Answers are provided by speakers from “Securing supply of COVID-19 diagnostics” PATH Live Forum - Neha Agarwal, Senior Commercialization Officer, Diagnostics, PATH; David Boyle, Chief Scientific Officer and Diagnostics Program Lead, PATH; Elliot Cowan, Principal, Partners in Diagnostics, LLC; Sira Thiam Konate, Program Coordinator for Global Health Security, Health Systems Innovation and Delivery, PATH; Richard Thayer, Managing Partner, Halteres Associates.
Access to quality diagnostic tools is our first line of defense for protecting communities from disease. An extraordinary amount of resources have been mobilized in an attempt to rapidly research, develop, and deploy diagnostic testing for the SARS-CoV-2 virus. However, access to quality diagnostics remains a challenge. Newly developed tests have varying or unknown performance and quality, manufacturing capacity is unable to meet global demand, and low- and middle-income countries (LMICs) have been priced out of available supply. PATH is monitoring these supply insecurities and the needs of clinicians and health providers around the world and is providing guidance and resources to industry partners and countries to rapidly address these challenges.
As part of PATH’s Live Forum series, speakers shared their insights on these topics and answered questions from our audience.
Speakers:
- Neha Agarwal, Senior Commercialization Officer for Diagnostics, PATH
- David Boyle, Chief Scientific Officer and Diagnostics Program Lead, PATH
- Elliot Cowan, Principal, Partners in Diagnostics, LLC
- Sira Thiam Konate, Program Coordinator GHSA, Health Systems Innovation and Delivery, PATH
- Richard Thayer, Managing Partner, Halteres Associates, LLC
Below, please find answers from our panelists to some of the questions we didn’t have time to address during the live forum.
What is the timeline for LMICs to receive new diagnostic tests once they have been developed?
Wow, this is a very tough question to answer as it varies considerably from manufacturer to manufacturer, depending on their location, experience base, supply chain logistics and requirements and capacities, cost of goods, ability to scale, financial expectations, and many other factors.
With COVID-19, we are seeing developers that can develop new tests for SARS-CoV-2, transition to manufacturing, and introduce them to the market in a matter of 2 to 3 months. This is quite rapid and is only possible in this reduced regulatory environment. With more stringent (or more typical) regulatory oversight, time to market would more normally be a minimum of 12 to 15 months (or longer for more complex tests that require reagents and materials that must be uniquely developed or lengthy clinical trials).
Rapid diagnostic tests for COVID-19 should have high sensitivity and specificity (about 90%). With no standard validation results available and no World Health Organization endorsement, what recommendation will you give for the use of RDTs in resource-limited settings where such tests need to be affordable and easy to use?
Ideally, an RDT (rapid diagnostic test) should have sensitivity and specificity greater than 99%. For serology tests used to determine whether an individual was previously exposed to the SARS-CoV-2 virus, the emphasis should be on high specificity to minimize the possibility of false positive results. False positive individuals remain at risk of becoming infected with and potentially transmitting the virus later should they become exposed.
When rapid antigen or RNA tests become available, the emphasis should be on high sensitivity to minimize the possibility of false negatives. A false negative individual is someone who has RNA or antigen in their system and who could potentially be infectious but is unaware of it. An antibody serology test should not be used as a standalone (without RNA testing) as it does not test for the possibility of current infection. Conversely, if an individual wishes to return to work or to be with at-risk friends or family members, a negative RNA test alone does not mean that they may not become infected and infectious later.
If possible, the optimal solution would be to provide both antibody and antigen testing. The minimum sensitivity currently noted by the US Food and Drug Administration (FDA) for a direct detection antigen assay is 80%.
What advice do you have for pooled sample testing for COVID-19 diagnosis?
In principle, pooled sample testing for COVID-19 could potentially be effective, provided the testing can still pick up low titer/concentration specimens (this should be carefully validated) and the "deconvolution" workflows at the back end can be adequately supported by the lab or testing site without undue workflow impact or errors.
A great deal of emphasis has been placed on the development of tests. What work is being done to build capacity to manufacture these tests?
As you will appreciate, most developers and manufacturers consider their manufacturing processes to be proprietary. There are very few diagnostics manufacturers working with third parties to manufacture their products in times of peak demand (although this is more common in other industries). Part of the reason for this is that the reagents, materials, equipment, and expertise required for diagnostic manufacturing have definitive, relatively short "shelf-lives." Thus, it is very challenging to keep a third party consistently engaged to help satisfy periodic, unplanned demands. In addition, the reagent, raw materials, and consumable supply chains themselves may not be able to meet surge demands—something that has been clearly demonstrated during this COVID-19 pandemic. A potential solution would be for manufacturers to establish an international consortium of partners with capacity and contractual capabilities to meet spikes in demand. Several large molecular companies have announced that they are scaling production facilities to meet the anticipated needs by Q3 2020, but it is anticipated that these companies will be primarily focused on supporting markets in high-income countries. As a result, depending on their performance, direct antigen detection RDTs may be the best tools for meeting this demand.
Can you please speak to the challenges and benefits of decentralized versus centralized testing in different settings?
This is quite an involved question and one that can have many answers, depending on the intended use and setting. There are many factors to consider, including ease of use, cost of goods, sample collection, handling, transportation and storage requirements, time constraints, loss to follow-up concerns, population health concerns, supply chain requirements (e.g., cold chain), and level of automation. Centralized testing often costs less and is potentially more efficient. However, it also necessitates that samples are easily collected, stable, and transportable; that there is time for results to be processed; and that there is low risk to the health of the individual or the population. If results are required immediately and the sample must be collected and tested locally, or is not stable in transport, then decentralized testing might be the best solution. In the case of COVID-19 and other pathogens that might require the use of personal protective equipment (PPE), and when potentially positive individuals must be isolated, having local (point-of-care), rapidly available test results might be the best solution. This also assumes adequate test performance and the ability to reproducibly perform the test.
A challenge with decentralized testing using RDTs is that performance tends to drop compared to lab-based testing, even when using the same test. It would be ideal to use a reader to allow for connected diagnostics. Understanding the burden and distribution of COVID-19 infections is essential to managing the disease, yet decentralized testing with RDTs increases the risk of poor data management and its distribution as it does not allow for the aggregation of data and results. A reader-based diagnostics method offers important improvements to decentralized testing through more accurate test results, electronic data storage/dissemination, enhanced test and user performance, and the implementation of an external quality assurance (EQA) program to address multiple potential failure points across the test continuum.
The US government wants up to 1 million tests per day, and other governments will likely want quantities relative to their populations as well. How can the supply chain meet these needs?
Although it does seem likely that the supply of diagnostic tests, especially high-quality tests, still lags demand, this is not an easy question to answer. With many, many sources of demand, and few, if any, systems in place for consolidated ordering, it can be very difficult for manufacturers to know what the true demand is likely to be and how many tests to produce. This situation can be especially difficult when dealing with a novel test that may, or may not, have a very long shelf life and for which the supply chain logistics may or may not yet be determined. As a result, manufacturers, especially smaller ones, cannot afford to risk overproduction and a resulting need to offload unsold inventory. As the pandemic continues, it is becoming evident that there will be many entities besides the government requiring access to these tests. Since demand from these various institutions can and likely does overlap, understanding the true market need for tests for a novel pathogen is very challenging.
Can you comment about the global effort to secure the availability of diagnostics within the allocations secured with manufacturers? How are different stakeholders supporting the Senegalese government through this process?
I cannot provide a clear response to your question. In Senegal, we have a few functioning molecular biology laboratories that can perform RT PCR (reverse transcription polymerase chain reaction), but access to the reagents has been quite difficult and in limited supply. The World Health Organization is supporting the Senegalese Ministry of Health with the supply of reagents through a regional platform to consolidate regional demand. However, other laboratories are purchasing reagents directly from suppliers or distributors at an increased cost.
We have all heard about the tests that have failed due to low sensitivity and specificity. Many governments are now looking to onshore these tests if they can enhance their specificity and sensitivity and pass an EUA (emergency use authorization). Where will this manufacturing capacity come from and are you aware of government funding to put this capacity in place?
Supply and demand are currently being coordinated on an ad hoc basis by individual institutions and manufacturers. There are several early-stage coalitions being convened to coordinate at a global level and to secure necessary funds to increase manufacturing capacity.
