Underpinnings of molecular diagnostics in emerging healthcare practices
This review article is a summation of the ever-changing underpinnings in medical laboratory practice occurring daily at an amazing speed. The resources in framing these contents are webinars, discussions in representative online forums, journals and personal thinking. I have taken deliberate efforts to eliminate personal bias as far as possible, but readers are urged caution and suggested to critically evaluate the conclusions in their specific work environment. My intention is a template for thought process for those interested in molecular genetics.
The surge of customers for clinical gene testing due to Affordable Care Act (ACA) is similar to the current trend in the healthcare arena. Before the ACA, up to 47 million were uninsured.1 A Gallup-Healthways Well-Being Index survey data shows current first quarter of 2015 uninsured rates to be about 12 percent.1 An offshoot of these changes could be the increased attention to regulate Laboratory Developed Tests (LDTs) and other molecular diagnostic tests by Food& Drug Administration(FDA) and Center for Medicare Services(CMS).
The “Individualized Quality Control Plan” (IQCP) is the Clinical Laboratory
Improvement Amendments (CLIA) Quality Control (QC) policy as an alternate quality control option allowed by CMS.2 IQCP will replace the current Equivalent Quality Control (EQC) procedure, which was designed as a standardized approach and intended to minimize the amount of external QC required and laboratory costs.3 Risk evaluation tools are also being recommended for molecular tests.4 The FDA has publishes its intention to regulate the laboratory developed Tests (LDTs) as a medical device and, hence, requiring premarket approval for high-risk LDTs similar to class III medical devices.5 At the same time, the FDA has also shown its intention to encourage value-added gene testing with the release of Blooms syndrome Direct-To-Consumer testing (DTC) from 23andMe – at least, in autosomal recessive carrier testing.6
LDT regulation by Food & Drug Administration
On July 31, 2014, the FDA notified the United States congress of the agency’s intent to issue a draft oversight framework for LDTs based on risk to patients, rather than whether they were made by a conventional manufacturer or a single laboratory. At the same time, the FDA also posted a notification regarding LDTs and the details of the draft guidance for public viewing.7 Recently, the FDA also notified that it plans to begin premarketing approval (PMA) review requirements within 12 months after a final guidance for the highest risk devices, and phase it in over four years for the remaining high-risk devices. The devices would stay on the market during FDA review. LDT developers hold to the agency’s traditional view that the tests are “laboratory testing services” and not medical devices subject to the Food, Drug and Cosmetic Act (FDCA). At present, labs certified under the Clinical Laboratory Improvement Amendments (CLIA) waiver program may develop and use their own diagnostic tests internally without FDA oversight.8
Meaningful use of health information initiatives have resulted in the migration of part of the molecular test to electronic ordering. Buccal swab or mouth wash specimens, combined with the increased sensitivity of NGS technology, tackled specimen integrity, low quality or quantity issues. Connectivity issues between Laboratory Information Systems (LISs) and medical records (MR) or Hospital Information System (HIS) would require financial expenditure.
The availability of ClinVar database has boosted utility of molecular or NGS findings, but contradictory information about the utility of genomic test findings could still limits the use in clinical practice. The controls, setting (hospital or centralized laboratory) and the ethnicity of the patient population served also determine the utility of the NGS sequencing results. The gene variants in public data bases are not representative of the varied ethnicity or nationality of the human population, and caution should be exercised in extrapolating the results while interpreting the findings. Technical issues related to identification of indels and splice site variants and higher efficiency output are currently being addressed by the next generation sequencing (NGS) manufacturers.
Apart from these, reimbursements, diagnostic codes, quality control and maintenance and increasing regulations are major issues. The integration of molecular genetic results into LIS and MR still remains an issue, especially for a laboratory located in another geographic region remote from the specimen collection or initial patient consultation site for molecular testing. The precision medicine initiative, with 215 million in the President’s budget for 2016, might be a step in that direction to bring it one more step closer to the target goal.9 Choosing Wisely is an initiative of the ABIM Foundation to help providers and patients engage in conversations to reduce overuse of tests and procedures and support patients in their efforts to make smart and effective care choices.10Attention to value addition or alternate testing methodologies (ASCP participation in choosing wisely initiative) and evaluation of test utility (eg: finding that mammograms in less than 50 yrs. women does not save lives) are also influencing the laboratory workplace.
Surprisingly, the ASCP list of tests (that should questioned by patients and physicians about clinical utility) includes widely discussed and marketed tests for HPV (in low-risk cases), Vitamin D testing (in general population) and pre-operative laboratory testing (in low-risk surgeries). Molecular testing, including NGS technology, offers potential hope for achieving personalized medicine.