Diagnostic Developers Look to EUA Submission to Combat Novel Coronavirus (COVID-19)

China initiated its highest level of emergency response to the COVID-19 outbreak (also referred to as the novel Coronavirus) on 20 January 2020. The National Medical Products Administration (NMPA), the National Institutes for Food and Drug Control (NIFDC) and the Center for Medical Device Evaluation (CMDE) have all been tasked with supporting emergency preparedness through the development and availability of medical products to combat the virus.

Just days later, on 31 January, the World Health Organization (WHO) declared the outbreak as a Public Health Emergency of International Concern (PHEIC), calling on the medical device industry as a whole to provide an effective roadmap for emergency diagnostics and to offer a clear path for evaluation of diagnostic tests during, and potentially after, this state of emergency.

To contain this situation, the NMPA has permitted EUA (Emergency Use Authorization) of several polymerase chain reaction (PCR)-based tests, as indicated within the timeline and activities below:

26 January: In just four days, the NMPA issues EUAs to four domestic manufacturers and approves two PCR-based tests to detect COVID-19 from HuaDa Biotech, Shanghai ZJ Bio-Tech Co and GENEODX. One test is cPAS-based (combined probe anchored polymerization sequencing method) from BGI, along with a software system for COVID-19 analysis from BGI (WUHAN).

27 January: The NMPA permits the provincial food and drug administration to authorize the emergency import of unapproved medical products by NMPA from the U.S., Europe and Japan.

Each overseas manufacturer is permitted to enter the Chinese marketplace and, if approved, the provincial food and drug administration will issue a statement for rapid custom clearance by facilitating and requesting the following documentation from each manufacturer:

• Free Sale Certificate/Certificate of Marketing Authorization from the country-specific (region) Competent Authorities
• China Type Testing Report (each provincial food and drug administration will open a green channel to get type testing reports within the most expeditious timeline)
  • Note: Type testing typically requires at least four to six months, or in some cases up to nine months; this has been shortened to ten days under the EUA pathway
• Self-assurance declaration from the Sponsor for the product quality, performance, safety, and effectiveness

28 January: The NMPA issues EUAs to two domestic manufacturers and approves two PCR-based tests to detect COVID-19 from DAAN GENE and Sansure Biotech.

31 January: The NMPA issues EUA to one new domestic manufacturer and approves this PCR-based test to detect COVID-19 from BioGerm.

3 February: The China-Japan Friendship Hospital in Beijing begins clinical trials enrolling approximately 452 subjects (NCT04257656) with severe COVID-19 respiratory disease and 308 subjects (NCT04252664) with mild to moderate 2019-nCoV Respiratory Disease using an experimental drug called Remdesivir. This drug, from Gilead Science in the United States, claims to have successfully treated one case in the U.S. The Phase III clinical trial began on February 3 and will close on 27 April for NCT04252664 and 1 May for NCT04257656. Additional information: https://www.clinicaltrials.gov/ct2/show/NCT04252664?term=remdesivir&draw=2&rank=2

Whereas a normal phased approach to launch a drug (Phase I-III) can take several years, in emergency use, the drug trial was advanced to Phase III and is estimated to be completed within three months.

Regulations Governing Emergency Use Products
Currently, the following regulatory acts govern the preparedness for, and response to, emergent public health hazards in China.

1. Regulations on Preparedness for and Response to Emergent Public Health Hazards (State Council Decree No.376), March 28, 2008
   
2. Emergency Use Authorization (Guo Shi Yao Jian Xie [2009] No.565), published on August 28, 2009
3. Supervision and Administration of Medical Devices (State Council Decree No.680), published on May 4, 2017
   
4. Provisions for Medical Device Registration (NMPA Decree No.4), published on July 30, 2014
5. Provisions for In Vitro Diagnostic Registration (NMPA Decree No.5), published on July 30, 2014
   

These regulations govern targeted medical products, referred to as “medical countermeasures” (MCMs). These include products that can directly detect or treat COVID-19-related disease and include drugs (e.g. antivirals and antidotes), biological products (e.g. vaccines, blood products, and biological therapeutics) and devices (e.g. in vitro diagnostics and personal protective equipment). PCR-based technologies that detect COVID-19 are classified as Class III.

There is a set fee associated with securing new product registration in China, which every Sponsor has to factor into their budget, as the following table demonstrates:

Device Class	Registration type	Domestic registration fee	Imported registration fee (RMB)	Imported registration fee (USD)	Imported registration fee (EUR)
Class III	New registration	￥153,600	￥308,800	$43,921	€39,191

Proposed Pathway to Secure EUA under NMPA
To submit an EUA application for COVID-19, an IVD manufacturer must follow the process outlined below.

• Abide by Section 2 of No. 565 that states “unified command, early intervention, rapid and effective approval under scientific basis”
• Submit EUA application to the NMPA or Provincial Food and Drug Administration
• NMPA or Provincial Food and Drug Administration to organize one panel meeting within three days of receipt of the EUA application to decide on final result; if yes, Competent Authority will define the product classification
• For Class I tests/devices, the NMPA will issue a EUA certificate within five days
• For Class II tests/devices, a complete technical review is completed within five days of receipt of application and the NMPA will issue a EUA certificate within three days
• For Class III tests/devices, the NMPA will offer a complete technical review within ten days of application and will issue a EUA certificate within three days (Note: An entire product registration for a Class III device can typically take up to 3.5 years)

Conditional Approval
It is also important to note that under section 3 of No. 565, the NMPA may revoke a EUA certificate if, among other things, the criteria for issuance are no longer met.

Under section 4 of No.565, a EUA certificate may be issued only if the NMPA concludes there is no adequate, approved and available alternative to the product OR the approved available products are not sufficient enough for diagnosing, preventing or treating the disease or condition.

Demonstrating Clinical Evidence for EUA
As with all tests, there is always debate as to how much clinical evidence is required to secure a EUA certificate in China. It is important to note that, although the NMPA has issued a total of eight EUAs for COVID-19 IVDs, all of these are conditionally approved with a one-year license.

Additional considerations:

• The NMPA has requested each EUA applicant continue a clinical study at a minimum of three sites (involving China CDC) with a statistically significant sample size to extend the shelf life of the assay on the market post the expiry of its current license.
• The NMPA has also requested that each EUA applicant continue studies such as the analytical and stability performance, and other associated R&D trials, in order to complete the renewal of the product license.

Conclusion
The NMPA is diligently working through aggressive timelines in an effort to provide effective treatments for COVID-19, including faster turnaround times for type testing and drug trial evaluation. Due to the epidemic of this disease, other type testing projects have been on hold while patient health related to COVID-19 is addressed. Given the ample sample size of infected individuals, IVD Sponsors are able to quickly ramp-up and complete a clinical trial within a shortened timeframe.

CMDE has taken steps to limit face-to-face window consultations and applicants may only send questions online with responses expected by email or by phone.

How Can NAMSA Help?
NAMSA is the industry leader in driving successful regulatory outcomes through effective interactions with China’s NMPA. Our internal team of IVD development experts communicate with Chinese entities routinely and are the most experienced in industry at accelerating regulatory submissions and approvals for IVD manufacturers.

Learn more about NAMSA’s regulatory service offerings by visiting namsa.com/services/consulting/. We also invite you to get in touch by submitting a request at: https://www.namsa.com/contact-us/.