User:Mac/Literature Review

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Lit Review

Diagnostic R&D Lit Review

Phillips, K.a., Van Bebber, S. & Issa, A.M., 2006. Diagnostics and biomarker development: priming the pipeline. Nature reviews. Drug discovery, 5(6), 463-9.

• "pipeline problem" defined as decrease in the rate of introduction of drugs and diagnostics to market in recent years, despite major scientific acheivement and investment that might have predicted otherwise.
• NIH Roadmap Initiative and FDA Critical Path Initiative (CPI) emphasize addressing the pipeline problem, mostly for drugs.
• FDA regulates diagnostics kits or systems in interstate commerce
• Centers for Medicare and Medicaid Services (CMS), through the Clinical Laboratory Improvement Amendments (CLIA), oversees laboratory testing services commercially offered at single sites, in-house or "home-brew" tests.
• Reagents for in-house tests can be developed internally or sold commercially to CLIA-approved laboratories as analyte-specific reagents (ASRs).
• ASRs do not generally require full FDA pre-market review (PMA)
• A significant portion of future diagnostic development will occur to support the utility and prescription of particular theraputics. Some pharmaceutical companies directly contract diagnostic companies to develop tests for specific therapeutics.
• "In addition to the regulation and development model, two issues stood out as major reasons for the diagnostic pipeline problem: money, and lack of samples for validating and testing biomarkers."
  • The lack of money is complex and has to do with payers (usually insurance companies) not perceiving a net economic benefit from conducting a diagnostic and doctors not perceiving a clinical benefit from ordering the test. Hence, even when a test on the market, there may be little or no demand for it because insurers won't pay for it and doctor's won't recommend it.
• "Availability of samples is considered instrumental to the development (or lack thereof) of diagnostics because an abundance of samples is crucial for determining test performance (analytical validity, clinical validity and clinical utility).
• "Diagnostic development involves an iterative process (for example, performance characteristics are continuously fed back into the design) so that diagnostics can ultimately be shown safe and effective for their intended use, which are the FDA criteria for approval."

selected references:

• Rothstein, M.A., Pharmacogenomics: social, ethical, and clinical dimensions [book]
  • information on the regulatory process behind diagnostics (in chap 8?)
• Hoag, H., 2004. Testing new ground. Nature, 429(6992), 682-3.
• Goodman et al. The Value of Diagnostics: Innovation, Adoption and Diffusion Into Health Care. (2005)

Hoag, H., 2004. Testing new ground. Nature, 429(6992), 682-3

• Field of Molecular Diagnostics is expanding from disease detection to include Prognostics (prediction of disease risk) and tests for a patients response to treatment. Lots of discoveries of new genetic targets and biomarkers enabled by genomics and proteomics.
• Biomarkers may be indicators of disease as well as potential drug targets
• Molecular Diagnostic market revenue: 2001- $1.2B; 2007- $4.2B? (actually an over-optimistic estimate)

Kalorama Information (Rosen). Diagnostic Test Service Commercialization: A Roadmap to Diagnostics in the 21st Century. (2008)

• Esoteric test services (see Blum and Dearing for more background on the term) encompass the growing long tail of molecular diagnostics. The term tends to imply the tests are conducted by specialty "reference" labs instead of in a clinic's in-house lab with more conventional tests.
  • "clinical chemistry, immunoassays, coagulation, histology/cytology, molecular tests and flow cytometry... are the lab segments in which esoteric tests are generally found." (pg. 18)
• "Esoteric test service revenues earned by reference labs and CLIA-registered company test service offerings reached approximately $4.8 billion in 2007 or 12% of the U.S. lab service market that is estimated at $40 billion in 2007. With growth expected at roughly 15%, the testing services market could reach 9.2 billion by 2012. Most of these tests involve panels of protein and genetic biomarkers and specialized tests using biopsied tissue (anatomical pathology PCR, ISH and IHC tests)." (pg. 6)
• Kalorama's keys to successful IVD (in-vitro diagnostic) marketing strategy: "uniqueness of the test; significant perceived need; reimbursement by public and private payers; the incumbent test/technology is not seen as efficient; the test uses a technology that falls within the realm of current medical practice; and evaluations of the test effectiveness have been published in peer reviewed medical journals." (pg. 7)
• Many in-lab tests and test services are performed with analyte specific reagents (ASRs), sold to labs as individual components for in-lab developed test procedures. ASRs are not finished kits that include all reagents, calibrators, and controls to perform a test; the do not provide a test procedure.
  • "ASRs were initially introduced to improve the availability of immunohistochemical stains for which manufacturers had not sought FDA market clearance because the cost was too high for the revenues that would come from such products. The ASR regulatory path has become the chosen commercialization route for many molecular tests for similar cost-versus-revenue reasons. The minimal regulatory burden involved in releasing tests as ASRs allowed for a lucrative market, even in the earliest stages of this market sector." (pg. 10)
• LabCorp & Quest diagnostics are the two largest independent reference labs in the U.S. They provide routine and specialized tests and grow by internal R&D and by acquiring smaller IVD companies. Other big labs: ARUP, Specialty Labs, US Labs. (pg. 13)
• "The major national reference labs including Quest, LabCorp, Specialty/Ameripath, Mayo and others account for at least 60% of the market for esoteric test services. The remaining 40% is shared by a group of some 3000 small, local market laboratories. The major reference labs have built a comprehensive menu of specialized test services and continue to expand their offerings via collaborations with leading medical research centers. They offer a huge presence in the market and manage distribution networks that touch just about every medical specialty. Thus many CLIA-registered company sponsored test services avail themselves of the marketing resources offered by the national reference labs." (pg. 22)
• Genomic Health is by far the most successful company among CLIA-registered testing labs, going from $5m in 2005 to $63m in 2007 with 24,450 tests. Genomic Health reported that much of their Oncotype DX tests success is linked to its endorsement and recommendation by major cancer organizations. (pg. 24)
• Pg. 26 outlines an evaluation scheme for measuring the marketing strategy of a diagnostic. Key (subjective) metrics are: uniqueness, need, reimbursement, incumbent technology, recognized/peer-reviewed.
• "Pathologists have criticized physicians for falling into the marketing hype surrounding these multi-analyte tests. They say that these expansive test services use markers that are well known and validated and for which reagents are readily available. It would be very easy for most hospital labs to set up similar test panels at a fraction of the cost. Test services such as Oncotype, MammaPrint and Mammastrat succeed because of the way they have packaged the scientific knowledge related to breast cancer markers." (pg. 29)
• Pgs. 31- 35 describe in brief the trip out of the pipeline to market for a variety of tests (breast, colon, ovarian cancer) and the journey often involves IP changing hands. LabCorp or Quest license the tests from developers and run them in their national labs. Later LabCorp or Quest may develop their own version of test for the same thing, sometimes involving a core technology from the earlier test, which they license. So there may be a lot of examples of licensing or sharing between the companies doing R&D to develop new tests and the big testing providers.
• Pgs 41-43 display a large table of CLIA-registered lab services.
• Conclusions (pg. 171) - lots & lots of growth potential in diagnostics. New tests are mostly used clinically by early adopters, although proven clinical utility could take them from esoteric to mainstream.
• FDA uses following three criteria to distinguish IVDMIAs: uses clinical data; uses an algorithm; result requires test developer's help to interpret. (pg. 174)
  • FDA won't give PMA or market clearance for an IVDMIA to be run in a hospital lab because the technologist / pathologist has to rely on the diagnostic developer unless they also supply the algorithm (IP chokepoint?)
  • However, FDA may give market clearance for IVDMIAs to run in a reference or in-company lab
    • FDA did not require premarket approval for Agendia's MammaPrint; instead it granted de novo 510(k) status (only granted if diagnostic/device is low-risk and has no "predicate" i.e. is unique to market in utility?).

Market Reports

• Molecular Biomarkers for Clinical Diagnostics and Drug Discovery and Development: http://www.reportbuyer.com/pharma_healthcare/drug_discovery/molecular_biomarkers_clinical_diagnostics_drug_discovery_development.html
• Biomarkers and Related Tests for Molecular Diagnostics and Pharma/ Biotech R&D: http://www.mindbranch.com/Biomarkers-Related-Tests-R183-014/
• Combination Drug/Diagnostic Products: Pathways to R&D and Commercial Success: http://www.the-infoshop.com/report/cd52985-pathways-rd_toc.html