This document provides an overview of precision medicine and pharmacogenomics. It discusses barriers to implementing pharmacogenomic testing, key medical settings and patient populations to target, and considerations for integrating test results into clinical workflows. Evidence is presented showing pharmacogenomic testing can reduce adverse drug reactions and alter prescribing. The document emphasizes engaging patients and generating more evidence of the clinical value and economic benefits of pharmacogenomic testing.

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Solving the Puzzle
of Better Prescribing
in the Era of Precision Medicine
Peter H. O’Donnell, M.D.
Department of Medicine
Committee on Clinical Pharmacology and Pharmacogenomics
Center for Personalized Therapeutics
The University of Chicago
“If it were not for the great
variability among individuals,
medicine might as well be a
science and not an art.”
--Sir William Osler (1892)

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Pharmacogenomics (PGx)
• Study of the effect of genetic variation
on drug response or toxicity

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Barriers to Realizing Pharmacogenomic
Implementation
• Test indicated / available?
• Delay in obtaining results
• Are results findable within EMR / clinical
workflow?
• Lack of provider knowledge / concerns
regarding interpretation
• Evolving PGx evidence base / what is bar to
change practice?
• Who Pays? Johnson et al., Clin Pharm Ther (2012)
O’Donnell et al., Clin Pharm Ther (2012)
image credit: qimono, Pixabay

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Does What We’re Offering to the Clinician
Matter to the Next Decision
They Have to Make?

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Pain Prescribing
Davidson, CJASN (2019)
DPYD / 5-FU Toxicities
• Mucositis/stomatitis
• Diarrhea
• Hand-foot syndrome

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Cancer Prospective Testing
Deenen et al. JCO (2016)
Genotype-Directed Dosing
Deenen et al. JCO (2016)
*Net savings to the institution with preemptive screening
($3,767/patient; $3,828/pt for nonscreening)

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8% of patients carried one of these variants
Lancet Oncology (2018)
“Since fluoropyrimidines are among the most
commonly used anticancer agents, these findings
suggest that implementation of DPYD genotype-
guided individualized dosing should be a new
standard of care.”
Should this be a standard of care?
14
northjersey.com (2019)
legiscan.com

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DNA Sample Obtained
Medical Oncology Patients
GI/Breast/H&N
“The PhOCus Trial”
PGx information & GPS access is
provided to clinicians to inform initial
dosing decisions
Upfront
genotyping
*All patients in the control arm will be genotyped with results and GPS access provided to their clinical team 6 months after study enrollment
Patients initiated
on chemotherapy
Randomization
Primary Endpoints:
Pdev: 1st cycle dose modifications
Ptox: Incidence of ≥ Grade 3 adverse
events
Patient Enrollment
Primary Endpoints:
Pdev: 1st cycle dose modifications
Ptox: Incidence of ≥ Grade 3 adverse events
PGx information & GPS access is
not provided and initial dosing is according
to standard of care
Secondary Endpoints:
• Cumulative Drug Dose Intensity
• Progression Free & Overall Survival
• Dosing of PGx Supportive Care
Medications
• Quality of Life
• Patient Understanding of PGx
PGx Arm Control Arm*
Are There Key Medical Settings
(or Patient Populations)
To Target for Testing?

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Model
BROAD SCOPE
(all PGx actionable meds)
PREEMPTIVE TESTING
(not reactive)
UTILITY ASSESSMENT
(multiple hospitalizations/clinic visits, med decisions)
PATIENT and PROVIDER
ENGAGEMENT
Pharmacogenomics Alters Drug Prescribing
No pharmacogenomically high-risk medications were prescribed during the entire
study when physicians consulted the GPS tool
O’Donnell et al., Clin Pharm Ther (2017)

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Are There Populations at Higher Risk?
• Adverse drug reactions are the 5th leading cause of
in-hospital death in U.S.
Davies et al., Curr Drug Saf. (2007); Langley et al, Pharm World Sci (2005); cdc.gov
Inpatient Medicine
• Number of medication
changes per admission = 3.8
• Number of new
medications per admission
= 2.5
• Number of medication
changes for PGx drugs = 1.1
per admission
• Percent of hospitalizations
involving at least 1 PGx med
= 50%
• Percentage of patients
prescribed one of just 8 PGx
medications = 55%
Lee et al., Pharmacogenet Genomics (2019)

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Inpatient Hospital Medicine Project
High Utilizer Patients Are Identifiable
Results as of 11/26/19; *as of May 2019

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PGx Results Review Varies by Provider Type
Results as of 1/13/20
Medications Added During Admissions
Data from 8/1/2020 - 2/17/2020
411
medications
added
376 with no
PGx
information
35 with PGx
information
19 (54%)
green light
12 (34%)
yellow light
0 (0%)
red light
(8%)

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Discharge Medications
Data from 8/1/2020 - 2/17/2020
921
discharge
medications
772 with no
PGx
information
149 with PGx
information
105 (70%)
green light
29 (19%)
yellow light
0 (0%)
red light
(16%)
Key Implementation Considerations
• Many Providers Touch the Patients
-Providers in the Emergency Department
-Readmissions to Other Services (e.g., Cardiology, Surgery)
-Verifying Pharmacists (are involved in all med orders)
• Assimilating Results into Clinical Workflow as a
Requested Point of Focus

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Best Practice Alerts
Affecting Prescription Decisions
How often have pharmacogenomic test results changed how you have prescribed or administered
medications within the past 6 months?
63%
23%
13%
0.7% 0%
24%
37%
37%
0% 0%
15%
30%
46%
7%
0%
0%
10%
20%
30%
40%
50%
60%
70%
Never Almost never Sometimes Frequently Almost always
%
of
Respondents
Baseline
6-month
1-year
n=137 (baseline), n=45 (6 mo), n=13 (1yr)
Data collected as of 5/29/19 at UChicago, UIC, Northwestern

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Perioperative PGx
?
Perioperative Medicine: A Unique Opportunity for Better Care
• 5.3% medication
administrations
involved an error or
ADE
• 44.8% of
operations
included at least 1
medication error
and/or ADE
• 68.9% of ADEs
were “serious”
Nanji et al., Anesthesiology (2016)

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Potential Value for Multiple Medications
• Malignant Hyperthermia (RYR1)
• Butyrylcholinesterase activity
(muscle relaxants)
- 25% of the population carries BCHE variant allele(s)
• Awakening Time
• Post-operative N/V
• Post-operative Pain Control
Lando et al., Pharmacogenetics (2003); Gatke et al., Anesthesiology (2005); Yen et al., Clin Chem (2003)
Perioperative Care – The ImPreSS Trial
Truong et al., Clin Pharm Ther (2019)

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0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
Yes No
%
Responses
Faculty Housestaff
CRNA/APN Pharmacists
PGx Opportunity in Perioperative
Medicine is Large
• 90% of providers stated their awareness about PGx
information is lacking
• <30% felt skeptical about the usefulness of PGx
Truong et al., ASCPT abstract (in press 2020)
Ever ordered
PGx test?
Cost of Testing

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Reimbursement
Hertz and McLeod, Clin Pharm Ther (2016)
Precision Medicine for Disease Treatment

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2014
2018 – National Coverage Determination

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• The idea that [genomics] is only going to be
accessible by wealthy, well-educated patrons
who can pay out of pocket is anathema to the
goals of the publicly funded Human Genome
Project, and creates new disparities in our
health care system.”
Dr Jonathan Berg, Univ of North Carolina, quoted in StatNews (2019)

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Race as One Consideration within Health Disparities
Black patients are more interested in implementing pharmacogenomics
I wish my healthcare
providers would make
my care more
individualized:
I think my personal genetic
information should have a
greater role in my treatment
decisions:
Negative =
Disagree
strongly,
Disagree
Somewhat, Not
Sure
Positive =
Agree Strongly,
Agree
Somewhat
P= 0.006
P =0.014
N=355 Whites / 152 Blacks completing surveys Traore et al., ASCPT abstract (in press 2020)
The Most Important Piece:
Patients

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Patient – Provider Communication

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Patient-Facing Results Delivery
Deserves Thoughtful Examination
45
Truong et al., Clin Transl Sci (2020)
Patient Access to PGx Results
Increases Knowledge
• Medication
knowledge scores
rose by 20% post-
portal access
• Patient perceptions
of PGx also improved
• More patients
wanted their
providers to access
test results
• More would
encourage
family/friends to get
testing Truong et al., Clin Transl Sci (2020)

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Future Methods of Patient Safeguarding?
safety-code.org
upgx.eu/faq
48

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We Must Keep Generating
Evidence of Value
40%
of us
+
All of us!
the lifetime utility of comprehensive
pharmacogenomic testing may be substantial
Woodcock and Lesko, NEJM (2009)
O’Donnell et al., Clin Pharm Ther (2016)

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Other Benefits – Medication Adherence?
Illustration by Jeffrey Chase (2018)

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Evidence is the Answer
• Outcomes
Measurements
– do we actually
decrease adverse
events or non-
response events?
• Large Consortia
– e.g. IGNITE
• Randomized Studies
(in select settings)
Routine
Clinical
Use
PHASE II/III
RESEARCH
PHASE I
COMPLETION
Summary
• Individualized health care models of preemptive
pharmacogenomic testing are feasible
• Identifying patients (and medications) most
likely to matter is important
• Providers want to practice in ways aimed at
reducing patient risk
• Engaging patients (safely) in their own results
cannot be ignored

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Project Team
Keith Danahey
Mark Ratain Jerry Yeo
University of Chicago Advanced
Technologies Laboratory
David Meltzer
Elizabeth Lipschultz
Center for Research Informatics
Jeff Apfelbaum
Xander Van Wijk
Randy Knoebel
Tien Truong
Natalie Reizine
CJ Christian
Sam Volchenboum
Sang Mee Lee
Ted Karrison
ACCOuNT Study Team Brittany Borden Emily Schierer Debby Stoit
Lilu Wan
Merisa Middlestadt
David George Larry House
Acknowledgements
NIH 1R01HG009938-01A1
NIH 1U54MD010723-01
Bucksbaum Institute Associate Faculty Scholar Pilot Grant
Chicago Innovation Exchange - Innovation Fund Award
The University of Chicago Cancer Research Foundation Auxiliary
The University of Chicago Office of Clinical Effectiveness
Innovations Grant
The William F. O’Connor Foundation
Benjamin McAllister Scholars Program

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Follow
@UChicagoPGx