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Executive Summary

US FDA’s Medical Countermeasures Initiative authorities like emergency use authorization have not yet had much of an impact on drugs and biologics, but agency is committed to supporting a swift response to the new strain of coronavirus.

The US Food and Drug Administration’s efforts to build a framework for speeding responses to emerging infectious diseases and biowarfare threats – collectively known as medical countermeasures – have seen far more use by diagnostics developers than by drug and vaccine sponsors, but the agency’s multi-pronged MCM initiative is readying potential responses to the emerging coronavirus.

“FDA stands ready to work with medical product developers to clarify regulatory and data requirements necessary to move products forward in development as quickly as possible,” the agency stated on a new landing page for its coronavirus response. “There are currently no FDA-approved medical countermeasures for 2019-nCoV.”

“The agency is sharing updates on processes in place to help developers understand the pathways, including Emergency Use Authorization (EUA), that may be available to more rapidly advance and make medical countermeasures available for this virus, including diagnostic tests,” FDA said in a 27 January statement.

Diagnostics take precedence in the face of an emerging infectious disease. “Being able to quickly and accurately diagnose patients infected with the novel coronavirus is an essential step in helping patients identify the need for care and mitigate the spread of the virus to additional individuals,” FDA emphasized.

“Currently, there are no commercially available products that are authorized to detect novel coronavirus; however, the FDA is actively working to facilitate the development and availability of diagnostics.” FDA pointed to work with “public health partners to advance and share the reference materials necessary to facilitate diagnostic development.”  (Also see "FDA ‘Stands Ready’ To Fight Coronavirus Via Emergency-Use Test Kits While WHO Mulls Virus Spread, Gets Out Guidance" - Medtech Insight, 23 Jan, 2020.)

Authorizing Emergency Use

One of FDA’s key tools against emerging infectious threats remains the EUA pathway, established by the Project BioShield Act in 2004 to allow the authorization of unapproved medical products (or unapproved uses of approved products) during a declared emergency stemming from biological, chemical, radiological or nuclear material (CBRN) or a naturally occurring emerging infectious disease.

The authority has been expanded and reinforced by the Pandemic and All-Hazards Preparedness Reauthorization Act in 2013 and the 2019 Pandemic and All-Hazards Preparedness and Advancing Innovation Act of 2019.

The EUA pathway has been well-used by the diagnostics industry. Infectious disease assays and tests are available under active EUAs for anthrax, Ebola virus, enterovirus D68, H7N9 influenza, Middle East respiratory syndrome coronavirus (MERS-CoV) and zika virus.

Fewer therapeutic or prophylactic products have obtained EUAs. Of the two that are active, neither is for an infectious disease.

Story continues after the table…

Emergent BioSolutions Inc. is seeking an EUA for its next-generation anthrax vaccine candidate AV7909, formerly NuThrax, in partnership with BARDA. AV7909 is an adjuvanted vaccine that the company says elicits a faster immune response than available vaccines like the company’s Biothrax.

Under a pre-EUA agreement, AV7909 was introduced into the US Strategic National Stockpile in the third quarter 2019, Emergent said. A BLA filing is planned for fourth quarter 2021.

Incentive Programs

The highest profile MCM program at the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research would be the MCM priority review voucher, which is awarded upon approval of qualifying new molecular entity or novel biologic MCM agents. The MCM PRV program parallels the agency’s tropical disease PRV and neglected pediatric disease PRV programs.  (Also see "Priority Review Vouchers Post Lower Average Approval Times Than Priority NMEs" - Pink Sheet, 15 Oct, 2019.)

Only two MCM PRVs have been awarded: toSiga Technologies Inc.’s smallpox treatment Tpoxx (tecovirimat), approved July 2018, and
Bavarian Nordic AS' Jynneos vaccine for smallpox and monkeypox, approved September 2019.

Some emerging infectious disease therapies can qualify for either the MCM PRV or the tropical disease PRV, but not both. Diseases eligible for tropical review PRVs include cholera, filovirus diseases, dengue, Zika and Lassa virus diseases, and chikungunya.

FDA has issued 11 tropical disease PRVs, most recently upon the approval ofMerck & Co. Inc.’s Ebola Zaire virus vaccine Ervebo on 19 December 2019. Other infectious disease vaccines with tropical disease PRVs includeSanofi’s dengue vaccine Dengvaxia, approved in May 2019, andPaxVax Inc. (now Emergent BioSolutions Inc.’s) cholera vaccine Vaxchora in 2016.

Approval Pathways

FDA’s broader approval pathways offer regulatory options for MCM infectious disease developers, in particular accelerated approval and the animal rule. Both pathways, however, rely on a well-characterized disease knowledge that can justify surrogate endpoints and animal models that are reasonably likely to predict clinical benefit. That kind of knowledge is conspicuously lacking in emerging disease situations like the coronavirus.

The Animal Rule pathway is an option for situations where human challenge studies are not ethical and field trials of efficacy are not feasible. FDA can base an approval decision (supplemental or original) on well-controlled animal studies that establish a reasonable likelihood of clinical benefit in humans. Human safety data is still needed.

The animal rule is unlikely to be applicable to emerging diseases like the coronavirus, where the human course of the disease is still being determined, let alone well-validated animal models. But the FDA’s animal rule has been invoked to support eight infectious disease approvals, including smallpox treatment Tpoxx in 2018 and new plague indications for the antibiotics Levaquin (2012), Cipro (2015) and Avelox (2015).

Anthrax is represented with three therapy approvals –Elusys Therapeutics Inc.’s Anthim (obiltoxaximab) (2016),Cangene Corp.’s anthrax immune globulin Anthrasil (2015), andHuman Genome Sciences Inc.’ (nowGlaxoSmithKline PLC’s) raxibacumab (2012) – as well as Emergent’s Biothrax vaccine for post-exposure prophylaxis (2015).

The most recent use of accelerated approval to support an infectious disease indication was the 2017 clearance ofChemo Group’s benznidazole for Chagas disease.Johnson & Johnson’s treatment for pulmonary multi-drug resistant tuberculosis Sirturo received accelerated approval, and Levaquin and Cipro both hold accelerated approval for anthrax indications.

How Fast Can Sponsors Go?

Against a backdrop of steady media attention to the coronavirus, the private sector has leapt into the development of 2019-nCoV therapies – with some very ambitious timelines.

Janssen began work on characterizing the 2019-nCoV virus several weeks ago, using a viral genome sequence released by Chinese scientists. (Also see "Coronavirus: Can Companies Achieve Vaccine Ambition?" - Scrip, 28 Jan, 2020.)

J&J’s chief scientific officer and infectious disease veteran Paul Stoffels has declared that the company can develop a vaccine and make it available at scale within 8-12 months.

“We are comfortable that we can create a vaccine and scale it up,” Stoffels told CNBC on 27 January.

“We have done this in Ebola in six months from having a construct virus to scaling it up and bringing to humans,” Stoffels said. “With Zika we’ve done that in 12 months where we did not have the virus and we had to start from scratch. Here we are in the same situation as Zika, we had to start from a sequence.”

A public-private partnership established at Davos in 2017, the Coalition for Epidemic Preparedness Innovations (CEPI), is floating an even faster process, with a goal of moving from generating candidates to commencing clinical trials within 16 weeks.

Janssen is developing at least five different virus constructs with different partners around the world. The company also has a team constructing an animal model in which to test these candidates, and a team scaling up production capacity for if and when an active vaccine is discovered.

Stoffels said that the company was confident that its next-generation manufacturing processes, including its AdVac adenovirus vector platform, would allow it to produce up to 300m doses a year.

The nCoV-2019 virus offers the first test of the CEPI model to promote vaccine development to stop future epidemics. CEPI announced the initiation of three programs on 23 January. Two build on existing partnerships that are targeting another coronavirus, Middle East respiratory syndrome (MERS-CoV). (Also see "Moderna, Inovio Coronavirus Vaccine Candidates Fast-Tracked By International Coalition" - Scrip, 27 Jan, 2020.)

Inovio Pharmaceuticals Inc.’s CEPI funding will support preclinical and Phase I clinical testing of INO-4800, the company’s DNA vaccine matched to the 2019-nCoV outbreak strain. CEPI and Inovio already have a partnership for DNA vaccine candidates against MERS -CoV and Lassa fever. CEPI and the University of Queensland have been working on a “molecular clamp” vaccine platform under a January 2019 agreement to produce vaccines against pathogens including MERS-CoV and influenza and conduct Phase I. The technology, which synthesizes viral surface proteins while “clamping” them into a stable shape, “can be used to develop vaccines against a wide range of enveloped viruses,” CEPI noted.

Moderna Inc.will develop a messenger RNA vaccine against 2019-CoV with CEPI funding. Moderna collaborated with the Vaccine Research Center at the National Institutes of Health to design the vaccine, and NIH will conduct IND-enabling studies and Phase I.

“Our mRNA vaccine technology offers potential advantages in the speed of development and production scalability,” Moderna said in announcing the CEPI deal.

The surge of publicity and concern about nCoV-2019 can help to move drug development along faster, but there are hurdles that cannot be bypassed if a therapeutic or vaccine is to receive FDA approval.

Fast-moving infectious diseases, especially those with sporadic and unpredictable outbreaks, are difficult targets for clinical efficacy trials – by the time a clinical trial is up and running, the outbreak may have waned – yet the absence of trusted immune correlates of protection or animal models leaves little in the way of the alternatives. An FDA advisory committee dived into such issues in its discussion of chikungunya virus vaccine development. (Coverage will appear in a subsequent issue of the Pink Sheet.)

The example of Merck’s Ervebo may be more optimistic. The first Ebola vaccine received full approval on 19 December 2019, earning a tropical disease PRV. CBER Director Peter Marks lauded the clinical program, which used a ring vaccination strategy. "The research approach used to study the effectiveness and safety of this vaccine was precedent-setting during a public health emergency and may help create a model for future studies under similar circumstances," Marks said in a statement.  (Also see "Keeping Track Of The US FDA's Final Novel Approvals, CRLs Of 2019" - Pink Sheet, 5 Jan, 2020.)

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