Many challenges exist to bringing these much-needed pharmaceuticals to the public. Likely candidate products must be identified or developed, and preliminary testing must be performed to demonstrate that the product shows a promise of efficacy and that it is safe enough to use in humans. Companies must submit an Investigational New Drug (IND) application to the FDA for review and clinical trials must be performed to evaluate the safety and effectiveness of the proposed product. If clinical studies demonstrate an acceptable risk: benefit ratio, companies must prepare and submit a marketing application (New Drug Application (NDA) or Biologics License Application (BLA)) to the FDA for review and approval, and, finally, once the product is approved, it must be manufactured and distributed in sufficient quantities to meet the needs of the healthcare system and the goal of controlling the spread of the disease.
This final hurdle may prove to be one of the most challenging and will likely require a large amount of support from the contract manufacturing sector. Fortunately, the pharmaceutical industry, National Institutes of Health (NIH), the Biomedical Advanced Research and Development Authority (BARDA), Centers for Disease Control (CDC), and the regulators at the Food and Drug Administration (FDA) understand the criticality of achieving these goals and are working in concert under “Operation Warp Speed” to make the process as efficient as possible while still ensuring the safety and efficacy of any products approved.1
Potential efficiencies and bandwidth enhancements may be built in to manufacturing processes in order to facilitate accelerated delivery of candidate products to patients. The requirement for large numbers of doses may necessitate temporary re-purposing of facilities and personnel in order to meet demand and ensure continuous availability. The application of robust Quality Risk Management principles to quality systems, such as change control and deviation management, will be key to ensuring that GMP standards are met when such efficiencies and bandwidth enhancements are implemented.
The FDA’s draft guidance document titled, “Planning For The Effects Of High Absenteeism To Ensure Availability Of Medically Necessary Drug Products,” which was issued in March 2011,2 outlines measures such as production equipment routine maintenance and utility system performance checks and maintenance which may be reduced in frequency, delayed, or substituted by a suitable alternative when there is a requirement for continued supply of medically necessary products.
The European Medicines Agency (EMA) issued a Notice to Stakeholders on May 26, 2020,3 outlining permitted temporary flexibility regarding equipment and premises qualification and process validation requirements as well as permitting bandwidth enhancements by permitting temporary changes across a number of areas of routine quality operations, such as periodic review of Pharmaceutical Quality System documents, periodic re-trainings and deferral of stability testing. Additionally, the scope of the Notice to Stakeholders extended to imported medicines and the normal testing requirements for products imported from a third country.
Opportunities for vaccines
It has been estimated that it will take from 12–18 months to develop and test candidate vaccines that could prevent infection by SARS-CoV-2.4 If a candidate vaccine is found to be safe and effective in the requisite clinical trials, we would anticipate that it will take an additional 6–12 months to prepare the BLA and get approval from FDA. However, if the FDA issues an Emergency Use Authorization (EUA) for a promising candidate, the vaccine could be made available to the public prior to BLA approval.
Once the vaccine receives FDA approval, it will be necessary to manufacture enough product to vaccinate a substantial portion of the population. Based on the estimates of the infectivity of SARS-CoV-2, it is anticipated that approximately 70% of the population will need to be immunized in order to achieve herd immunity5 and an effective vaccination will require two doses administered approximately two weeks apart.6 Since the current population of the U.S. is approximately 330 million, it will require a minimum of approximately 462 million doses of vaccine to immunize 70% of the people. However, to make the vaccine available to anyone who wants to be vaccinated, the total number of doses needed will be closer to 700 million. This is approximately four times the number of flu vaccines distributed in the U.S. for the 2019-2020 flu season.7 Given that the need for vaccines against SARS-CoV-2 will be additive to the current need for vaccines to prevent other infectious diseases (e.g., flu, measles, mumps, rubella, tetanus, etc.), there will be a huge need to increase the capacity for vaccine production.
BARDA has invested over $2.2B to support the development of SARS-CoV-2 vaccines via grants to five pharmaceutical companies:8
• AstraZeneca has received $1.2B to develop and produce a replication-deficient simian adenovirus expressing the Spike Protein antigen of the SARS-CoV-2 virus (designated: AZD1222). This grant is to cover late-stage clinical testing of about 30,000 subjects, the development of large-scale manufacturing, processes, technology transfer (presumably to some contract manufacturers), and production of 300 million doses of vaccine.
• Janssen Research and Development, LLC (a subsidiary of Johnson & Johnson) has received over $456M to develop a SARS-CoV-2 vaccine utilizing their Adenovirus serotype 26 (Ad26) platform technology. Ad26 gains entry to cells via binding to cell surface sialic acid.9
• ModernaTX, Inc. has received $430M late-stage development and eventual FDA licensure of their SARS-CoV-2 mRNA-1273 vaccine which is currently in Phase-1 clinical trials. The mRNA of this vaccine is packaged into lipid nanoparticles for intramuscular administration and encodes the prefusion stabilized SARS-CoV-2 Spike Protein.10
• Protein Sciences (a subsidiary of Sanofi-Pasteur) has received nearly $31M to support non-clinical and Phase-1 clinical studies of a recombinant baculovirus vector expressing the SARS-CoV-2 spike protein.
• Merck and IAVI has been awarded approximately $38M to develop a vaccine based on a live recombinant vesicular stomatitis virus (VSV) that expresses the SARS-CoV-2 Spike protein. This VSV vaccine platform has been previously approved by the FDA for an Ebola virus vaccine.11
Opportunities for therapeutics
Because the COVID-19 disease detrimentally affects multiple physiological functions, the scope of products that are needed to treat the disease is broader than that of the vaccine product. In addition, the number of doses of therapeutic products will not be as massive as that required for a vaccine, since the population needing treatment will be less than the multitude who need to be vaccinated.
In the therapeutics arena, BARDA has provided over $356M to eight companies to develop treatments for the COVID-19 disease:12
• Janssen Research & Development, LLC was the big winner here, receiving nearly half the total pot of money ($152.3M) to screen a multitude of existing compounds for antiviral activity against SARS-CoV-2. This work will be done in collaboration with the Rega Institute of Medical Research in Belgium. The work will focus on compounds that already have prior safety and clinical trial data.
• Regeneron Pharmaceuticals, Inc. is next in line, having secured two grants. One for $82.4M to develop new therapeutic monoclonal antibodies (mAbs) against the SARS-CoV-2 virus and a second grant for $16.4M to perform a Phase-2/3 clinical trial to determine if the FDA-approved anti-IL6 mAb (Kevzara (sarilumab)) can reduce symptoms of inflammation in hospitalized patients with critical or severe COVID-19 disease.
• Genentech USA, Inc. has received two grants. One for $25.1M for a clinical study to determine if their FDA-approved mAb against the IL6 receptor (ACTEMRA (tocilizumab)) can be an effective treatment for the uncontrolled inflammatory response in patients with severe COVID-19 disease. The other is for $22.6M to perform a Phase 2 clinical trial to evaluate the safety and efficacy of a combination therapy of a mAb against the interleulkin-33 receptor (anti-ST2) and a recombinant interleukin-22 – Fc fusion protein.
• AstraZeneca has received a grant for $23.6M to develop a combination product composed of two mAbs against the SARA-CoV-2 Spike protein and perform a Phase 1 clinical trial with the investigational drug product.13
• Emergent Biosolutions’ Center for Innovation in Advanced Development and Manufacturing (CIADM) and Grifols Shared Services North America, Inc. have received grants of $14.3M and $12.6M, respectively, to develop investigational therapeutic treatment options based on polyclonal antibodies derived from the sera of recovered COVID-19 patients. These grants do not include support for clinical studies.
• SAb Biotherapeutics, Inc. was granted $7.2M to develop an investigational therapeutic polyclonal Ab product (SAB-185) using their proprietary in vivo platform technology that does not require sera from survivors of COVID-19 as a starting material.
Opportunities for diagnostics
BARDA has awarded 22 grants for the development of diagnostic test kits and reagents totaling $41.7M USD.14 Half of these devices (eleven) have received EUAs from the FDA. The three largest awards are to Hologic, Inc. ($13M), Cue Inc. ($13.7M), and Cepheid ($3.7M) for the development of virus detection test kits. The remaining awards to the other 19 companies are each for less than a million dollars. Among the devices being developed, 16 are for detection of viral nucleic acids (DNA or RNA) and six are for detection of anti-SARS-CoV-2 antibodies in human serum.
Recently published FDA guidance for industry
Since March 17, 2020, the FDA has published 54 COVID-19-related guidance documents for Industry, FDA staff, and other stakeholders.15 Twenty-four of these guidances are relevant to drugs and biologics and 20 are relevant to medical devices. Of the medical device guidances, 15 describe temporary enforcement policy changes that will be in place during the COVID-19 health emergency. We have selected three of the recent guidance documents for summary here:
• “COVID-19: Developing Drugs and Biologics for Treatment or Prevention
– Guidance for Industry,” July/August 2020,16 provides guidance for clinical development of drugs and biologics for the treatment or prevention of COVID-19. Although preventative vaccines and convalescent plasma products are out-of-scope of this guidance, FDA has published a separate guidance document regarding development of convalescent plasma products (see below). Some salient points from this guidance include the following:
- A strong recommendation to utilize randomized, placebo-controlled, double-blind clinical trials using a superiority design to evaluate potential therapeutics or preventative drugs.
- Virological endpoints are not appropriate for demonstrating efficacy in Phase-3 clinical trials of therapeutic products. Endpoints should evaluate how a trial subject feels, functions, and/or survives.
For preventative products, the primary endpoint should be the occurrence of SARS-CoV-2 infection through a specified time-point.
Statistical analysis of the primary efficacy endpoint should be performed on the intent-to-treat population.
• “Investigational COVID-19 Convalescent Plasma – Guidance for Industry,” May 1, 2020,17 provides guidance for healthcare providers and investigators regarding the requirements for administering convalescent plasma to COVID-19 patients under an IND, an Expanded Treatment Protocol, or a Single-Patient Emergency IND. Some salient points from this guidance include the following:
- Convalescent plasma is an investigational drug and must only be administered under an IND
- A National Expanded Access Treatment Protocol for patients who are not eligible for, or who are unable to participate in, a randomized clinical trial is available through the Mayo Clinic.18
- The process for obtaining authorization for a Single Patient Emergency IND are provided.
- Regardless of the type if IND pursued, the convalescent plasma product must be from eligible donors, have assurances of adequate chemistry, manufacturing, and controls, and preferably have a SARS-CoV-2 neutralizing antibody titer of at least 1:160.
• “COVID-19 Public Health Emergency: General Considerations for Pre-IND Meeting Requests for COVID-19 Related Drugs and Biological Products – Guidance for Industry and Investigators,” July/August 2020,19 provides guidance on the preparation of pre-IND meeting requests for therapeutic and preventative investigational drug and biological products. Some salient points from this guidance include the following:
- Communications with FDA regarding a new investigational drug or biologic for treatment or prevention of COVID-19 should be initiated via a pre-IND meeting request, even if the product is currently being studied under an IND for a different clinical indication.
- Unlike the normal meeting request process (i.e., separate submission of a meeting request and a pre-meeting package of information), pre-IND meeting requests for COVID-19 products should include the meeting package, the protocol, and the questions about which the sponsor is seeking input on.
- To expedite the process, pre-IND meeting request should be submitted through the Electronic Submissions Gateway (preferred), via CDER’s NextGen Portal, or to CBER via email at eMailSub@fda.hhs.gov.20
Although we are faced with significant challenges, hopefully the recently published guidance documents from the FDA in conjunction with the financial support from the Federal government and the efforts and ingenuity of the industrial sector will provide us with vaccines, therapeutics, and diagnostics that will allow the healthcare system to control the spread of the SARS-CoV-2 virus and minimize devastating health impacts of the associated COVID-19 disease.
9. (Science Advances: Vol. 5, eaax3567,https://advances.sciencemag.org/content/5/9/eaax3567