The Path from Biomarker Discovery to Regulatory Qualification

Section 1: Introduction

1. Biomarker Applications in the Pharmaceutical Industry

Diagnostic Applications

Prognostic Applications

Intervention Management/Monitoring

Concluding Remarks

References

2. Impact of Biomarker Qualification Regulatory Processes on the Critical Path for Drug Development

Introduction

Has the Process at the FDA (CDER) Achieved the Goals Originally Proposed by the Pharmacogenomics Guidance in 2005 and the Critical Path Opportunities List and Report in 2006?

What are the Strengths and Weaknesses of the Different Versions of a Biomarker Qualification Process Developed in Each ICH Region?

How Well Have the Different Versions of This Process Been Harmonized across These Regions?

What are the Opportunities and Challenges for a Single, Universal, Biomarker Qualification Process?

How Can We Develop Metrics with Which to Measure the Impact of These Processes on Drug Development and Their Acceptance by the Pharmaceutical Industry?

Summary

References

3. Regulatory Experience of Biomarker Qualification in the EMA

Other Informal Interactions with the EMA

Examples of Qualification Opinions

4. Regulatory Experience at the FDA, EMA, and PMDA: Regulatory Experience at the PMDA

Acknowledgment

References

Section 2: Biomarker Development and Qualification in the Pharmaceutical Industry

5. The Impact of Changing Context of Use on Weight of Evidence for Qualification of Biomarkers: A Case Study in Ischemic Stroke

6. Safety Biomarker Development and Qualification in the Pharmaceutical Industry

7. First-Ever Regulatory Biomarker Qualification – Review and Insights by a Participant

References

8. Metabolomics-Derived Biomarkers of Drug-Induced Skeletal Muscle Injury and Urinary Bladder Transitional Cell Carcinoma in Rats

Metabolomic Biomarker for Drug-Induced Skeletal Muscle Injury in Rats

Metabolomic Biomarker for Causation of Bladder Tumorigenesis in Rats

Summary

References

9. Molecular Biomarkers for Patients with Castration-Resistant Prostate Cancer: Validating Assays Predictive of Tumor Response

Unmet Needs to be Addressed with Biomarkers

FDA-Approved Method and Demonstrated Use

Emerging Molecular Biomarkers

Validating Genomic Biomarkers in CTCs

Molecular Biomarkers in a CLIA-Certified Laboratory

Changing the Paradigm for Assessment of Recurrent Prostate Cancer: a Liquid Biopsy

References

Section 3: Toxicogenomic Biomarkers

10. Gene Logic and Toxicogenomics Biomarkers

References

11. The When, Where and How of Toxicogenomic Submissions to Regulatory Agencies: The Deliberations of the HL7/CDISC/I3C Pharmacogenomics Data Standards Track 1 Toxicogenomics Working Group

Acknowledgments

Introduction and Background

Toxicogenomic Applications in Drug Discovery and Development

The Case Examples

A Hypothetical Submission in Support of the Safety Claims for a Hypolipidemic Drug

Highlights from the Discussions

Conclusions

References

12. Biomarker Qualification – Past, Present and Future: Initiating a Cross-Sector Toxicogenomics Biomarker Initiative – Health and Environmental Sciences Institute (HESI) Committee on Application of Genomics to Mechanism-Based Risk Assessment

HESI’s Contributions to the Emerging Field of Toxicogenomics

Use of Toxicogenomics to Biological Assess Mechanisms – Case Studies

Current Focus and Activities of the HESI Genomics Committee

Summary and Future Horizons

References

Section 4: Biomarkers of Drug Safety

13. ‘Classic’ Biomarkers of Liver Injury

Bilirubin

Alternative and Discarded Biomarkers

Aminotransferases (Transaminases)

Combined ALT and TBL Measurements

Conclusions and Recommendations

References

14. Qualification of Urinary Biomarkers for Kidney Toxicity

Regulatory Framework: Advancing the Science of Biomarkers

Kidney Injury Molecule-1: Characteristics

Collaborations in Consortia

Interactions with the FDA and EMA

Translation to Clinical Use

Conclusions

References

Section 5: Consortia

15. Renal Biomarker Qualification: An ILSI Health and Environmental Sciences Institute Perspective

Safety Biomarker Research – the Origin of this Activity in HESI

Creation of Biomarker Working Groups

Biomarkers of Nephrotoxicity Committee (BNC)

Biomarker Qualification: the Changing Landscape

References

16. Vignette Regarding Consortia: C-Path Institute

17. The Telemetric and Holter ECG Warehouse to Enable the Validation and Development of Novel Electrocardiographic Markers

Introduction

QT Interval as a Safety Marker in Drug Development

QT Interval: from a Biomarker to a Surrogate Marker

The Thorough QT Studies (TQT)

Improving the QT Marker

QT, Heart Rate and Autonomic Regulation

Inception of the Telemetric and Holter ECG Warehouse (THEW): a Model to Develop Academia-Regulators-Industries Partnerships

Involving the FDA and Industry

Participation by the National Institutes of Health

Facilitating the Submission of New ECG Markers to the FDA

Conclusions and Perspectives

References

Section VI: Path to Regulatory Qualification Process Development

18. Path to Regulatory Qualification Program Development: A US FDA Perspective

Acknowledgments

The Biomarker Qualification Process at US FDA

Current Status of Biomarker Qualification Submissions

Future Perspectives

References

19. Path to Regulatory Qualification Process Development

Acknowledgment

References

20. The Tortuous Path From Development to Qualification of Biomarkers