NEW YORK (GenomeWeb) – Molecular diagnostics, particularly nucleic acid amplification tests (NAATs), are fast becoming the gold-standard for a number of pathogens, and clusters of commercial tests are aggregating around infective agents that are relatively easy to detect or have high incidence rates.
But clinical lab end users — or in the case of CLIA-waived assays, clinicians themselves — must rely on available evidence to decide whether to change their protocols and adopt new technologies. This process can involve investment in equipment, retraining of personnel, and justifying the transition to institutions and funding agencies.
And with hype about sequencing-based infectious disease diagnostics on the horizon, perhaps it might even make sense for clinical labs to be cautious, for fear NAATs will wind up being a transitional product and become quickly outdated.
In this decision tree, guidelines from professional societies — such as the Infectious Disease Society of America (IDSA) — could potentially play a pivotal role.
Acute pharyngitis, otherwise known as sore throat, results in 15 million primary care consultations each year in the US, with up to 30 percent of pediatric cases caused by Group A Streptococcus.
The IDSA guidelines for pharyngitis caused by Group A Strep (GAS) advise clinicians to perform rapid antigen tests or culture on patients whose pharyngitis symptoms don't appear to be caused by viral infections. Children and adolescents with negative antigen tests should then get backup throat cultures, the guidelines say.
But the guidelines were published in 2012, and the committee that created them began the writing process in 2009. Although there are now five molecular tests cleared by the US Food and Drug Administration, three years ago there were none.
The guidelines "really did predate the modern molecular tests that are now available," Stanford Shulman, chair of the guideline committee and a professor of pediatrics and infectious diseases at Northwestern University Feinberg School of Medicine, emphasized to GenomeWeb in an interview.
"I think the committee will need to take a new look at the field given what has happened in the last few years in terms of the development of molecular testing," he said
"I've been thinking for some time now that we probably should take a look at this," he said, but added, "We don't have a timeline."
Since the guidelines were written, he said, there have been a number of "quite impressive" studies on molecular tests. Shulman, who has consulted for Quidel in the past, was a co-author on an assessment of Meridian Bioscience's Illumigene GAS assay published in 2013 in the Journal of Clinical Microbiology.
This research on new molecular diagnostic tests "should be taken into account when guidelines are redeveloped," he said.
In a presentation to investors last month at the Wells Fargo Healthcare Conference, Quidel executives suggested that a lack of guidelines endorsing NAATs for Group A Strep may be influencing potential customers for its point-of-care molecular tests.
Quidel currently makes a few different platforms that can run GAS tests. AmpliVue runs single isothermal tests, while Solana runs 12 of these at a time. Quidel also manufactures a GAS test for its Sofia fluorescent immunoassay line and three different tests for its QuickVue lateral flow brand.
The AmpliVue molecular GAS test was approved last year and does not require culture backup. As previously described, the firm's Solana GAS test runs in about 30 minutes and was FDA-approved in June along with the platform itself.
In the Wells Fargo presentation, available on Quidel's website, the firm said its market research in the physician office lab market suggested that, in the short- to medium-term, Sofia-like platforms will remain the top choice over POC tests.
"While physicians are aware that there are MDx assays that have a 'no-culture-backup-required claim,' they do not see significant clinical benefit and the IDSA guidelines do not support molecular testing," the firm wrote in a presentation slide.
"Based on our research and our deep understanding of our customers, we believe that a strategy to encourage our customers to migrate to molecular over the next couple years is not viable, and that significant efforts to do so would not be rewarded," the firm said.
Instead, the company suggested that it intends its molecular tests to compete as a faster alternative to culture tests that are run to confirm negative rapid antigen detection assays.
"In the longer term, assuming a guideline change and certainty with respect to reimbursement, customer propensity to migrate to molecular GAS testing may increase," the firm said.
In addition to Quidel, four other test makers have FDA-approved GAS assays.
Alere's isothermal molecular GAS test was cleared by the FDA in April and CLIA-waived in July. Roche's Cobas Liat, a 15-minute real-time PCR-based test, was cleared in November of last year and CLIA-waived in May. Both of these GAS tests are POC assays that can be used in physician's offices.
Cepheid is also developing a 15-minute GAS test on its new POC platform, the Omni, and the firm aims to launch in the US in 2016 and to seek CLIA waiver.
Quest subsidiary Focus Diagnostics' GAS assay was cleared as a moderately complex test in April of this year, enabling some clinicians to perform the test directly.
Notably, approval of these tests is too recent to even make it onto the FDA's list of approved nucleic acid-based in vitro diagnostics, as that list was last updated in January.
Meridian Bioscience's Illumigene assay, a lab-based test, is the only Group A Strep test currently listed.
Validation studies of these commercial products are ongoing, but guidelines from a respected agency clearly communicating the benefits of switching from rapid immunoassays and culture to molecular tests could potentially open a floodgate of uptake.
Representatives at Alere and Roche discussed this issue with GenomeWeb in emails recently.
"When most of the current recommendations were written, the idea of a CLIA-waived molecular platform capable of providing a Strep A result in less than 10 minutes was not an option," KC McGrath, Alere's product manager for point-of-care diagnostics, said.
"We would anticipate an update from the IDSA now that these rapid molecular diagnostics are available," he added.
The 2015 Pediatric Redbook has made an adjustment, McGrath noted. That guide now states: "The FDA recently approved an isothermal nucleic acid amplification test for detection of Group A streptococci from throat swab specimens. These tests may be as sensitive as standard throat cultures."
However, McGrath asserted that "the ability to provide an actionable result with the confidence of a molecular diagnostic while the patient is still in front of the clinician is what has continued to drive the rapid adoption of the [Alere i] platform."
Alan Garrett, director of strategic affairs for Roche Diagnostics, told GenomeWeb that testing guidelines issued by respected medical groups play an important role in diagnostic testing and patient care, and the firm discusses GAS testing guidelines, such as those issued by IDSA, in conversations with healthcare professionals about the Strep A assay for the Cobas Liat PCR system.
"However, guidelines often lag behind science, and in some cases customers easily recognize that new technology, especially tests that are FDA-approved and CLIA-waived, can contribute to improved patient care despite not yet being addressed or advocated in formal guidelines," Garrett said.
He noted that customers have been enthusiastic about rapid PCR tests for GAS because they have the potential to reduce the need for confirmatory lab tests, lower costs, enhance care, and improve antibiotic stewardship.
"In addition, many customers don't actually incorporate guidelines into their day-to-day practice; some use rapid antigen tests, some use clinical presentation alone, and others send samples directly to the lab for either culture or PCR testing," he said.
Updated guidelines advocating molecular testing "would help eliminate any existing barriers to adopting the technology for certain types of institutions," Garrett said. But, he added, "Our general experience has been that the absence of specific guidelines supporting molecular GAS testing has not had a significant impact on customer enthusiasm or decisions."
Roche provides customers with published studies and FDA-approved literature on assay performance. Particularly for institutions transitioning to new technologies, the firm finds "peer-to-peer collaboration among healthcare professionals holds significant weight, and ... this consultative process has played a key role in adoption of the Cobas Liat system technology."
Similarly, at the American Association for Clinical Chemistry meeting in July an Alere representative told GenomeWeb that the company also uses technical consultants and a "tech-to-tech" approach to sales and marketing.
Changing guidelines change practices
While it may be too early to know whether changes in guidelines directly impact test sales, there are some hints that is the case, and newly approved tests do seem to spark discussions on how guidelines should be adapted.
For example, in April the FDA approved Roche's human papillomavirus DNA test for use in primary cervical cancer screening. But the benefits of this approach are the subject of ongoing debate in the literature, as is the meaning of variations amongst the different tests, as reported previously.
In the first half of this year Roche's sales for molecular diagnostics rose 9 percent over the same period last year, with the firm citing major contributions from virology testing and HPV screening.
A recent update to US Centers for Disease Control and Prevention guidelines provided endorsement of NAATs for Trichomonas vaginalis and routine trichomonas screening in high-risk populations, which might be expected to impact test adoption, particularly for the two tests specifically named by the agency.
And last year, chlamydia and gonorrhea testing guidelines were updated from a 2007 version to unequivocally endorse NAAT methods, which could impact no fewer than six different companies that make molecular CT/NG tests.
In the first quarter of this year, Cepheid's sexual health business — including tests for chlamydia and gonorrhea, Group B strep, human papillomavirus, and Trichomonas vaginalis — more than doubled year over year, with growth driven by the Xpert CT/NG and Xpert GBS tests, the firm reported.
Hologic reported growth in it's women's health assays for chlamydia and gonorrhea, HPV, and trichomonas in the third quarter this year, and noted that all won important new competitive accounts.
Becton Dickinson, meanwhile, reported in the third quarter last year that share loss in its ProbeTec CT/NG test was behind it, and the firm obtained CE marking for a test detecting chlamydia, gonorrhea, and trichomonas from a single specimen, with an anticipated US launch in 2016.
Adoption of NAATs for Clostridium difficile has also come with debate and discussion. Representatives at the US Centers for Disease Control and Prevention have claimed that the Centers for Medicare and Medicaid Services value-based purchasing program, or pay-for-performance, will be able to take into account the increase in cases anticipated when highly sensitive molecular tests are adopted. However, other recent research covered by GenomeWeb claimed that these tests also pick up an inordinately high number of asymptomatic carriers.
On the other hand, detecting carriers is the object of universal surveillance for methicillin-resistant Staphylococcus aureus (MRSA). It is a policy that is mandated in US Veterans Affairs Medical Centers and some other hospitals. This practice is far enough along that cost-effectiveness studies are being done comparing the different commercial molecular tests, as previously reported.