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Investigational New Drug Application Review
- 1. Investigational New Drug Application Review Gautam Mehta, MD Division of Oncology 2 Office of New Drugs, CDER
- 3. 3 FDA Mission • The FDA is responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices; and by ensuring the safety of our nation's food supply, cosmetics, and products that emit radiation. • Drug and biologics must be proven safe and effective to FDA’s satisfaction before companies can market them in interstate commerce. • FDA does not take into account cost or payment issues. • FDA does not regulate “practice of medicine”.
- 4. 4 • Regulatory review spans drug development and starts with the IND • Purpose: Protection of clinical trial participants and evaluation of quality of scientific study in later phases Investigation New Drug (IND) Application IND application Marketing approval Phase 0/1 Phase 2/3 Post-Marketing
- 5. 5 What Qualifies for an IND? • Investigational – Any experiment (any use of a drug except for the use of a marketed drug in the course of medical practice) in which a drug is administered or dispensed to or used involving one or more human subjects. • New • Drug – Recognized in US Pharmacopoeia, Homoeopathic Pharmacopoeia, etc. – Intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. – Intended to affect the structure or any function of the body. – A food or dietary supplement is a drug if it meets these criteria (e.g. curcumin)
- 6. 6 Project Management Non-Clinical Pharmacology & Toxicology Product Quality Clinical Pharmacology Clinical Team (Specialty Expertise) Statistics Multi-Disciplinary IND Review
- 7. 7 • 30-day Safety Review • Determines if IND is “safe to proceed” or placed “on hold” • Reviewed on the following criteria: – Does not pose an unreasonable or significant risk of illness or injury – Is adequately designed to meet its stated objectives IND Review Process
- 8. 8 •Biopsies for specific biomarkers –IND submitted to CDER risk determination asked of CDRH –Often a selection biomarker for enrollment on trial –For solid tumors that are incurable or hematologic malignancies without long survival rate • Available therapies may not provide meaningful benefit • Patients could delay alternative therapies until after a clinical trial –Requires patients can be adequately consented IND Risk Determination
- 9. 9 • Jennifer Gao, MD (OCE) • Harpreet Singh, MD (CDER) • Jeffery Seidman, MD (CDRH) • Julia Beaver, MD (OCE) Contacts: Gautam.Mehta@fda.hhs.gov Jennifer.Gao@fda.hhs.gov Acknowledgements
- 10. Backup Slides
- 11. 11 Role of the FDA • An IND is needed whenever studies in humans are conducted in the U.S. – First-in-human and exploratory/proof-of-concept studies: safety – Confirmatory safety and efficacy studies: safety and quality of scientific evaluation • Review teams discuss IND at safety meeting • FDA teams may send Information Requests for revisions or clarifications – Deficiencies: these changes must be made – Comments: suggestions to think about • FDA has 30 days to review an IND – Multidisciplinary team: manufacturing, clinical pharmacology, statistics, pharmacology/toxicology, clinical
- 12. 12 Safety Reporting Report any suspected adverse reaction that is both serious and unexpected – must meet all three definitions • Suspected: any adverse event for which there is a reasonable possibility that the drug caused the event • Unexpected: not listed in the investigator brochure • Serious: – Death or life-threatening – Hospitalization – A medical/surgical intervention to prevent any of the above – A persistent/significant incapacity or substantial disruption of the ability to conduct normal life functions – Congenital anomaly
- 14. 14 Meetings with FDA • FDA meeting categories – Pre-IND meeting – End-of-phase 1 meeting – End-of-phase 2 meeting/pre-phase 3 meeting – Pre-NDA meeting • Meeting formats: – Face to face at FDA White Oak (pre-COVID) – Teleconference – Written responses only
- 15. 15 Biomarkers: More Than Prediction of Response • Biomarkers have potential value across the full spectrum of cancer drug development and clinical care – Facilitate diagnosis – Select optimal dose – Inform prognosis – Select patients for treatment (in trials or in practice) – Predict response to therapy – Monitor response to treatment
- 16. 16 Important Caveats • Not every drug will have an identifiable, testable biomarker. • Not every biomarker will be essential to safe and effective use of the drug. • Some drugs will have more than one biomarker. • Inclusion of some “marker-negative” patients early in development is beneficial
Editor's Notes
- I wanted to acknowledge the following individuals and provide our contact information if you have any further questions.
- other sources of information that would be used in the consideration of "unexpected". Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
- Biopsies can be taken at different time points during a trial and can have different purposes. Biopsies taken during the screening process, whether using fresh or archival tissue, can be used to determine whether a given patient expresses a biomarker, making them eligible for a trial or a particular drug. Biopsies taken at the time of progression can be used to understand tumor biology and drug resistance mechanisms. And some biopsies, whether liquid or solid, can be taken at various time points to look at PK, PD, and targetable biomarkers. We should incorporate them whenever possible.
- Lack of harmonization/ standardization of assays PD-L1 IHC Each agent with own assay, cell-type, threshold/ cut-off Efforts such as Friends of Cancer Research WG to harmonize TMB assays Technology has outpaced the evidence Better clinical decision support needed Will need multiple technologies- assessing DNA, RNA, protein (longitudinally) to get a more holistic snapshot of patient’s disease course Real World Evidence for clinical validation (rare molecular subsets)