Commentary on Whoessential Diagnostics List Proposal

Commentary on WHOEssential Diagnostics List proposal

Lee Schroeder, Tim Amukele & Madhu Pai

At the initial stage, the WHO will focus on IVDs, rather than all diagnostics (e.g. imaging).

• This seems reasonable as the first EDL will help identify issues that need to be addressed for the larger list.

WHO is planning to accept applications both for classes of tests and for specific IVDs.

• The argument for focusing primarily on classes of tests is that the EDL should be about access to testing not to specific platforms. Furthermore, by focusing on individual devices, the EDL expert committee may become over-burdened with accuracy and performance studies, essentially assuming the responsibility for the WHO prequalification program and picking winners in the IVD space. It may be a more effective use of the committee’s time to focus on test classes and algorithms, as well as requirements for accuracy and performance. Then, the WHO PQ program could approve IVD products based on the approved test profile. Where only a single product exists (e.g. Xpert MTB/RIF), the EDL committee could still describe the class and possibly also characterize performance requirements of the class (e.g., accuracy, turn-around time).
• The argument for including actual IVD products in the EDL is that there will be no ambiguity in recommendations. Akin to the EML, the EDL will be recommending a well-defined product. Also, by listing IVD products, there is implicit vetting for quality of devices, ensuring that countries invest in accurate instruments. It also naturally includes test features of EDL diagnostics such as infrastructural requirements. Finally, test classes might work well for some tests (e.g. blood glucose), but not for others (e.g. Xpert MTB/RIF for TB):
• There are diseases where WHO has only endorsed some products within a class. For example, within TB molecular tests, WHO has only endorsed GeneXpert, line probe assays and LAMP while in-house PCR is NOT endorsed by WHO.

WHO suggests that an EDL will include tests at various levels of the healthcare system

• Yes, makes a lot of sense; some essential tests can be done at the peripheral level, while others will require more centralized labs.
• Also, some testing algorithms may require health centers/labs across the value chain.
• However, the decision to place a specific test at a specific tier is a complicated and multi-factorial decision that will have a large impact on costs and workflow. For example, which tier should Xpert MTB/RIF be placed? Country implementation will always be a balance between peripheral testing and courier of samples. It will be difficult to make effective tier-level determinations that will be useful to all countries in all situations. While certainly valuable to recommend tier-specific testing, perhaps these should be softer recommendations, or include a range of appropriate tiers.

Selecting which tests/diagnostics to consider for EDL evaluation:

• WHO will initially focus on a few conditions where strong programmes are in place for diagnosis and treatment and where recommendations of diagnostics followed the formal process of the WHO Guidelines Review Committee including the use of the GRADE process.
• Seems reasonable, since a clear link with essential medicines is necessary, and making a strong connection between EDL and EML will likely make this more appealing for countries to adopt and implement.Furthermore, a diagnostic should already be vetted and validated, with a policy endorsement from a credible agency to make it into an EDL. We cannot afford to have bad tests on the EDL!
• Where international guidelines exist, the EDL committee should not have to make policy decisions on tests – that task may have already happened within various WHO or UN departments, for example. For example, WHO Global TB Department has already endorsed several TB tests based on the GRADE process.
• These policy endorsements take a lot of time, evidence reviews, committee work, etc., and the group tasked with EDL will not need to make those investments.

• Long-term selection of tests/diagnostics should be based on transparent criteria
• The idea of automatically including tests that have been previously vetted by the WHO is a great one, no need to reinvent the wheel. However, the concern is that if we only select those diseases that already have working groups around them, or good treatment programs in place (HIV, TB, Maternal / Child Health) we end up starving-out the very diseases whose management could be helped by an EDL.
• To ensure long term success, there should be transparent criteria in place to guide the consideration of test classes/diagnostics – either disease burden, or the EML (as in the NEJM publication). Perhaps the WHO could select the top 5 or 10 causes of DALYs lost using GBD estimates for developing countries, and consider tests with clear impact on outcomes/management.
• We also encourage use of the application mechanism, similar to the EML approach, to allow groups outside of the WHO to propose EDL additions.

WHO evaluation process for the initially proposed EDL additions:

• We support the focus of the initial list on tests with policy recommendations from WHO (and encourage use of recommendations from other organizations, e.g., professional societies, NICE). This will ease the creation of an EDL and reduce the burden of work.
• But one issue is concerning – if several TB tests, for example, are endorsed by WHO (and they are), then will all of them make the EDL automatically?
• Pros:
• Diagnosis and monitoring almost always requires algorithms, rather than single tests. Examples include smears, followed by Xpert, followed by cultures/LPA for TB; HIV rapid tests, followed by viral load assays.
• If we include some parts of the algorithm and not others in the EDL, it might create a bottle neck for patients
• Also, we should consider the diagnosis and monitoring tests as both essential, since one cannot treat without checking for cure/progress (initial HIV test and viral load during ART is a great example; or initial test for MDR-TB, with repeat cultures for follow-up)
• Cons:
• There may be several tests that are WHO endorsed, but countries are struggling to decide on which ones to scale-up and not all may be considered ‘essential’ or priority
• For example, if Xpert is already scaled-up in a country, why would LAMP be included in the essential list? LAMP is less accurate, requires more technical expertise, and does not provide RIF resistance data that is valuable.
• A possible solution is to include diagnostic classes in the EDL (akin to EML therapeutic classes like protease inhibitors) and then consider diagnostic algorithms as a single entry in the diagnostic class (akin to an EML fixed-dose combination). A country could choose to include one test or algorithm from a class in their national EDL.
• Will any test that is already WHO prequalified be automatically considered eligible for EDL? Or will WHO PQ be a pre-requisite for EDL inclusion? If not, how else will an EDL ensure quality of the tests that are included?

Diseases with IVDs that are likely ready to be included in the initial EDL without additional significant review of evidence include TB, malaria/G6PD, HIV and hepatitis B & C.

• Pros:
• These 5 infections seem like a good start point, and all have good policies in place with clearly endorsed tests (some are WHO PQ).
• So, starting with these 5 will likely mean that the first EDL can be generated fairly quickly and it will inspire more thinking about how to move forward
• Cons:
• But should the first ever EDL not send a clear message that an EDL is not just about infectious diseases, but will also cover NCDs of great importance?
• The EDL should prioritize burden of disease (whether derived from DALYs, EMLs, surveys etc.) rather than previously established funding streams.
• There are NCDs with clear treatment programs that can be included to pilot test the NCD aspects of EDL
• Blood glucose or Hb A1c for diabetes management
• Troponin and lipid panels for ischemic heart disease
• Plasma/serum creatinine for renal disease
• Anemia and iron panel testing in pregnant women
• The WHO could select the top 5 or 10 causes of DALYs lost using GBD estimates for developing countries, and then pick those that can be linked with clear treatments/essential medicines.
• If we look at GBD and select World Bank low income countries, the top 5 causes of DALYS lost are:
• LRI
• Malaria
• HIV/AIDS
• Diarrheal diseases
• Neonatal encephalopathy
• For World Bank Lower Middle income region:
• Ischemic heart disease
• LRI
• Neonatal preterm birth complications
• Neonatal encephalopathy due to asphyxia
• Diarrheal diseases

So, we could develop a matrix with highest burden conditions using GBD, and then see which of those have clear treatments/link to essential meds, and what diagnostics are recommended in various guidelines, and then see which of those dx can be deemed ‘essential’?

WHO plans to discuss merits of including tests for diseases with weaker support programmes

• This will clearly involve more work on the part of the EDL expert committee, as WHO guidelines that thoroughly evaluate tests will not be available. However, we believe inclusion of a test on the EDL will indeed stimulate strengthening of these weaker programs.
• Several tests are not the primary test for a priority condition, yet still are important to many. The CBC and comprehensive metabolic panel fall in this category, as they are important for evaluating general physiological states and toxicity to EML medicines.Also, liver enzymes in the comprehensive metabolic panel are important for cirrhosis/hepatitis pathways, renal function tests are important for CKD, and glucose is important for diabetes.
• Some thought might be given to the medium-term breadth of test methodologies included in the EDL. For instance, it could be advantageous to include tests that fall into one of the several categories present in well-functioning labs: chemistry analyzers, immunoassays, hematology analyers, lateral flow diagnostics, nucleic acid testing, microscopy, and bacterial culture. This would prevent major gaps from persisting in a country’s laboratory capacity.

Some challenges to consider:

• That with limited funds, investing in diagnostics will take from other priority projects. Or, that investing in diagnostics for multiple conditions will take from diagnostics for priority conditions.
• Data from mature markets (USA, Europe)1 as well as in studies from East Africa2 show that although diagnostic testing has a far reaching impact onhealth care, it accounts for <5% of the total health spending. However, currently much of this investment is wasted because diagnostic selections are haphazard and of low quality. The EDL will help to address this haphazard distribution and ultimately drive improved quality of available diagnostics.
• It would be helpful for the WHO EDL committee to craft target implementation schemes for countries with various levels of available investment in diagnostics (‘ideal’ EDL roll-out for a country of 10 million people, vs. ‘realistic’/’low-budget’ roll-out). This could follow the form of the core/complementary EML list approach. This would beadditional work for the committee but would vastly improve the utility of the EDL.
• With increased uptake and demand of IVD, patent infringement cases similar to those seen in essential medicines (e.g. TRIPS regulations) may develop.

Definitions of EDL entries:

• A significant amount of thought has gone into definitions of terms relevant to IVD. It may be useful to use these terms in describing EDL entries. Consider glucose testing of plasma. Theanalyte is the molecule glucose, the measurand is glucose in a particular matrix (e.g. plasma) measured as a concentration (mmol/l). The measurement principle is activity of a glucose-selective electrode and the measurement method will be a description of the actual implementation that uses the measurement principle. Also, commentary on metrological traceability to a reference method and standard might be useful for harmonization. These are the relevant documents: JCGM 200:2012 “International vocabulary of metrology – Basic and general concepts and associated terms (VIM) and ISO 15193:2009

Piloting:

• Lastly, a key follow-up on the first EDL should be to work with a few countries and help them convert this into EDL at the country level and see how it plays out, and what benefits accrue, and whether there are any unintended consequences.

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