TDM JOURNAL CLUB
Personalized Medicine— Disregarding the Obvious: Analysis of Trends Among Articles Published on “Personalized Medicine” Personalized medicine (PM) is a relatively recent medical approach of selecting therapeutic modalities for patients based on their individual characteristics, rather than according to the classical model of population means.1 During the last decade, in parallel with the explosion in molecular genetics, PM has emerged as a major new direction in clinical and experimental medicine, with increasing numbers of academic institutions developing PM programs to address individual patient needs. Searching PubMed reveals only 3 references corresponding to “personalized medicine” in 1999, 53 in 2004, 313 in 2009, 523 in 2011, and 3,575 in 2014. Because of its routes in genetic medicine,2 PM is commonly identified with using technological means to detect sources of variability that can affect individual therapies. Although the term PM was indeed coined in the field of genetics, it has been subsequently recognized that patients vary widely in many other important characteristics that affect individual response to treatment. But is it really the case? Have other patient characteristics with wide interpersonal variability really been invited into the new world of PM? In a survey I conducted among our 31 advanced trainees in pharmacology (PhD students) and clinical pharmacology (clinical fellows), they were asked to identify, based on their understanding and knowledge, what is included in the term PM. Nineteen respondents mentioned “genotype,” 3 included each of “phenotype,” “medical history,” and “pharmacokinetics,” and 2 noted each of “therapeutic drug monitoring,” “socioeconomic class,” and “height and weight.” The following were mentioned once each: “patient preference,” The authors declare no conflict of interest. Correspondence: Gideon Koren, MD, FRCPC, FACMT, FAACT, Hospital for Sick Children, 555 University Avenue, 8th Floor Black Wing, Toronto, Ontario, Canada M5G 1X8.
”pharmacodynamics”, “family history,” “ethnicity,” “age,” and “sex.” Accessing PubMed on January 15, 2015, revealed 3585 citations of articles published in 2013 under PM. All of them dealt with genetics, proteomics, metabolomics, molecular medicine, and biomarkers. None dealt with other important sources of measurable variability in patients. With pharmacogenetics holds tremendous hope in improving patient care, presently pharmacogenetic research has led to more than 130 drugs to receive the FDA label recommendations for PN3 (and for only very few of them, there are evidence-based data on improved patient care after addressing pharmacogenetic variability). To document how this reality “disregards the obvious” (a term coined by the late philosopher Martin Buber), please consider the case of variability in patient adherence to medications. Less than 50% of patients take their medications as prescribed,4,5 and poor adherence is a major source of morbidity and mortality.6 The following example painfully reminds us how patient’s adherence has been left out of PM. Warfarin is among the most effective stroke prevention medications for high-risk individuals suffering from atrial fibrillation. In 2009, Gladstone et al4 analyzed data from a prospective database of consecutive patients with stroke admitted to 12 designated stroke centers in Ontario between 2003 and 2007. They included patients admitted with an acute ischemic stroke who1 had a known history of atrial fibrillation,2 were classified as high risk for systemic emboli, and3 had no known contraindications to anticoagulation. Among patients with atrial fibrillation admitted with a first ischemic stroke (n = 597), 40% were on warfarin, 30% on antiplatelet therapy, and 29% did not take any antithrombotics. Of those taking warfarin, three-fourths had a subtherapeutic international normalized ratio (,2.0) at the time of stroke admission. Overall, only 10% of patients with acute stroke with known atrial fibrillation were adequately anticoagulated at admission. Even worse, among stroke patients with a history of atrial fibrillation and a previous transient ischemic attack or ischemic stroke (n = 323), only 18% were taking warfarin with therapeutic international normalized
Ther Drug Monit Volume 37, Number 5, October 2015
ratio at the time of admission for stroke, 39% were taking warfarin with subtherapeutic international normalized ratio, and 15% were on no antithrombotic therapy! Warfarin is one of the drugs where pharmacogenetic variability is included in the FDA labeling to guide dosing changes.3 But, what is the utility of these discoveries if most patients are not taking warfarin or taking it inappropriately? And, although billions of dollars are spent yearly on pharmacogenetic research, very little is invested into understanding why people do not take their life-saving medications. Hence, the almost absolute identification of PM as a synonym of genetic and molecular variability has serious risk for the future of medicine, as it may further lead physicians to look at laboratory markers rather than looking in the eyes of their patients and talking to them in an attempt to understand their preferences and their reasons not to take life-saving medications. If pharmacogenetic and molecular medicine will drive us away from basic principles of therapeutics and humane medicine-suffer will the patient. Gideon Koren, MD, FRCPC, FACMT, FAACT Hospital for Sick Children Toronto, Ontario, Canada
REFERENCES 1. Roden DM, Tyndale RF. Genomic medicine, precision medicine, personalized medicine: what’s in a name? Clin Pharmacol Ther. 2013;94:169–172. 2. Langreth R, Waldholz M. New era personalized medicine: targeting drugs each unique genetic profile. Oncologist. 1999;4:426–427. 3. The Food and Drug Administration. Table of Pharmacogenomic Biomarkers in Drug Labels. Available at: http://www.fda.gov/Drugs/Science Research/ResearchAreas/Pharmacogenetics/ ucm083378.htm. Accessed January 16, 2015. 4. Gladstone DJ, Bui E, Fang J, et al. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke. 2009;40:235–240. 5. Kumbhani DJ, Steg PG, Cannon CP, et al; REduction of Atherothrombosis for Continued Health Registry Investigators. Adherence to secondary prevention medications and fouryear outcomes in outpatients with atherosclerosis. Am J Med. 2013;126:693–700. 6. Hugtenburg JG, Timmers L, Elders PJ, et al. Definitions, variants, and causes of nonadherence with medication: a challenge for tailored interventions. Patient Prefer Adherence. 2013; 7:675–682.
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Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Personalized Medicine— Disregarding the Obvious: Analysis of Trends Among Articles Published on “Personalized Medicine” Personalized medicine (PM) is a relatively recent medical approach of selecting therapeutic modalities for patients based on their individual characteristics, rather than according to the classical model of population means.1 During the last decade, in parallel with the explosion in molecular genetics, PM has emerged as a major new direction in clinical and experimental medicine, with increasing numbers of academic institutions developing PM programs to address individual patient needs. Searching PubMed reveals only 3 references corresponding to “personalized medicine” in 1999, 53 in 2004, 313 in 2009, 523 in 2011, and 3,575 in 2014. Because of its routes in genetic medicine,2 PM is commonly identified with using technological means to detect sources of variability that can affect individual therapies. Although the term PM was indeed coined in the field of genetics, it has been subsequently recognized that patients vary widely in many other important characteristics that affect individual response to treatment. But is it really the case? Have other patient characteristics with wide interpersonal variability really been invited into the new world of PM? In a survey I conducted among our 31 advanced trainees in pharmacology (PhD students) and clinical pharmacology (clinical fellows), they were asked to identify, based on their understanding and knowledge, what is included in the term PM. Nineteen respondents mentioned “genotype,” 3 included each of “phenotype,” “medical history,” and “pharmacokinetics,” and 2 noted each of “therapeutic drug monitoring,” “socioeconomic class,” and “height and weight.” The following were mentioned once each: “patient preference,” The authors declare no conflict of interest. Correspondence: Gideon Koren, MD, FRCPC, FACMT, FAACT, Hospital for Sick Children, 555 University Avenue, 8th Floor Black Wing, Toronto, Ontario, Canada M5G 1X8.
”pharmacodynamics”, “family history,” “ethnicity,” “age,” and “sex.” Accessing PubMed on January 15, 2015, revealed 3585 citations of articles published in 2013 under PM. All of them dealt with genetics, proteomics, metabolomics, molecular medicine, and biomarkers. None dealt with other important sources of measurable variability in patients. With pharmacogenetics holds tremendous hope in improving patient care, presently pharmacogenetic research has led to more than 130 drugs to receive the FDA label recommendations for PN3 (and for only very few of them, there are evidence-based data on improved patient care after addressing pharmacogenetic variability). To document how this reality “disregards the obvious” (a term coined by the late philosopher Martin Buber), please consider the case of variability in patient adherence to medications. Less than 50% of patients take their medications as prescribed,4,5 and poor adherence is a major source of morbidity and mortality.6 The following example painfully reminds us how patient’s adherence has been left out of PM. Warfarin is among the most effective stroke prevention medications for high-risk individuals suffering from atrial fibrillation. In 2009, Gladstone et al4 analyzed data from a prospective database of consecutive patients with stroke admitted to 12 designated stroke centers in Ontario between 2003 and 2007. They included patients admitted with an acute ischemic stroke who1 had a known history of atrial fibrillation,2 were classified as high risk for systemic emboli, and3 had no known contraindications to anticoagulation. Among patients with atrial fibrillation admitted with a first ischemic stroke (n = 597), 40% were on warfarin, 30% on antiplatelet therapy, and 29% did not take any antithrombotics. Of those taking warfarin, three-fourths had a subtherapeutic international normalized ratio (,2.0) at the time of stroke admission. Overall, only 10% of patients with acute stroke with known atrial fibrillation were adequately anticoagulated at admission. Even worse, among stroke patients with a history of atrial fibrillation and a previous transient ischemic attack or ischemic stroke (n = 323), only 18% were taking warfarin with therapeutic international normalized
Ther Drug Monit Volume 37, Number 5, October 2015
ratio at the time of admission for stroke, 39% were taking warfarin with subtherapeutic international normalized ratio, and 15% were on no antithrombotic therapy! Warfarin is one of the drugs where pharmacogenetic variability is included in the FDA labeling to guide dosing changes.3 But, what is the utility of these discoveries if most patients are not taking warfarin or taking it inappropriately? And, although billions of dollars are spent yearly on pharmacogenetic research, very little is invested into understanding why people do not take their life-saving medications. Hence, the almost absolute identification of PM as a synonym of genetic and molecular variability has serious risk for the future of medicine, as it may further lead physicians to look at laboratory markers rather than looking in the eyes of their patients and talking to them in an attempt to understand their preferences and their reasons not to take life-saving medications. If pharmacogenetic and molecular medicine will drive us away from basic principles of therapeutics and humane medicine-suffer will the patient. Gideon Koren, MD, FRCPC, FACMT, FAACT Hospital for Sick Children Toronto, Ontario, Canada
REFERENCES 1. Roden DM, Tyndale RF. Genomic medicine, precision medicine, personalized medicine: what’s in a name? Clin Pharmacol Ther. 2013;94:169–172. 2. Langreth R, Waldholz M. New era personalized medicine: targeting drugs each unique genetic profile. Oncologist. 1999;4:426–427. 3. The Food and Drug Administration. Table of Pharmacogenomic Biomarkers in Drug Labels. Available at: http://www.fda.gov/Drugs/Science Research/ResearchAreas/Pharmacogenetics/ ucm083378.htm. Accessed January 16, 2015. 4. Gladstone DJ, Bui E, Fang J, et al. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke. 2009;40:235–240. 5. Kumbhani DJ, Steg PG, Cannon CP, et al; REduction of Atherothrombosis for Continued Health Registry Investigators. Adherence to secondary prevention medications and fouryear outcomes in outpatients with atherosclerosis. Am J Med. 2013;126:693–700. 6. Hugtenburg JG, Timmers L, Elders PJ, et al. Definitions, variants, and causes of nonadherence with medication: a challenge for tailored interventions. Patient Prefer Adherence. 2013; 7:675–682.
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Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
