumstances normal testing requirements may be accelerated.

 

For example, in the context of COVID-19, the life sciences company Moderna Therapeutics was able to move its investigation product (mRNA-1273) into Phase 1 clinical testing without first conducting animal studies. Instead, the National Institutes of Health (NIH) is working on nonclinical animal research for the drug in parallel. The pace and extent of the COVID-19 outbreak and the need for expedited therapies is justifying simultaneous processes that would normally be done sequentially.

Based on limited research and data, however, it may be difficult to identify the appropriate animal models to support development of therapeutics and vaccines to be used in COVID-19 patients. Potential speciesinclude mice, ferrets, pigs and macaques.

 

 

Clinical studies

Potential approaches to testing COVID-19 treatments can be ascertained by evaluating the approaches used for influenza.

 

In those studies, patients in early-stage testing (Phases 1 and 2a) are first exposed to a drug to determine the pharmacokinetics of the drug (what the body does with the drug) and the tolerability of the drug and its effects. The drug is then introduced to healthy patients who have been exposed to a mild influenza virus to establish its safety. This test is known as a “challenge trial.”

 

Challenge strains are viruses that produce a milder set of symptoms compared to naturally occurring strains. Endpoints for such trials include clinical respiratory symptoms, nasal discharge weight and quantitative measurements of viral shedding in nasal washes. Although challenge trials should not be considered to be efficacy trials, the trials can provide useful exposure-response and safety information.

 

However, challenge trials are not always feasible and proposals for such trials should be discussed with CBER review team in regard to safety, ethics and containment. Within the context of COVID-19, it’s not clear if a “challenge strain” of the virus is even available, which could preclude the use of this approach during early-phase studies.

Companies also need to consider how to determine the appropriate dose for a product, which is typically determined in Phase 2b studies. Such studies need to have enough participants to determine differences in viral shedding, as well as basic endpoints to determine if a drug is effective at treating clinical symptoms. This information allows for companies to determine the best dose to bring into Phase 3 “pivotal” clinical trials.

 

The FDA generally advises that clinical trials include a wide range of individuals, including adults, pediatric, the elderly and patients with underlying medical conditions. However, this may be easier said than done, since those patients may metabolize drugs differently or have underlying health conditions which could put them at risk of harm. For example, an immunocompromised patient could react differently than a patient who is healthy. Children and the elderly may react differently to drugs than adults between the ages of 20 and 65, since the organs that metabolize drugs may not yet be fully developed or may be deteriorating with age.

 

Additionally, antiviral drug efficacy in children cannot be extrapolated from data generated from trials in adults because of prior exposure and immunity typically present in adults is generally different. As a result, to fulfill the Pediatric Research Equity Act requirements, sponsors need to conduct adequate and well-controlled trials with clinical efficacy endpoints and safety evaluations.

 

 

Endpoints
One critical aspect of any trial is measuring the extent to which a drug substance is effective at treating, preventing or curing the underlying medical condition. To measure these effects, a trials’ sponsor will propose to study various “endpoints,” including primary and secondary endpoints.

 

Choosing an endpoint for a clinical trial is dependent on the clinical setting and viral strains. Sponsors should provide evidence for the ability of their proposed endpoint to directly measure how a patient feels, functions and survives using available literature and clinical trial data.

 

For example, for the treatment of seriously ill hospitalized patients with influenza, a primary endpoint might include clinical signs and symptoms, duration of hospitalization, time to normalization of vital signs and oxygenation, requirement of supplemental oxygen or assisted ventilation and mortality.

 

Similar endpoints are likely to be used in ongoing COVID-19 trials.

Based on AgencyIQ’s review of outcome measures listed by current sponsors registered in Clincialtrials.gov, the relief and/or disappearance of major symptoms is a primary endpoint used by several companies.

 

This includes fever, cough, dyspnea, blood oxygen level, the need for a mechanical ventilation, and other measures that indicate improved clinical recovery time. Sponsors are also measuring if the SARS-CoV-2 pathogen is at a detectable level and how long it takes for it convert to being undetectable.

 

From a safety standpoint, current sponsors are evaluating adverse events that may lead to patients being unable to continue in the trial. For instance, Ascletis Pharma is conducting a study using a fixed dose combination of two HIV-1 protease inhibitors, ASC-09 and Ritonavir, a treatment approved in 1996 under the name Noravir by Abbott. The trial is using outcome measures such as time to recovery (rate of no fever, no cough, no dyspnea), patients no longer requiring supplemental oxygen, as well as the incidence rates of adverse outcomes.

 

According to the FDA guidance on developing drugs for treatment of influenza, virologic endpoints (such as the presence or absence of a virus) are not considered appropriate primary endpoints in Phase 3 trials but are important as secondary endpoints and components of entry criteria (i.e., who is enrolled in the study). The reason these endpoints aren’t seen as acceptable is because of a lack of established predictive relationship between magnitude and timing of viral reductions and extent of clinical benefit of how a patient “feels, functions, or survives.”

 

 

What’s Next

Drug discovery and development is a complicated process during ordinary times. It can be far more difficult during a pandemic of a deadly virus.

 

The FDA has said it recognizes that the conduct of clinical trials during a pandemic comes with challenges: Quarantined patients, supply chain interruptions, shortages of products and clinical protocols that can be put at risk. In guidance released on March 18, 2020, the FDA offered general considerations to assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic.

However, a pandemic provides an opportunity to leverage data from outside of the United States as well.

 

The FDA has previously published guidance on regulatory pathways to use in the development of vaccines to protect against global infectious diseases. Notably: Sponsors may submit data from clinical trials conducted outside the U.S. to support product licensure. The FDA will accept this data to support an IND or an application for marketing approval. However, the data must be from a well-designed and well-conducted foreign clinical study. For example, the study should be conducted in accordance with good clinical practices and include review and approval by an independent ethics committee.

 

The Agency doesn’t require studies to support vaccine licensure to be conducted in US population. CBER evaluates trials conducted outside the U.S. to determine if the vaccine is safe and effective for use as proposed in labeling. As part of this evaluation, the FDA’s Center for Biologics Evaluation and Research (CBER) considers factors such as disease epidemiology, the study population, and the environmental and medical care conditions under which the study took place. CBER may request a smaller US study to ensure the product works in US patients.

 

Sponsors should carefully consider using appropriate outcome measures for ongoing and upcoming COVID-19 trials. Finding a safe and effective vaccine and/or treatment is of utmost importance while facing numerous challenges in running a clinical trial. One of the ways to mitigate risks is to prepare and use a study protocol that plans for potential modifications and deviations due to COVID-19. Sponsors should also keep in close contact with the Agency and have an open line of communication to receive real time feedback during development. If clinical trials are for products that are already in testing or approved for other indications, sponsors should evaluate available data specially in regard to safety information prior to clinical use in COVID-19 patients. The FDA’s goal during this time is to assure the safety of trial participants and minimizing risks to trial integrity while working with sponsors to bring vaccines and therapies to market.

KEY DATES AND DOCUMENTS

To contact the author of this piece, please email Kedest Tadesse (ktadesse@agencyiq.com).
To contact the editor of this piece, please email Alec Gaffney (agaffney@agencyiq.com).

 

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