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MDIC-FDA Workshop: Advancing EUA IVD Products Toward Full Marketing Status

On February 3, 2020, MDIC and FDA hosted a workshop on advancing emergency use authorization (EUA) in vitro diagnostic (IVD) products toward full marketing status at the FDA White Oak Campus in White Oak, Md. The 240 participants included FDA representatives, IVD sponsors, researchers, and organizations providing products and services related to the development and study of IVDs. About 150 people participated in the live meeting and about 90 people joined online.

Participants explored key considerations for using real-world data (RWD) to generate real-world evidence (RWE) to help support IVD products in advancing from EUA to full marketing status (De Novo or 510(k)). They identified challenges and next steps to the use of RWD and RWE to help support full marketing status for more EUA IVD products.

This summary provides a brief overview of each presentation and panel discussion, with links to videos of all presentations and discussions and slides from most presentations.

You can also access all the videos and slides here.

How to View the Sessions

To view the sessions, you’ll need to download Adobe Connect (at no charge).

Morning Sessions 1

Opening Session: Introduction to Emergency Outbreak Situations and Data Collection

Keynote: National Preparedness and Response in the 21st Century
Luciana Borio, MD
Vice President of Technical Staff, In-Q-Tel

The novel coronavirus, which hadn’t yet become a global pandemic at the time of the workshop, highlights the importance of diagnostic tests in outbreak management and control. Through EUAs, the FDA has provided timely access to diagnostic tests during the 2009 H1N1 influenza pandemic, the 2014 West African Ebola epidemic, and the 2016 Zika epidemic in the Americas. The agency worked alongside IVD developers in real time to validate and authorize these tests. In 2013, EUA authority was expanded to allow the FDA to act based on the threat of an emergency, instead of waiting until after the emergency has occurred.

Yet advancing EUA IVD products to full marketing status has been a struggle, due to lack of incentive for the commercialization of many diagnostic tests and government policies that prioritize therapies over diagnostic tests as countermeasures. Progress will require collaboration and funding by the U.S. government and other partners to promote the systematic collection of RWD that could be used to support FDA approval of IVDs.

The necessary collaboration can only take place if partners frankly discuss obstacles, understand the capability of each partner, and develop shared responsibility for advancing EUA IVD products to full marketing status.

Watch this presentation in Morning Sessions 1, starting at 7:14.

Keynote: Evaluating Novel Diagnostics in an Outbreak Setting: Lessons Learned from Ebola
Nira Pollock, MD, PhD
Associate Medical Director of Infectious Diseases, Diagnostic Laboratory, Boston Children’s Hospital
Faculty Member, Division of Infectious Diseases, Beth Israel Deaconess Medical Center

During the Ebola outbreak in West Africa in 2014-2016, Pollock’s research team worked with Partners in Health to develop field studies in Sierra Leone to evaluate promising Ebola diagnostics. Challenges from evaluating novel diagnostics in the Ebola emergency setting can be applied to the COVID-19 pandemic. These challenges are related to:

• Ownership of samples and data
• Patient consent and approval of research protocols
• Regulatory authority
• Identifying a “gold standard” reference technology
• Communicating effectively.

A vision of a Global Emergency Diagnostic Framework emerged as a way to address these challenges. Such a framework would include standards for diagnostic evaluation (or, optimally, also development and evaluation) in an outbreak setting set in advance by an international expert committee.

Also, An R&D Blueprint for Action to Prevent Epidemics; Plan of Action came out of the Ebola outbreak (published by WHO in 2016 and updated in 2017 and 2018). If development efforts during outbreaks use
fair and transparent principles which will have been negotiated before the emergency by all stakeholders, the global community will benefit, according to the blueprint. Stakeholders must work together to develop a framework for development and evaluation of diagnostics in an outbreak setting.

Watch this presentation in Morning Sessions 1, starting at 23:38.
View the slides.

FDA Perspective

Four representatives of the FDA shared the agency’s perspective on EUAs.
Perspective from the FDA Chief Scientist
Rear Admiral Denise Hinton
FDA Chief Scientist

Collaboration and coordination are mandatory to expedite the development and availability of safe and effective medical countermeasures, such as diagnostic tests, for use during a potential public health emergency. FDA collaborates with interagency partners, product developers, international partners, and global regulators to help drive and foster innovation to advance public health and strengthen national security.

At the onset of an outbreak such as the novel coronavirus, there are typically no legally-marketed tests for clinical use. FDA experts collaborate with other U.S. government agencies and international partners to speed the processes necessary to make tests available for emergency use under FDA’s EUA authority. Since 2009, FDA has issued more than 60 EUAs for diagnostic tests for infectious diseases such as H1N1, MERS, coronavirus, Ebola, and Zika.

Within days of receiving the genetic code for the 2019 novel coronavirus FDA drafted EUA review templates for CDC and other test developers. The agency is also developing reference materials for developers to use to validate their diagnostic tests (as of February 2020).

Watch this presentation in Morning Sessions 1, starting at 1:03:21.

OIR Perspective
Timothy Stenzel, MD, PhD
Director, OHT7: Office of In Vitro Diagnostics and Radiological Health, CDRH

With an EUA, FDA can authorize the use of an unapproved medical countermeasure or the unapproved use of an approved medical countermeasure for serious or life-threatening diseases or conditions caused by threat agents. Of the 57 EUAs that FDA has approved only 4—less than 10%—have progressed to De Novo or 510(k) status. There is an urgent need for more EUA products to progress to full authorization.

RWD and RWE may be one solution to removing barriers to full authorization. In 2017, the FDA published Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff. This guidance document highlighted the importance of relevance and reliability in using RWE. Establishing pathways for the use of RWD and RWE would remove inhibitions about using these. CDRH/OIR is committed to working with all stakeholders to advance EUA products to full marketing status as efficiently and effectively as possible.

Watch this presentation in Morning Sessions 1, starting at 1:12:05.
View the slides.

Transitioning Diagnostics from Emergency Use Authorization (EUA) to Marketing Applications
Uwe Scherf, MSc, PhD
Director, Division of Microbiology Devices, OHT7, Office of In Vitro Diagnostics and Radiological Health, CDRH

FDA encourages sponsors to interact with the agency during the EUA process and to transition EUAs to marketing applications. Under the right conditions, RWD—data relating to patient health status and/or the delivery of health care that are routinely collected—can potentially be used to support regulatory decisions. Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff describes FDA’s thinking about RWD and RWE. RWD must demonstrate relevance and reliability. Uses of RWE, the clinical evidence about the use and potential benefits or risks of a medical product derived from analysis of RWD, include:

• Expanded indications of use
• Post-market surveillance studies
• Post-approval device surveillance as a condition of approval
• Control group
• Supplementary data
• Objective performance criteria and performance goals.

Sponsors can use data obtained for an EUA in a marketing application if they have not modified the device since the EUA. If modifications have been made, a risk assessment is required to determine the extent of the changes and the influence of the changes on performance. Data generated outside the U.S. can also be used in an FDA submission if the test procedure was performed according to the package insert with no deviations. This presentation also describes the EUA and the differences between EUA and pre-market study requirements.

Watch this presentation in Morning Sessions 1, starting at 1:21:44.
View the slides.

Real-World Evidence (RWE): Context for Supporting Regulatory Decisions
Michael Waters, PhD
SHIELD Team Lead/CDRH RWE Tactical Team OIR Representative

Use of RWE to support device pre- and post-marketing decisions is a commitment made in the FDA Reauthorization Act and a strategic priority of the CDRH. Data generated in healthcare settings can be used in supporting regulatory decisions if they are high quality and provide valid scientific evidence. Data used in regulatory decisions must be fit for the purpose: complete, consistent, accurate, and contain all critical data elements needed to evaluate a medical device and its claims. They must also be relevant and reliable, and show that the benefits outweigh the risks.

FDA cleared two 510(k)s for sequencing assays for variant/variant combinations associated with cystic fibrosis using a public next-generation sequencing database. This approach of using a publicly-maintained database could also be used to support an IVD’s clinical validity in lieu of clinical trials in the EUA space. Partnerships between the sponsor, the database holders, and the FDA would be necessary to develop interoperability for the data and establish appropriate quality checks.

Watch this presentation in Morning Sessions 1, starting at 1:43:00.
View the slides.

Morning Sessions 2

Industry Perspectives on Challenges and Opportunities

Case Study: From EUA Through Direct De Novo Marketing Authorization
Estela Raychaudhuri
President, InBios International, Inc.

InBios used the EUA pathway for its ZIKV DetectTM 2.0 IgM Capture ELISA with a concurrent goal of achieving full market clearance. Interaction between InBios and the FDA smoothed the EUA process and led to the EUA for the Zika test being granted in August 2016. The FDA continued to provide feedback to InBios during the De Novo submission process, and the agency provided full marketing clearance in May 2019.

During the process, interaction with FDA and the mindset that full FDA clearance was the goal were key. Since minimal clinical data were available when the EUA was granted, InBios needed to continue to evaluate the assay with customer feedback and seek ways to improve it prior to full clearance. Collaborators, including CDC and BARDA, also played an important role. InBios also needed to prepare customers in advance of market authorization so that they could plan for validation. This presentation also covered challenges, opportunities for improvement, and how to incorporate RWE into a 510(k).

Watch this presentation in Morning Sessions 2, starting at 0:02:48.
View the slides.

Industry Panel
Moderator:
Danelle Miller, JD
MDIC Clinical Diagnostics Steering Committee Chair

Panelists:

Tracy Bush, PhD
Head of Regulatory Policy – Personalized Healthcare, Roche Diagnostics
Thomas D. Ippolito
VP Quality & Regulatory Affairs, ChemBio Diagnostics Systems, Inc.
Annabel Tsai, PhD
Sr. Manager/Scientist, Quality and Regulatory Affairs, InBios International, Inc.
Jeff Zinza
Sr. Director, Regulatory Affairs, Hologic, Inc.
Tiffany Miller, RAC
Sr. Director Regulatory Affairs, OraSure Technologies, Inc.

This panel discussion covered barriers and potential solutions in the EUA process and in developing EUAs into marketed IVDs, and the use of RWD and RWE in EUAs. Panelists shared their experiences with IVDs for Ebola and Zika. Obtaining data and samples is a key challenge both during the emergency and post-outbreak. When moving from an EUA to a marketing application, data that were sufficient for the EUA may not meet the standards for a marketing application.

Often, it is difficult to make the business case for doing a marketing application due to the cost of this process and the likely lack of commercial sustainability after the emergency. The need for fresh reagents in IVDs leads to production issues and long lead times for ordering IVDs.

Solutions for moving an EUA to a fully approved IVD included:

A sample bank and data repository that meets FDA’s standards for full marketing authorization and is available to all sponsors
A national stockpile of IVDs to fulfill demand with reasonable reimbursement to manufacturers even if the IVDs are not used
Partially processed test kits that could be finished when ordered.

RWD could be used for clinical validity. Developing sample panels and RWE platforms that are available to all sponsors would reduce the need for new clinical investigations.

Watch this presentation in Morning Sessions 2, starting at 0:21:00.

Afternoon Sessions 1

Data Approaches and Opportunities

Surveillance in Data Management in the DRC Ebola Response
Commander James Coburn, MSc, CPH
Senior Advisor for Emerging Technologies, Office of Counterterrorism and Emerging Threats, Office of the Chief Scientist, FDA

During the Ebola outbreak in the Democratic Republic of the Congo, Commander Coburn was detailed to the CDC within the Provincial Department of Health in Goma. The goal of his work was to Improve data collection and management for potential and validated alerts by standardizing procedures and creating better software tools. Surveillance was done through active research, which involved sending teams into medical facilities and to do home visits.

While there were many challenges in conducting active research, digitizing data, and using the data that were collected, much progress was made. The teams were dedicated and training led to improvements in data management, collection, and analysis. Training also helped build capacity to continue surveillance once all of the groups working in the Democratic Republic of the Congo left.

Watch this presentation in Afternoon Sessions 1, starting at 0:00:00.
View the slides.

Real-World Evidence for Diagnostics: Data Collection and Quality
Richard Gliklich, MD
CEO, OM1

In using RWD and RWE in diagnostics, three things are most important:

Getting relevant data
Ensuring that data are reliable and “regulatory grade”
Analyzing data for decision-making.

In developed locations, RWD can be collected by leveraging health information technology systems. In less developed locations without health information technology infrastructure or data availability, it may be necessary to implement a new data collection system. Another approach that is scalable, lower cost, and potentially faster is to use existing infrastructure and de-identify the data. Data from different sources must be standardized and normalized to a common data structure in order to be usable.

The use of RWD in regulatory decision-making is rapidly evolving and relies on both old and new FDA requirements and guidances. RWD needs to be fit for purpose, the study design used must provide adequate scientific evidence, and the study conduct needs to ultimately meet the FDA’s regulatory requirements.

Watch this presentation in Afternoon Sessions 1, starting at 0:06:37.
View the slides.

SHIELDx: Harmonizing Standards Application to Accelerate Innovation
Michael Waters, PhD
SHIELD Team Lead/CDRH RWE Tactical Team OIR Representative | FDA

SHIELDx is a public-private partnership focused on the adoption/development, harmonized application, and implementation of diagnostic data standards to advance innovation. The goal of SHIELDx is to describe the same test data the same way. Doing this requires engaging with stakeholders across the board.

The partnership seeks to accurately describe the test, the question being asked of the specimen, and the answer in a harmonized way. Pilots in the U.S. are underway to develop an ecosystem that supports manufacturers/industry in providing vetted and harmonized descriptive IVD codes to labs to improve utility for consumers. A regulatory framework has also been established and the IVD Industry Connectivity Consortium has already made a harmonized structure format available for free internationally. Having harmonized IVD codes would facilitate real-time transmission of test results to WHO, CDC, and registries.

Watch this presentation in Afternoon Sessions 1, starting at 0:22:30.
View the slides.

BARDA Support for Emerging Infections Diagnostics
Nina El-Badry, MS, RAC (US, EU)
Regulatory Branch Chief (Acting) Regulatory & Quality Affair, Biomedical Advanced Research and Development Authority (BARDA)

BARDA forms unique public-private partnerships to develop medical countermeasures and make them available. Along with medical countermeasures, BARDA provides core services including regulatory pre-EUA and EUA support to contractors funded by BARDA. Since 2007, BARDA has contributed to 53 FDA approvals, licensures, and clearances.

The diagnostics program for emerging diseases seeks to provide clinical diagnostic tests for rapid public health emergency response. International initiatives to address sample sharing issues include the WHO Pandemic Influenza Preparedness (PIP) Framework, International Reagent Resource, and WHO R&D Blueprint and COVID-19. The National Institute of Allergy and Infectious Diseases’ BEI Resource Repository provides reagents, tools, and information for static priority pathogens, emergent infectious disease agents, non-pathogenic microbes, and other microbiological materials.

This presentation also covered BARDA’s work in recent outbreaks of Ebola and Zika, and lessons learned about developing diagnostics for emerging infections.

Watch this presentation in Afternoon Sessions 1, starting at 0:30:12.
View the slides.

RWE Panel Discussion

Moderator:
Richard Gliklich, MD
CEO, OM1

Panelists:

Nina El-Badry, MS, RAC
Regulatory Branch Chief (Acting) Regulatory & Quality Affair, Biomedical Advanced Research and Development Authority (BARDA)
Michael Waters, PhD
SHIELD Team Lead/CDRH RWE Tactical Team OIR Representative
Commander James Coburn, MSc, CPH
Senior Advisor for Emerging Technologies, Office of Counterterrorism and Emerging Threats, Office of the Chief Scientist, FDA
Nira Pollock, MD, PhD
Associate Medical Director of Infectious Diseases, Diagnostic Laboratory, Boston Children’s Hospital
Faculty Member, Division of Infectious Diseases, Beth Israel Deaconess Medical Center

This panel discussion covered data approaches and opportunities for advancing EUAs to full marketing status. Panelists noted the importance of public-private partnerships and the need to prioritize resources.

Transitioning EUAs to full marketing status is not profitable. Companies do this to improve healthcare. Public and private stakeholders need to come together to develop a sustainable ecosystem, including for simplifying data collection, to support companies in making the transition. Resources such as funding from BARDA help move more EUAs to full marketing status. This funding sometimes provides the incentive that companies need to move from EUA to full marketing status.

Watch this discussion in Afternoon Sessions 1, starting at 0:53:48.

Afternoon Sessions 2

Biorepositories and Reference Materials

Are All Assays Equal?
Mark Page, PhD
Principal Scientist, Head of Emerging Viruses Group, Division of Virology, National Institute for Biological Standards and Control

The National Institute for Biological Standards and Control is a U.K. government institute that makes about 95% of the world’s international standards under the auspices of WHO. The institute’s work includes in vitro diagnostic standards: assay monitors and CE marked.

Dr. Page described the standards development process and highlighted the following key points:

External run control material improves consistency and traceability, ensuring the accuracy of results.
The result provided by one assay is not comparable with another unless they are calibrated to a common standard.
Different controls may have different applications, but they complement each other in the overall assurance of a test result.
Controls must be calibrated correctly and formulated from appropriate materials in order to yield meaningful results.

Watch this presentation in Afternoon Sessions 2, starting at 0:17:30.
View the slides.

Issues Related to Providing Reference Materials During an Outbreak Scenario
Mark Page, PhD
Principal Scientist, Head of Emerging Viruses Group, Division of Virology, National Institute for Biological Standards and Control

During the Ebola and Zika outbreaks, the National Institute for Biological Standards and Control identified issues related to providing reference materials during an emergency, including viruses that require high laboratory containment, inability to assure the safety of inactivated pathogens, difficulties sourcing antibodies and pathogens, and lack of suitable reagent panels for validating diagnostics for emergency use. Solutions developed by the institute included:

Nucleic amplification technology standards to make synthetic RNA packaged in lentiviral vectors
Antibody standards using transchromosomal bovines immunized with DNA/recombinant immunogens
Pseudotyped viruses in which antibodies were characterized by neutralization assays.

Dr. Page described the process used and a collaborative study during the Ebola outbreak, which resulted in the first International standard for an Ebola antibody and reference panel. He noted the need for a global framework of networked labs in order to respond rapidly to outbreaks, that real-time response is difficult, and that the next outbreak cannot be predicted.

Watch this presentation in Afternoon Sessions 2, starting at 0:29:55.
View the slides.

WHO EUAL: Past and Future
Ute Ströher, PhD
Technical Officer, World Health Organization

WHO’s Emergency Use Assessment Listing (EUAL) is a rapid assessment of the quality, safety, and performance of IVDs during an outbreak, based on a minimal level of necessary information. The key difference between the WHO EUAL and the FDA EUA is that to be considered for listing by WHO, the product must be commercially available. Challenges in the EUAL process during the Ebola and Zika outbreaks included:

Lack of a standard or benchmark
Bio banking
Access to panels and laboratories
The need of many manufacturers for R&D capacity building
Lack of clear roles and responsibilities within WHO.

The WHO EUAL was revised in 2017 to improve regulatory preparedness and to address public health emergencies, and to change the name from EUA to EUAL. The revised EUAL calls for plans for pre-emergency activities to allow a rapid listing decision once the emergency is declared. Future considerations include sustainability; curation of IVDs outside outbreaks; differential diagnosis; specimens, panels, biosafety, and inactivation; reference materials; and ease of use of specimen types versus sensitivity.

Watch this presentation in in Afternoon Sessions 2, starting at 0:46:19.

Challenges and Future Steps: Panel Discussion and Q&A
Moderator:
Sally Hojvat, MSc, PhD
Independent Consultant
Director of OIR Microbiology Division 2003-2015, CDRH, FDA

Panelists:

Jasmine Chaitram, MPH, MT (ASCP)
Associate Director for Laboratory Preparedness
Director, CDC Biorepository
Chief, Informatics and Data Science Branch, Division of Laboratory Systems, Centers for Disease Control and Prevention (CDC)
Richard Gliklich, MD
CEO, OM1
Mark Page, PhD
Principal Scientist, Head of Emerging Viruses Group, Division of Virology, National Institute for Biological Standards and Control
Nira Pollock, MD, PhD
Associate Medical Director of Infectious Diseases, Diagnostic Laboratory, Boston Children’s Hospital
Faculty Member, Division of Infectious Diseases, Beth Israel Deaconess Medical Center
Estela Raychaudhuri
President, InBios International, Inc.
Ute Ströher, PhD
Technical Officer, World Health Organization
Jeff Zinza
Sr Director, Regulatory Affairs, Hologic, Inc.
Uwe Scherf, PhD
Director, Division of Microbiology Devices, OHT7, Office of In Vitro Diagnostics and Radiological Health, CDRH

This panel reviewed the challenges identified during the workshop and highlighted next steps for moving forward in advancing EUA IVD products toward full marketing status. RWD and RWE could be a solution for many of the challenges, however, common standards must be developed. Ways to deal with uncertainty about the quality of the RWD should be discussed with the FDA before submitting a marketing application.

What constitutes sufficient clinical and analytical validity must be determined. Currently, it is difficult for FDA to make risk assessments. FDA has worked and will continue to work with manufacturers if there is a public health need to move an EUA to full marketing authorization rapidly.

Multiple challenges in increasing the availability of specimens require bringing government officials together to harmonize the framework for specimen collection and distribution and to develop a network. Funding to pay for specimens, which is now available, and development of an international IRB standard for use in public health emergencies, would be helpful. Other topics discussed included challenges in conducting studies outside the U.S. and the need to protect public health by offering financial incentives to manufacturers to move from EUA to full marketing authorization.

Watch this discussion in Afternoon Sessions 2, starting at 1:17:48.

Workshop Summary

Timothy Stenzel, MD, PhD
Director, OHT7: Office of In Vitro Diagnostics and Radiological Health, CDRH

Dr. Stenzel summarized the key challenges and takeaways from the MDIC-FDA Workshop: Advancing EUA IVD Products Toward Full Marketing Status. Key challenges include lack of samples and barriers to accessing RWD. “We need a global effort here to address these global infectious threat issues,” said Dr. Stenzel. “Solutions will involve building effective collaborations wherever and whenever possible as we prepare for outbreaks and as outbreaks occur.”

Solutions to the challenges identified during the workshop include:

Depositing RWD and samples from public health labs and other public efforts into a database
Continued funding for repositories and data
Establishing in advance material transfer agreements, IRB agreements, and so forth in order to be prepared for the next outbreak.

Successes include:

CDC and other biorepositories that have provided samples used to validate and develop IVDs
Available resources to assist in advancing EUA IVD products toward full marketing authorization.

“Working together, we can drive this forward,” concluded Dr. Stenzel.

Watch the workshop summary in Afternoon Sessions 2, starting at 2:24:30.

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Current as of January 6, 2021