# Presentation: 251379

## Regulatory Experience with VGDS: Do they help to qualify genomic biomarkers?

- Robert J. Meyer, MD
- Director, Office of Drug Evaluation II, CDER

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- Disclaimer
- The contents of this talk should NOT be taken as official FDA policy, but represent the opinions of the speaker.  The contents are not binding on the regulated industry nor the FDA.

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- Purpose:
- To give a clinical viewpoint on VGDS experiences and PGx in general
- To discuss some of the promises of PGx from an FDA perspective and some of the cautions

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- Can VGDS aid in validating genomic biomarkers?
*I assume they can and likely will in some cases, but they haven’t yet (insufficient maturity of the experience)*

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- What value has been gained by VGDS to date?
- Has allowed for regulatory / scientific learning that will help inform future guidance and policy development regarding genomics development and data
- Provided a forum for scientific discussions of issues and hypothetical situations between sponsors and FDA, outside of formal submissions/regulatory meetings
- Allows sponsors who submit under VGDS to hone their further efforts

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

*What is needed to validate a clinical genomic biomarker?*
- As with any surrogate marker, one needs convincing, reproducible data that the marker in question reliably predicts response with regard to efficacy, safety or possibly both

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

*What is needed to validate a clinical genomic biomarker?*
- Many current, well accepted surrogate endpoints are established through large clinical trials and or epidemiologic studies
- LDL-C and total-C and CV disease risk
- CD4 counts and viremia in AIDS/HIV disease
- Hgb A1C and the DCCT trial

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

*What is needed to validate a clinical genomic biomarker?*
- Paradigm we are seeing proposed here is somewhat different in intent and scope
- Best validated genomics biomarkers are directly related to the target of therapy (Her-2 in breast CA) or to polymorphic metabolism (UGT1A1 status for irinotecan), possibly EGFR for EGFR targeted therapies

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

*What is needed to validate a clinical genomic biomarker?*
- Pathway to “validation” of markers directly related to the drug effect or target and to polymorphic drug metabolism reasonably well understood from experience and direct pathophysiology

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

*What is needed to validate a clinical genomic biomarker?*
- Bigger challenges and unknowns for validating other PGx biomarkers
- Two broad categories many PGx efforts fit into :
- Assessment of candidate genes (genes believed related to the disease or drug response)
- Broad assessment of genetic predictors/markers
- Genomic SNP scans
- Gene expression profiles

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

*What is needed to validate a clinical genomic biomarker?*
- Such assessments offer both significant challenges and offer significant hope for individualized medicine
- It is clear that there is a tremendous impetus to develop pharmacogenomics and I am sure the VGDS experience will grow and prove helpful in furthering these developments
- For FDA, for Industry and for the Public

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- Three drivers amongst factors “pushing” towards pharmacogenomics being common place in research and medicine:
- Rapid advances in molecular biology and pathology
- Shortcomings of current drug development model
- Change in expectations
- Focus on individual risks/benefits

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- Three drivers amongst factors “pushing” towards pharmacogenomics being common place in research and medicine:
- Molecular biology and pathology
- Great advances in the understanding at the genetic and structural level of disease processes and physiology – new targets, new mechanisms
- Shortcomings of current drug development model
- Focus on individual risks/benefits

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- Three drivers amongst factors “pushing” towards pharmacogenomics being common place in research and medicine:
- Molecular biology and pathology
- Shortcomings of current drug development model
- Focus on individual risks/benefits

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- Drug discovery is an increasingly challenging and costly endeavor
- Increasing failure rate in all phases of development, including phase 2 and 3
- Cost of R+D *per* successful new drug reportedly in the hundreds (800 – 1,700) of millions
- Only _***30%***_ of drugs attain revenues that outweigh development costs
- NME submission and approvals trending downwards

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- Three drivers amongst factors “pushing” towards pharmacogenomics being common place in research and medicine:
- Molecular biology and pathology
- Shortcomings of current drug development model
- Increased focus on individual risks/benefits

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- Focus on individual risks/benefits – Personalized Medicine
- For the most part, drugs have been approved based on overall assessments of risks and benefits
- Hypothetical:
*Drug X shows mean, important response in 45% of patients compared to placebo*
*Drug X has a serious, but rare, “idiosyncratic” adverse event at a rate of 1 in 25,000*
*For 1,000,000 patients treated, benefit is being conferred in 450,000; serious risk faced by 40 patients, only 18 of which are “benefiting”*
- Ability to predict the 40 or, even more importantly, the 22 who are at risk without benefit, would be useful, as would the ability to predict the 450,000 responders even if no predictor of safety were available

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- Two main settings of PGx in drug development to date:
- Target-based use of PGx where the therapeutic is based on a specific molecular/genetic target and therefore is primarily useful in patients with that target
- Example – trastuzumab Correlative use of PGx, where genomics is used to try to predict efficacy or safety response, with or without prior mechanistic knowledge
- Examples – use of proteomic profile to predict responsiveness to chemoRx in Breast CA or HLA-B57 association with hypersensitivity skin reactions with abacavir

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- In addition, it is possible that evaluation of the response in the transcriptome or proteome could serve as a surrogate endpoint for drug response
- This raises all the usual caveats about surrogate endpoints, including the need for good validation of the endpoint in predicting the outcome of interest prior to its use in drug trials for registration purposes
- Getting the dose right can depend on knowing the metabolic phenotype/genotype
- Example – TPMT with 6-mercaptopurine in leukemia or CYP2B6 status in efavirenz
- CDRH recently approved the AmpliChip to address CYP2D6 and 2C19 genotypes

- DIA meeting on Genomic Biomarkers

## Regulatory Experience with VGDS

- Can a PGx approach help improve the effectiveness of a drug candidate that has not proven to be successful overall?  *MAYBE:*
- Some approaches/treatments may truly be ineffective, even if founded in ‘good’ science
- Other therapies may be suboptimally effective due to inherent complexities of the disease, not just genetics
- In deciding if PGx may be useful to “rescue” a drug, pattern of response may be important

- DIA meeting on Genomic Biomarkers

## Efficacy Considerations

- % patients

- Response

- Inadequate delta

- Test drug

- Reference

- Enhanced response

- DIA meeting on Genomic Biomarkers

## Efficacy Considerations

- % patients

- Response

- Inadequate delta

- Enhanced response

- Test drug

- Reference

- Responder

- DIA meeting on Genomic Biomarkers

## Efficacy Considerations

- If a responder analysis shows a 30% level for placebo and a 35% for the test drug, that means the response attributable to drug is only 5%
- You have no way of identifying, short of complicated multiple “n of 1” trials which 1 of seven apparent drug responders is a true responder
- PGx marker correlations to response for the entire 35% more likely to identify markers of spontaneous regression than markers of drug response

- DIA meeting on Genomic Biomarkers

## Efficacy Considerations

- Prospective use of PGx in clinical trials:
- When a marker is not fully validated or established, unselected patients could be randomized into the trial, but stratified based marker status.
- Such a trial could be used to confirm the predictive nature _and_ clinical utility of the marker
- Once utility of the marker is established, could study both responder and non-responders, or just responders
- Studying just responders has implications for generalizability and _*could*_ therefore limit indication or approval

- DIA meeting on Genomic Biomarkers

## Efficacy Considerations

- Whether studying _*only*_ a PGx enriched population would impact on approval/indication depends on:
- Knowledge of effect in marker negative patients (all or none response vs. graduated)
- Safety data availability for patients with lesser response and the severity of safety issues
- Availability of test to identify marker status

- DIA meeting on Genomic Biomarkers

## Safety Considerations - observations

- Enhancing efficacy and limiting toxicities by PGx-based patient selection may not be universally feasible
- With some drugs, major safety issues relate directly to pharmacology and the same genetics that increase effectiveness may then lead to safety concerns
- Targeted safety PGx associations therefore may be best used to identify patients at risk for “idiosyncratic” reactions or where pathophysiology of toxicity is clearly different from efficacy

- DIA meeting on Genomic Biomarkers

## Safety Considerations

- Enhancing efficacy improves benefit-risk, even if safety markers/selection not done
- Better pre-identifying responders may make serious safety issues more acceptable
- Enhancing safety would also improve benefit-risk
- Better pre-identifying those at risk of a serious AE may make efficacy more acceptable

- DIA meeting on Genomic Biomarkers

## Safety Considerations

- If selection of patients in clinical use (safety and/or efficacy) is dependant on safety biomarker
- Need marker widely available _*AND*_ utilized
- Will may be a challenge in practice
- Seldane-EES experience
- Could need riskMAP to assure use of marker and appropriate patient selection

- DIA meeting on Genomic Biomarkers

## Conclusions

- The rapidly evolving area of PGx is exciting and holds promise in helping lead to better drug discovery and development
- Experience in use in drug development is still limited
- However, may clinical trials issues are not unique or uncharted
- Industry, Academia and FDA will need to work together to help practically develop this use, efforts such as the VGDS will help advance this effort
- Smart drug development is smart drug development, so for PGx to enhance drug development, these new tools must be used and implemented intelligently

- DIA meeting on Genomic Biomarkers