Around the Globe

Improving Access: Singapore’s Innovations for COVID-19 Diagnostics and Therapeutics
Silke Vogel
James Leong
Uttara Soumyanarayanan
Centre of Regulatory Excellence, Duke-NUS Medical School
@dukenus
W

hat are the best drugs to treat COVID-19 patients? How long do antibodies offer protection against SARS-CoV-2 infections? When will the first vaccine be rolled out for mass immunization?

As the entire globe grapples with the COVID-19 pandemic, we are witnessing an unparalleled rate of advances in scientific research seeking to answer these questions. Owing to high-calibre scientific communities across the globe, there has been enormous progress in COVID-19 research within a short span, generating and evaluating a myriad diagnostic and therapeutic options. The rapidly evolving disease puts decision-makers in a precarious position, trusted with the responsibility to strike a cautious balance between safeguarding public health while accelerating access to these products.

The Centre of Regulatory Excellence (CoRE), Duke-NUS Medical School organised a webinar with experts from Singapore who are at the forefront of innovations during the COVID-19 pandemic. The scope of the webinar spanned developments in diagnostics, therapeutics, vaccines, and insights on regulatory systems to support their market launch.

Key Takeaways

  • Repurposing existing drugs (hydroxychloroquine and lopinavir/ritonavir) and other experimental treatments from past pandemics (e.g., remdesivir) has been one of the primary approaches to seeking a suitable treatment. However, conclusive data on efficacy and safety are still lacking.
  • Duke-NUS in collaboration with Arcturus Therapeutics is developing an mRNA vaccine against SARS-CoV-2. A crucial challenge is reducing the vaccine development timelines, preferably to one year.
  • Along with efficacious vaccine candidates, a good communication strategy is critical to execute an effective mass vaccination program.
  • The Singapore Health Sciences Authority (HSA) is providing provisional pathways for a risk-calibrated expedited review of diagnostic kits.
  • Multi-disciplinary collaborations between research institutes, the clinical community, and regulatory agencies were pivotal to facilitate timely access.

Repurposing Therapeutics for COVID-19

While a multitude of vaccine development programs are underway, repurposing existing drugs has been one of the primary therapeutic approaches adopted to address the ongoing medical crisis. Jenny Low Guek Hong (Singapore General Hospital) overviewed drugs currently being studied in hospitalised COVID-19 patients.

More than 100 therapeutics are under investigation for the treatment of COVID-19. Remdesivir, an investigational drug candidate that inhibits viral replication, has shown positive results when administered for compassionate use in critical patients. A few other immunomodulators are being tested for their response during the cytokine storm (an overreaction of the body’s immune system) in severe COVID-19 patients. Convalescent plasma containing antibodies from recovered COVID-19 patients in China has shown good clinical outcomes, shortened fever duration, and reduced inflammatory markers in five patients; these findings are yet to be corroborated in randomized controlled trials. Two repurposed drugs, hydroxychloroquine and lopinavir/ritonavir, have yet to demonstrate any substantial clinical benefits based on studies conducted to date.

Overall, conclusive safety and efficacy data on these treatment options are lacking and systematic trials evaluating their clinical efficacy against SARS-CoV-2 would reveal their true value in COVID-19 management. (After this webinar, US FDA announced the approval of remdesivir for emergency use, while Japan PMDA approved it for use in patients with severe COVID-19.)

Diagnostic Innovations in Singapore

Innovation in technology for infectious diseases is governed by multiple factors such as the nature of the pathogen, and the capabilities to detect, isolate, trace, and treat the infection. Sidney Yee (Diagnostics Development Hub [DxD Hub]) shared the team’s journey navigating the challenges posed for developing a SARS-CoV-2 diagnostic technology that not only fulfils the technical requirements but can also be effectively scaled up for mass production and supply. DxD Hub developed the RT-PCR-based Fortitude Kit for SARS-CoV-2 (COVID-19) detection within a month. The kit received provisional authorisation from the Health Sciences Authority (HSA) of Singapore and is being used in Singapore hospitals as well as in many other countries for diagnostic purposes.

The phase of infection and expected analytes in diagnosis are essential factors that dictate the type of technology to be employed. Apart from the gold standard RT-PCR, kits based on isothermal amplification and direct DNA hybridization principles have also been developed for detecting SARS-CoV-2. However, the choice of technology platform is not solely determined by its clinical utility; supply chain and procurement (nucleic acids, antibodies, etc.) must be borne in mind as shipment logistics are severely crippled in such situations.

Yee highlighted the importance of multi-disciplinary collaborations between research institutes and the clinical community as well as regulatory agencies in building and evaluating the various components of the kit and its subsequent launch in the market within a short time span.

Massive Challenge: Shortening Decade-Long Vaccine Development Timeline

Amid the uncertainties of antibody protection duration and probability of reinfections, scientists are racing against time and investing large amounts of capital in pursuing the most hopeful tool to curb the COVID-19 impact – a SARS-CoV-2 vaccine. There are a number of approaches to viral vaccine development, including the use of inactivated or live attenuated virus, synthetic peptides, virus-like particles, DNA, or RNA. Much of the vaccine development effort across the globe is focused on the latter options, as developing live attenuated and inactivated vaccines is expensive and possibly long and drawn out.

Ooi Eng Eong (Duke-NUS Medical School) is developing in collaboration with Arcturus Therapeutics an mRNA vaccine that can be rapidly bulk-manufactured in laboratories. To meet such urgent need, developers face completing this mammoth task within a year. Eong urged for public advocacy for participation in these trials, suggesting that patient volunteers and funding are vital catalysts to compressing current clinical testing timelines. With limited resources and multiple potential candidates, understanding the molecular basis of the vaccine immune response is critical to making informed decisions on choosing and investing in the most viable candidates for further development.

Role of Regulatory Systems: Expediting Access to Safe Innovations

Quick advancements in COVID-19 innovation have placed the responsibility to speed up the review and approval of applications on HSA to ensure the safety and efficacy of these innovations.

Sethuraman Rama (Medical Device Branch, Singapore HSA) elaborated on this holistic approach, which ranges from pre-market consultations to ensuring compliance with post-market requirements. HSA’s scientific and regulatory input to innovators has been pivotal in the successful design, development, and launch of test kits. To support timely access, provisional authorisation pathways using risk-calibrated expedited review have been devised for approving reasonably safe and effective diagnostics. HSA has approved 16 SARS-CoV-2 diagnostic kits by this pathway since the outbreak of the pandemic. Post-approval requirements demand additional data on assay performance which are sought periodically. Furthermore, to specifically meet local clinical needs, HSA offers facilitated access to respiratory devices often required for critical care patients, such as ventilators.

With multiple repurposed drugs waiting to be tested, Foo Yang Tong (HSA) shared HSA’s strategies for expediting clinical trials of COVID-19 investigative treatments. Using input from a “Whole-of-Government” approach, HSA has recently approved three clinical studies involving remdesivir based on an adaptive design and rolling submission strategy. HSA has been actively engaging in dialogues with regulators across the globe, including the FDA, EMA, Health Canada, and other experts and platforms to facilitate coordinated action across multiple jurisdictions during the pandemic. Several drugs have shown promise in early phase COVID-19 testing, and regulators strongly recommend conducting multicentre randomized clinical trials that generate robust safety and efficacy evidence to enhance chances of regulatory approval.

How Would an Ideal Vaccine Work?

Various modalities are currently being explored for developing vaccine candidates, and a coherent framework is essential to measure their effectiveness in diverse populations. Tippi Mak (SingHealth Duke-NUS Global Health Institute) shared the salient points of the Target Product Profile guideline that WHO has formulated for an accelerated COVID-19 vaccine development program. These criteria–indications of preferred outcomes for vaccines, such as measures of efficacy, duration of protection and safety, are essential for developers when evaluating the efficacy of COVID-19 vaccines. Additionally, the document lists minimal outcomes to guide assessment during a pandemic. Although children do not constitute the COVID-19 vulnerable population, they can act as virus carriers, and vaccinating them is imperative for achieving herd immunity.

Further, phase 2 trials should assess the potential of the vaccine for “antibody dependent enhancement (ADE),” which is crucial when drawing conclusions about the benefit/risk profile of the candidate.

A few key considerations and planning strategies must precede the mass rollout of any COVID-19 vaccine. These include stretching global manufacturing capacity, establishing protocols for measuring safety and effectiveness, and leveraging technology throughout the development and lifecycle plan. Good communication strategies, along with an abundance of efficacious vaccine candidates, will be critical to execute an effective mass vaccination program.

A multi-pronged strategy blending every stakeholder’s role in the development of innovations will go a long way in helping the world cope with the COVID-19 pandemic. Multidisciplinary collaborations across nations will be crucial in delivering comprehensive solutions to meet massive global demand. Data requirements and interpretations might drive new measures in our current, rapidly changing scenario, but concerted effort from regulators and innovators will remain integral to driving and delivering safe and effective innovations to combat COVID-19.

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