In Gold Standard I, we considered some historical facts surrounding what determines a “GOLD STANDARD” analytical technique. Gold Standard II examines in greater detail alternate analytical techniques, which some manufacturers claim are Gold Standard methods.
By the mid-70s, gas liquid chromatography (GLC) had become clearly established as the GOLD STANDARD for most TDM analysis. GLC has its problems. Even though the analytical times were shorter, the sample preparation and run times still limited rapid result turnaround. There were also problems with naturally occurring compounds interfering with drug quantitation and no matter what you say GLC is finicky. (Our GLC was named Harvey. I walked into the lab every morning and said “Good morning Harvey. Please be nice to us today”.)
These problems were to a large extent resolved with the introduction of Syva’s homogeneous enzyme immunoassay system (EMIT). It is worth remembering “Necessity is the mother of invention”. The original Syva FRAT assays were developed to screen urine for drugs of abuse (DAU). It was too cumbersome to be converted to routine clinical laboratory use. To meet the necessity for simple DAU screening in the US, Syva developed EMIT.
Syva soon developed EMIT assays allowing antiepileptic drug (AED) plasma/serum quantification in less than one minute. This was a tremendous advance in patient care because a patient blood specimen could be drawn when they arrived at the clinic and the results would be in their charts before they saw their physician. Thus, the clinician was able to communicate directly with the patient, make appropriate dose adjustments and be sure the patient understood his condition before leaving. EMIT was valuable in the ER to distinguish non-compliant patients presenting with seizures from those who were compliant and having seizure exacerbations. (A patient with therapeutic phenytoin levels if given a loading dose would quickly reach toxic levels and their seizures would get worse instead of better.) EMIT quickly displaced GLC for routine AED TDM. GLC still remained the “GOLD STANDARD” of TDM assays
We all know competition for market share in the diagnostics industry assures new and improved analytical techniques are always under development. This was true for the homogeneous enzyme immunoassays. In the 1980s, Abbott Laboratories introduced their TDX florescent immunoassay system for drug quantitation. Abbott quickly gained a major portion of the TDM market share; however, GLC continued to be the TDM GOLD STANDARD.
During the 1990s and early 2000’s, significant advances in the instrumentation and science surrounding both gas and liquid chromatography/mass spectroscopy/mass spectroscopy (GC/MS/MS or LC/MS/MS) allowed new applications in all aspects of the diagnostic laboratories including TDM and Clinical Toxicology (CT). Today LC/MS/MS has displaced GC/MS/MS as the GOLD STANDARD of analytical techniques. This will be true until an even better technique displaces it.
Marketing interests have no hesitation to claim their product is a GOLD STANDARD. They did it in 1970’s; they are still doing it today. In reality, GOLD STANDARD as applied to analytical techniques are not static. GOLD STANDARDs evolve with science, technology, and time and should be subjected to careful review as they come to market. Always remember, Caveat Emptor!
About C. E. PIPPENGER, PH.D.
Dr. Pippenger is an Adjunct Professor in the Department of Neurosciences, University of Vermont, College of Medicine, Burlington, Vermont. After receiving his Ph.D. in Pharmacology from Purdue University in 1971, Dr. Pippenger was named Director of the Anticonvulsant Drug Evaluation Laboratory in the Department of Neurology at Columbia University College of Physicians and Surgeons. In 1975, he was promoted to Assistant Professor of Neuropharmacology in Neurology, and, in 1980, to Associate Professor of Neuropharmacology in Neurology at Columbia. In 1979, he was founding editor of the journal Therapeutic Drug Monitoring, and was co-editor until 1990. He also helped establish, with support from the Epilepsy Foundation of America, the Antiepileptic Drug Levels Quality Control Program, which was continued by the American Association for Clinical Chemistry as their Laboratory Improvement Program. From 1982 to 1990, he was on the staff of the Cleveland Clinic Foundation, where he headed the Section of Applied Clinical Pharmacology/Trace Metals in the Department of Biochemistry. He was Vice President of Research and Development, and Laboratory Director, at FRESA BioMedical Laboratories, Inc., from 1991-1995. From 1995 to 2002, Dr. Pippenger was the Director of the Peter C. and Pat Cook Health Sciences Research and Education Institute in Grand Rapids, Michigan. He was the Peter C. and Pat Cook Research Professor in the Department of Biomedical/Health Sciences at Grand Valley State University, Allendale, Michigan from 2002-2004.
Dr. Pippenger’s research interests are in clinical pharmacology and pharmacokinetics, anticonvulsant and convulsant drugs, pediatric and geriatric clinical pharmacology, biochemical pharmacology, trace elements, the role of glycoproteins in cellular communication and disease, and the role of free radicals in neurological disease. His major research efforts are directed to providing better treatment for patients with the epilepsies and free radical mediated diseases. He is the author of more than 150 scientific papers and co-editor of six books. A Fellow of the International League of Epilepsy and a Fellow of the National Academy of Clinical Biochemistry, Dr. Pippenger has received numerous awards including the President’s Award and Outstanding Scientist Awards from the American Association for Clinical Chemistry, the Distinguished Service Award from the Epilepsy Foundation of America, and The William G. Lennox Award granted by the American Epilepsy Society and the William G. Lennox Trust.