Phase 1 Clinical Studies First-In-Human (FIH) Pharmacologically-Guided Dose Escalation Jerry M. Collins, Ph.D. Developmental Therapeutics Program Division.

Slides:

Advertisements

Similar presentations

Small Molecule PD and Imaging – Models and Assay Development DCTD Phase 0 Primer, September 5, 2007 Ralph E Parchment, PhD SAIC-Frederick, Inc., NCI-Frederick,

Advertisements

Dr. Kumud More ICRI, Mumbai 15/04/10

Marc Bailie DVM, PhD Director In Vivo Facility Michigan State University, Chief Development Officer Integrated Nonclinical Development Solutions (INDS)

Regulatory Framework Leigh Shaw, Director.

Paula M. Jacobs, Ph.D. SAIC Frederick Cancer Imaging Program/DCTD/NCI/NIH September 5, 2006 Phase 0 Trials in Oncologic Drug Development DCTD Phase 0 Workshop.

Drug Research and Development (R&D) Karol Godwin DVM.

EXAMPLE OF DRUG DEVELOPMENT. Objectives of preclinical tests Preclinical tests helps to  Evaluate its toxicity  Assess its effectiveness  Propose a.

Clinical Trial Design, Biostatistics, Ethics, and Recruitment Clinical Trial Design  Anthony J. Murgo, MD.,MS; NCI/DCTD Biostatistics  Larry Rubinstein,

1 Pharmacology/Toxicology information to submit an IND for an anticancer drug.

Charlie Taylor, PhD CpTaylor Consulting Chelsea, MI, USA

Mitochondrial Manipulation Technologies: Preclinical Considerations

JMV 1843 pharmacological profile

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH Working with FDA: Biological Products and Clinical Development Critical Path.

What Do Toxicologists Do?

Title, in bold style Subtitle, in regular Max 3 lines of text totally NB! The graphic outside the slide will not show in “Slide Show” or on print WntResearch.

REGULATORY ISSUES IN HIV CURE RESEARCH HIV Cure Research Training Curriculum Regulatory Issues Module by: Damon Deming, Ph.D. FDA Division of Antiviral.

+ Drug Development and Review Process. + Objectives Learn the processes involved in drug discovery and development Define the phases involved in FDA drug.

Cancer Nanotechnology: New Opportunities for Targeted Therapies FDA Public Meeting October 10, 2006 Piotr Grodzinski, Ph.D. Director, Nanotechnology for.

Cellular Therapies for Cardiac Diseases – FDA Preclinical Perspective Richard D. McFarland Ph.D., M.D. CBER/OCTGT/DCEPT BRMAC # 37 March 18-19, 2004.

Re-Examination of the Design of Early Clinical Trials for Molecularly Targeted Drugs Richard Simon, D.Sc. National Cancer Institute linus.nci.nih.gov/brb.

NMF 3/6/03 Susan Galbraith, MB BChir PhD Vice President Clinical Discovery Oncology & Immunology Phase 0 Trials Why aren’t they more widely used by industry?

Clinical Pharmacy’s Role in Research Trials Sheree Miller Pharm.D. Investigational Drug Service University of Washington Medical Center.

Food and Drug Administration Preclinical safety data for “first in human” (FIH) clinical trials in healthy volunteer subjects Oncology Drug Advisory Committee.

Howard Fillit, MD Executive Director Improving Animal Trials for Alzheimer’s Disease: Recommendations for Best Practices.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH Working with FDA: Biological Products and Clinical Development IND Case Studies.

Stages of drug development

Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 1 Improvement in Dose Selection: FDA Perspective IDSA/ISAP/FDA Workshop.

Guidance for Industry M4S: The CTD-Safety

February 2008 William Petros, Pharm.D., FCCP

Obtaining and Negotiatiing a Position in Industry/Biotech Roy G. Smith Ph.D. Director, Huffington Center on Aging Professor, Department of Molecular and.

1 Phase 0 Trials Role in Radiation Mitigation Agent Development? Anthony J. Murgo, M.D., M.S. Office of Oncology Drug Products Center for Drug Evaluation.

Integrating Scientific Advances into Regulation: Pharmacogenomics and Pharmacogenetics Janet Woodcock, M.D. Director, Center for Drug Evaluation and Research.

Richard D. Hockett, Jr. M.D. Sr. Clinical Research Physician Group Leader, Genomic Medicine FDA Clinical Pharmacology Advisory Committee Integrating Pharmacogenomics.

Grand Challenges for Nanomedicine and Nanobiology Workshop Houston, Texas August 27 th, 2007.

Essential Considerations for Your IND Submission: Objectives and Pitfall Avoidance in Your Preclinical Program Darren Warren.

Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 In Vitro/Animal Models to Support Dosage Selection: FDA Perspective.

Animal Models for Porcine Xenotransplantation Products Intended to Treat Type 1 Diabetes or Acute Liver Failure CTGTAC #47 May 14, 2009.

Exploratory IND Studies

Nonclinical Perspective on Initiating Phase 1 Studies for Small Molecular Weight Compounds John K. Leighton, PH.D., DABT Supervisory Pharmacologist Division.

Investigational Drugs in the hospital. + What is Investigational Drug? Investigational or experimental drugs are new drugs that have not yet been approved.

ONCOLOGY Drug Development Fadi Sami Farhat, MD ONCOLOGY Drug Development Fadi Sami Farhat, MD Hematology Oncology

Update From FDA: Office of the Commissioner and Center for Drug Evaluation and Research Janet Woodcock, M.D. Acting Deputy Commissioner for Operations.

APPLYING PRE-CLINICAL DATA TO CLINICAL STUDIES-I Edward A. Sausville, M.D., Ph.D. Developmental Therapeutics Program National Cancer Institute October.

Background Objectives Data Simulation in human Conclusion -F14512, a polyamine-vectorized anti-cancer drug which combines an epipodophyllotoxin core targeting.

Preclinical Guidelines: Development of Radioprotective/Mitigative Agents Departments of Dermatology & Radiation Oncology University of Rochester Medical.

The New Drug Development Process (www. fda. gov/cder/handbook/develop

Clinical Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical Science Meeting April Quantitative risk analysis using exposure-response.

Traditional vs novel trial designing .

1 METHODS FOR DETERMINING SIMILARITY OF EXPOSURE-RESPONSE BETWEEN PEDIATRIC AND ADULT POPULATIONS Stella G. Machado, Ph.D. Quantitative Methods and Research.

Phase I Issues for Novel TB Drugs Dakshina M. Chilukuri, Ph.D. Office of Clinical Pharmacology and Biopharmaceutics, FDA OPEN FORUM ON KEY ISSUES IN TB.

FDA Office of Orphan Products Development

Grade Statistics without Bonus with Bonus Average = 86 Median = 87 Average = 88 Median = 89 Undergraduates Average=88 MS Average=92.

Chief, Gene Therapy Branch

Introduction to the Meeting Introduction to the Meeting Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee November 17-18,

Exact PK Equivalence for a bridging study Steven Novick, Harry Yang (MedImmune) and Xiang Zhang (NC State) NCB, October 2015.

European Patients’ Academy on Therapeutic Innovation The key principles of pharmacology.

1 The Role of Exposure-Response Evaluation in Drug Development and Regulatory Decisions Case Study: Rosuvastatin Hae-Young Ahn, Ph.D. Office of Clinical.

NCI Initiatives to Develop Non-Clinical Models for Pediatric Oncology Malcolm A. Smith, MD, PhD 17 March 2004.

Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 Current Status of Dose Selection in Antimicrobial Drug Development.

PRECLINICAL PHARMACOLOGY & TOXICOLOGY OF ANTI-NEOPLASTIC AGENTS  THE NCI PERSPECTIVE Joseph E. Tomaszewski, Ph.D. Toxicology & Pharmacology Branch.

Division of Cancer Treatment and Diagnosis Presented By: Michael Difilippantonio, Ph.D. October 1, 2015.

The process of drug development. Drug development 0,8 – 1 mld. USD.

for Human Pharmaceuticals Kyung-Chul Choi D.V.M., Ph.D.

The Stages of a Clinical Trial

Eucrisa™ - Crisaborole

Rational for the 5R Philosophy

Pillars of WARF Therapeutics: Invest - Develop - Partner

Considerations for Successful Biopharmaceutical Product Development: Discovery to Proof of Concept -A Panel Discussion Stanley C. McDermott, PharmD, MS,

Presentation transcript:

Phase 1 Clinical Studies First-In-Human (FIH) Pharmacologically-Guided Dose Escalation Jerry M. Collins, Ph.D. Developmental Therapeutics Program Division of Cancer Treatment and Diagnosis, NCI

→ Traditional IND Phase 1→ 2 → 3 Post-Approval Clinical Testing → NDA Phase 4 Pre-Clinical In vitro Subcellular Cellular In Vivo Rodents Non-Rodents and Non-Clinical Clinical

Guidance for Industry, Investigators, Reviewers Exploratory IND Studies January 2006 Categories of Studies: [1] Proof-of-Concept (Industry; Academia) [2] Selection of Lead Candidate from a Set of Options (Industry) [3] Imaging (parity with EMEA policy)

“Historical” Phases of Human Evaluation Phase 1: Safety, early signs of activity Phase 2: Is activity promising? Phase 3: Improve current therapy? Phase 0: Mechanism of Action

What is: Proof-of-Concept? What is: Phase Zero? Can You Articulate the Key Question? How Do You Answer This Question?

//nihroadmap.nih.gov

Re-Engineering Phase I (FIH) Trials 1. Pipeline/Funnel Pressure: combinatorial/HTS, new Sponsors 2. To Phase I Faster, Less Preclinical Work 3. Fewer patients, homeopathic doses 4. More patients “near-Phase 2” doses 5. “Value-Added” factors  PK only: variability, metabolism / pharmacogenetics  PD: Decisions to Drop/Continue

The PINK SHEET October 28, 2002 Daniel Vasella, MD CEO, Novartis Industry-Wide Trends in Clinical Trials Change # Ongoing 1995  2001 in 2001 Phase Phase 2+55%1,136 Phase 3(none) %

Design of Phase 1 (FIH) Trial Starting Dose Escalation Scheme For Both Elements, Conflict Between Caution/Safety vs. Efficiency/Efficacy

BIBLIOGRAPHY / COLLINS / PHASE 1 J.M.Collins, D.S.Zaharko, R.L.Dedrick, B.A.Chabner. Potential roles for preclinical pharmacology in Phase I trials. Cancer Treat. Rep. 70:73 ‑ 80, ** Message: we do a lot of preclinical pharm studies; - - what do we learn? - - how is it used? ** Initial proposal for customized dose escalation. J.M. Collins, C.K. Grieshaber, B.A. Chabner. Pharmacologically-guided Phase I trials based upon preclinical development. J. Natl. Cancer Inst. 82: , ** Note that title does not say “PK” Intended as an overall platform Summarizes mostly retrospectively

PK-PD Hypothesis: When Comparing Animal and Human Doses, Expect Equal Toxicity for Equal Drug Exposure Concentration of Drug as a Biomarker or Endpoint

Bridges Between Preclinical and Clinical Development Preclinical Clinical Pharm/Tox Phase 1 Trials Mouse MTD Starting Dose   Blood Levels   Escalation Strategy

Acute Toxicity of Anticancer Drugs Human versus Mouse Dose RatioAUC Ratio

Conclusion: Hypothesis has merit. Follow-Up: What is underlying reason for interspecies differences?

S.Markey, 8-Nov-01, Slide #54 Additional Effects on Drug Metabolism Species differences Major differences in drug metabolism in different species have been recognized for many years both in gut microflora and CYP proteins Example: phenylbutazone half-life is: 3 h in rabbit 6 h in rat, guinea pig, dog 3 days in humans

Metabolism as the Principal Confounding Factor for First-in-Human Trials

Gianni et al, JNCI (1990) AUC values in plasma for Iododeoxydoxorubicin (I-Dox) in Mouse & Humans at Equi-Toxic Doses Mouse Human I-Dox I-Dox-ol (metabolite)

Rule #1 Always Include Some Data from the Lab

In Addition to Explaining Interspecies Differences, Other Applications for Metabolism Studies in Phase 1: Learn/Confirm Major Pathways Learn/Confirm Active/Toxic Molecules

In Vitro – In Vivo Metabolic Profiling

terfenadine/SELDANE® fexofenadine/ALLEGRA®

Target-Guided Dose Escalation Preclinical Pharm/Tox Clinical Phase 1 Trials Safety Factor Reference Animal Dose  Starting Human Dose Stop or Escalate? Define Target Goal Assess Target Impact  

Functional Imaging via PET: Biomarkers for Treatment Evaluation  Does treatment impact the desired target?  What is the minimum/maximum dose?  How to select interval between courses? CONTEXT: Individual Patient, or New Agent Development

MAO-B Inhibition by Lazabamide J.Fowler,BNL Neurology(93 )

First-In-Human Trials Identity Crisis?

What is Inherent in First-In-Human Trials?

 Translational Research

FDA NIH NIEHS Pittsburgh Indianapolis NIA/NIDA/Baltimore Dartmouth UCLAUCLA