Precision Medicine: Levels of Evidence Required for Reporting Variants and Guiding Patient - PowerPoint Presentation

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Precision Medicine:

Levels of Evidence Required for Reporting Variants and Guiding Patient Treatment

Apostolia M. Tsimberidou, MD, PhDProfessor Investigational Cancer TherapeuticsSlide2

Incorporation of Levels of Evidence into Variant Reporting/Clinical Practice

Implementation of CAP, AMP, ASCO recommendations

What can the FDA do to move the field forward

Precision MedicineSlide3

Precision Medicine

A form of medicine that uses information about a person

’s genes, proteins, and environment to prevent, diagnose, and treat disease, NCI, 2011Personalized Medicine in Cancer Requires:Identification of genetic alterations that drive carcinogenesis

2. Treatment with drugs that can effectively inhibit the

function of the genetic alterations

Consistent use of molecularly targeted therapy

Current definition: Use of therapeutic agents that target any biological abnormality that is associated with carcinogenesis, including immunotherapy.Slide4

In recent years, molecular profile is ordered as:

Standard of care or

For clinical trials: i.e. IMPACT2, NCI-MATCH, MPACTInterpretation of molecular profile:Expert oncologists in precision medicineSpecialized team of molecular biologistsSelection and treatment on clinical trials is based on:Recommendation of tumor molecular boardClinical trial availabilityPatient preference and eligibility

Study sponsor and insurance approval

Stringent regulatory CRC/IRB/DSMB review and trial prioritization

Incorporation of Levels of Evidence into Variant Reporting/Clinical Practice at MD AndersonSlide5

Aggregates data directly from www.ClinicalTrials.gov identifier

If a trial was verified >2 yrs ago: assigned status: "Unknown”

Extracts state names (i.e., Texas => TX)Uses source data from:COSMICNational Library of MedicineEuropean Bioinformatics Institute (EMBL-EBI, 1000 Genomes Project)ClinVardbSNP EnsemblNational Human Genome Research Institute (BIC database)

Precision Oncology Decision Support Team

Landrum MJ, et al. ClinVar: public archive of interpretations of clinically relevant variants. 

Nucleic Acids Res

. 2016 44(D1):D862-8

 Slide6

Incorporation of Levels of Evidence into Variant Reporting/Clinical Practice

Implementation of CAP, AMP, ASCO Recommendations

What Can the FDA Do to Move the Field Forward

Precision MedicineSlide7

Li M, Datto M, Duncavage EJ, Kulkarni S, Lindeman N, Roy S, Tsimberidou AM, Vnencak-Jones C, Wolff D, Younes A, Nikiforova M J Mol Diagn 2017, 19: 4-23

Variant Categorization: AMP, ASCO, CAP recommendationsSlide8

Lung Cancer Mutation Consortium: Incidence of Driver Mutations

Kris MG, et al

JAMA 2014;311:1998-06

PD-L1 and others now overlappingSlide9

Precision Medicine in a Patient with Salivary

Cancer (BRAF V600E Mutation, Vemurafenib)Slide10

Incorporation of Levels of Evidence into Variant Reporting/Clinical Practice

Implementation of CAP, AMP, ASCO Recommendations

What Can the FDA Do to Move the Field Forward

Precision MedicineSlide11

Precision Medicine 2018: Characteristics

Multiple clinical trials with correlative scientific endpoints

Dynamic changes (time, space) of tumor, microenvironment, circulating tumor (ct)-DNAComplex molecular networks, immune

mechanisms, proteomic, transcriptome and epigenetic changes

Identification of multiple tumor/

ct

-DNA alterations in individual patientsProspective innovative trials with adaptive design will accelerate the drug approval process (reduced cost, time, number of patients)Slide12

Precision Medicine 2018: What Can the FDA Do to Move the Field Forward (I)

Facilitate approval of platform diagnostics (rather than requiring drug-specific companion diagnostic)

Make tumor NGS available to all patients Accelerate drug approval across tumor types based on biomarkersRaise awareness to drug development ECO-system for the most efficient methodologies to determine effectiveness of novel drugs

Encourage “basket” trials and combination regimens with innovative design to expedite biomarker-based drug developmentSlide13

Precision Medicine 2018: What Can the FDA Do to Move the Field Forward (II)

Lead the evolution to transition to the new environment: pharmaceutical companies are often not flexible in protocol design

Provide leadership by encouraging alignment in philosophy between FDA and IRBs (often IRBs cause non-value enhancing delays for FDA-approved protocols)Require minimal, essential data to decrease cost and complexity of trials

Encourage sophisticated phase 1-2 studies with innovative design Slide14

What Can the FDA Do to Move the Field of Precision Medicine Forward (III)Help develop innovative bio-analytical methods better adapted to the current precision medicine environment, for new classes of trials (i.e. for IO trials 2-yr Landmark analyses may be more meaningful than log-rank analyses)Continue to utilize the rapid approval process such as the breakthrough designation and fast track programsFor rare mutations, consider moving towards increasing use of “expanded access” patient data contributing to the approval of precision drugs for rare molecular alterations/diseases, rather than only considering patients treated on clinical trialsSimplify the use of “expanded access”Consider developing a novel, efficient pathway to expedite drug approval for patients with specific molecular characteristics based on well-curated “N of 1” databasesSlide15

It should urgently capitalize on the investment of EMRs and implement inter-operability and integration with NGS Long-term plan (3-5 years)It should direct setting up the informational infrastructure to be prepared for the AI (artificial intelligence) revolution: to use NGS data and EMRs to perform algorithm analysis, using AI in decision making for optimal drug selection, for More Effective Drugs, For More Patients, Faster. What Can the FDA Do to Move the Field of Precision Medicine Forward (IV) Slide16

Thank you!

atsimber@mdanderson.org