Regulatory Science Virtual Symposium: “Innovation to Translation: Role of Genomics in Medical Product Development:” Session 4: Pharmacogenomics Considerations for Clinical Research and Implementation (2021)

Objectives

1. Explain how genetic variation influences response to drug therapy
2. Introduce approaches to discover pharmacogenetic associations and to evaluate the clinical utility of pharmacogenomics in clinical practice
3. Summarize CYP2C19 genetic variability in ACS patients receiving clopidogrel post PCI

Precision Medicine and Pharmacogenomics

1. Some patients are responders vs. non-responders vs. at risk for other conditions

• Gartner’s Hype Cycle
  1. Describes the trend of expectations regarding innovation, expectations, and actuality

Pharmacokinetics and Pharmacodynamics

Translational Research

US FDA Approval of New Drugs

1. 694 drugs approvals over past 20 years
2. 178 or 26% of those have PGx labeling

Biomarker-drug pairs approved per year has grown since 2000

Pre-market Considerations

1. FDA has guidance published in 2013
2. Consider collecting DNA during drug development

Percutaneous Coronary Intervention (PCI)

1. Clopidogrel tablets – helps prevent clots
2. Individuals who are poor metabolizers should not take this medication

Clopidogrel Metabolism

Alternatives to Clopidogrel

1. Post-market researchers showed that there are alternatives

Genetic Subtypes

1. Prasugrel Evidence: Secondary Prevention
   1. Reduces ischemic events with a higher rate of bleeding
2. Prasugrel vs. Clopidogrel by Genotype: Genetic Sub-study of TRITON TIMI-38
   1. Risk vs. benefits
   2.  ADD
3. CPIC Guidelines
   1. CPIC = Clinical Pharmacogenetics Implementation Consortium
   2. ADD

Genetic Sub-studies Benefits and Limitations

1. Benefits
   1. Help determine effect of genetic markers in selected populations
      1. Responder vs. non-responder
      2. Outliers (toxicity)
2. Limitations

Randomized Clinical Studies

1. Different strategies to test value of incorporating PGx into clinical care
   1. Superiority
   2. Non-Inferiority
2. TAILOR-PCI Study
   1. Results
   2. Inclusion and Exclusion Criteria
3. Popular Genetics Study Results

Randomized Clinical Studies Benefits and Limitations

1. Benefits
   1. Good randomization will “wash out” any selection bias
   2. Can determine causality
   3. Help guide decisions for allocation of healthcare resources
2. Limitations
   1. Not clinical feasible or necessary for any pharmacogenomic applications
   2. Rigorously designing a scientific trial is not always ethical
   3. Financial constraints

Clinical implementation and feasibility studies (pragmatic trial)

1. IGNITE: Pharmacogenetics Working Group
2. Real-World Evidence
3. Results
4. Clinical Decision Support Example
5. Benefits
   1. Broad view of an intervention
   2. Allows for economic analysis
   3. Identified systematic, personnel, and technological barriers
6. Limitations
   1. Possibly overestimating benefits and underestimating harm
   2. Often involves complex interventions
   3. Investigators are responsible for recruitment, treatment, and follow-up of participants

Pharmacogenomics Research Resources

1. CPIC
2. Pharmagkb
3. Pharmacogenomics Research Network
4. Clinicaltrials.gov

Summary

1. PGx can be used to guide specific drugs with clinical evidence
2. Resources, like Pharm GKB and CPI C guidelines, can help with PGx considerations for research design and clinical recommendations
3. Opportunity to advance PGx research throughout translational spectrum
4. Clinical studies are warranted in diverse patients populations to determine the utility for pharmacogenomics and deliver reliable care

Accompanying text created by Annie Ly | Graduate Student, Regulatory Science, USC School of Pharmacy lyannie@usc.edu and Emily Donahue | Undergraduate Student, Pharmacology and Drug Development, USC School of Pharmacy emilydon@usc.edu