FDA s Critical Path Initiative and Drug Development

Transcription

1 FDA s Critical Path Initiative and Drug Development Duu-Gong Wu, PhD Executive Director, PharmaNet Consulting The views expressed herein are solely those of the author and do not necessarily reflect the official policy, position or opinions of PharmaNet Development Group, Inc. and its affiliates

2 Agenda FDA s Critical Path Initiative Pharmacogenomics, toxicogenomics and biomarkers New model of clinical development Quality by Design and manufacturing science Conclusion Page 2

3 FDA s Critical Path Initiative Page 3

4 Current Problems With Drug Development High failure rate for pre-ind development Less than 20% of NME INDs reaches NDA stage 50% failure for Phase III products due to lack of efficacy 30-40% of NMEs failed due to safety 8-10 years for a product to reach market Estimated cost of $800 million per NME product Multiple review cycles and longer approval time for most NME NDAs Pipeline problems for industry Page 4

5 Factors for Decline in New Biological Product Approval Pre-clinical studies Lack of animal models or failure to investigate pharm/tox in animals. Phase I/2: Animal model fails to predict response in human. Unexpected adverse events; Immunogenicity Lack of clinically relevant biological activity MOA in human not fully evaluated and understood. Appropriate endpoints not sufficiently investigated. No valid biomarkers for possible early insight until phase 3. Phase 2/3: Clinical Issues Insufficient dose ranging studies; wrong dose Unexpected adverse events with longer exposure Newer products are more complex with difficult safety and manufacturing issues Page 5

6 FDA s Critical Path Initiative FDA s Critical Path Initiative calls for all parties to work with FDA To identify opportunities to modernize tools for product development To help reduce existing hurdles in medical product design and development To take advantage of innovative science and technologies to reach commercialization of medical products Three crucial scientific/technical areas from scientific discovery to commercial product have been identified Safety Assessment how to predict if a potential product will be harmful Proof of Efficacy how to determine if a potential product will have medical benefit Drug Manufacture how to manufacture a product commercial scale with consistently high quality Page 6

7 Science Underlying the Critical Path of Drug Development Basic Research Prototype Design or Discovery Preclinical Development Clinical Development FDA Filing / Approval & Launch Preparations Transitional Research Critical Path Reserch Different approaches from traditional discovery science Page 7

8 FDA s Project Categories Animal testing Development of animal models Toxicogenomics Data mining (e.g., how predictable are current testing algorithms) Biomarker Development General conceptual framework Specific biomarker qualification / validation Clinical Development-streamlining clinical trials Early clinical work Model-based development Clinical trials modernization Manufacturing science PAT and Quality by Design Risk-based quality system Source: Janet Woodcock, M.D. May 5, 2005 Page 8

9 FDA s Selected Critical Path Projects Basic Research Prototype Design or Discovery Preclinical Development Clinical Development FDA Filing / Approval & Launch Preparations Toxicogenomics Exploratory IND Genomic Biomarkers Cancer Biomarkers Genetic basis of adverse events Streamline Clinical Trials *Positron emission tomography Page 9

10 Utility of Biomarkers Animal safety biomarkers to predict animal toxicity Genetic markers for metabolism Human safety biomarkers for early screening and monitoring of toxicity Biomarkers to assess disease severity or risk Biomarkers to select appropriate patient populations Human efficacy biomarkers to predict response to treatment Validated surrogates for clinical endpoints, e.g. blood pressure and serum cholesterol levels Page 10

11 Example of Valid Genomic Biomarkers Drug Indication Biomarker Test Required Imatinib mesylate Stomach cancer C-KIT expression 3 Voriconazole Celecoxib Acute pains CYP2C19 Variant 3 Cetuximab Colorectal Cancer EGFR expression 1 Rasburicase Uric acid level manag. G6PD Deficiency 3 Trastuzumab Breast Cancer Her2/neu overexpression 1 Warfarin Thrombosis Protein C Deficiency 2 Irinotecan Colon Rectum Cancer UGT1A1 variant 2 1=Test required; 2=Test recommended; 3= Information only Source: /genomics/genomic_biomarkers_table.htm Page 11

12 FDA Approved Device with Biomarker Tests HER2-neu trastuzumab (Herceptin)** C-kit mutations imatinib mesylate (Gleevec)** UGT1A1 irinotecan (Camptosar)** Cytochrome P-450 (CYP) 2D6 5HT3 receptor antagonists and codeine derivatives* * FDA package insert information * FDA approved device Page 12

13 Known Valid Markers Safety TPMT, 6TPMT (6-MP, MP, azathopurine) UGT1A1 (irinotecan) CYP2C9/VKORC1 (warfarin) CYP2D6 (strattera) Efficacy EGFR status (Colon cancer, Erbitux, Tarceva) Her2/neu status (Breast cancer, Herceptin) Philadelphia chromosome Bcr-abl (Leukemia, Gleevec) C-kit (Leukemia, Gleevec) * Labels for products marketed in U.S. Page 13

14 Metabolic Profiles and Biomarkers

15 Toxicity Screening Effect Known Toxic Profiles Test Compound Liver tox 1 Liver tox 2 Kidney tox Neuronal tox Cardiac tox Page 15

16 Biomarker and Assay Development Process Source: Felix W. Frueh, Ph.D, Office of Clinical Pharmacology, CDER/FDA R&D Leader Forum Spring 2007, March 5, 2007, Philadelphia, PA Page 16

17 Streamlining Clinical Trail Exploratory IND (guidance published) Microdose Screening Personalized medicines Biomarkers and diagnostic kits Guidance for new clinical model and design Multiple Endpoint Enrichment Design Non-inferiority design (issued) Adaptive Design (issued) Handling of Missing Data End of Phase 2A (issued) Page 17

18 Exploratory IND and GMP for Phase I Exploratory IND (2006 guidance): Phase 0 IND Sub-therapeutic dose for pharmacological or PK or imaging studies without toxic effects with a limited number of subjects and duration (7 days) Screening studies (single-dose or short term for up to 5 related compounds) Microdose (1/100 th of pharmacological dose; NMT 100 pg); 1/50 th of NOAEL Flexible and less extensive animal studies are acceptable depending on goals of microdose studies Limited but adequate CMC information cgmp for Phase I studies guidance Incremental approach to cgmp compliance for clinical products Extent of controls may differ for Phase I products Risk-based approach Special considerations for microdose/screening products, multiple product, biotech and sterile products Page 18

19 Microdose Studies Single dose PK or Imaging studies: Less than 1/100 th of the dose calculated to yield a pharmacological effect or <100 micrograms Single-dose animal studies to support a single-dose microdose study Single mammalian species justified by in vitro metabolism data Single dose exposure via intended clinical route 14 day observation with interim sacrifice at day 2 Endpoint include: body weight, clinical signs, chemistry, hematology and histophathology without genetic toxicology required Page 19

20 Personalized Medicine Example Herceptin Trials with Biomarker Trial Design With HER2 neu Without Number of Patients % Response Rate 50% 10% Years of Follow-up *The drug is effective only in situations where the cancerous tissue carries (over expresses) a specific gene marker. Page 20

21 Personalized Medicine Example: Irinotecan Irinotecan is a topoisomerase 1 inhibitor used to treat colon cancer 1994: introduced in U.S. market (accelerated FDA approval) 1997: severe toxicity observed in 2 patients with Gilbert s syndrome 1998: role of UGT1A1 in the metabolism of the active metabolite of irinotecan SN-38, described 2004: FDA advisory committee recommends label update to inform that patients with UGT1A1 deficiency may need a lower dose 2005: Irinotecan label was updated with recommendation to lower dose by 1 step if patient carries UGT1A1*28 allele 2005: First UGT1A1 genetic test (Invader Assay) was FDA-approved the way to Personalized Medicine for irinotecan was paved Page 21

22 ONDQA CMC Pilot (QbD) Program launched 7/05 Pharm CGMP for 21 st Century Initiative (Final Report) 9/04 Critical Path Initiative 3/ ICH Q10 reached Step 2 (5/07) FDA Quality Initiatives OGD QbR announced 1/06 ICH Q8 finalized 11/05 ICH Q9 finalized 11/05 PAT Guidance finalized 9/04 Quality Systems Guidance finalized 9/06 FDA Workshops

23 Quality by Design A systematic process of building desirable quality by a careful evaluation of all the attributes that go into characterizing quality from the inception of a product to its end use Involves stakeholders (the patient, the manufacturer, the physician and the regulator) Assures identity, purity, quality and strength/potency as it relates to the safety and efficacy of new drugs throughout product life cycle Page 23

24 Pharmaceutical Development Formulation Development Manufacturing Process Process Control Specification Process Improvement Regulatory Oversight Traditional Empirical, trial and error, data driven, retrospective Fixed In-process controls Primary product controls based on limit batch data Reluctant due to regulatory consideration Reviews and inspections for all manufacturing changes Quality by Design Systematic, multivariate experiments, knowledge driven, prospective Flexible and adjustable within design space Real-time monitoring of process operation Only part of overall quality controls based on product performance Continuous quality and process improvement under design space Flexible regulatory oversights based on risk; real-time release Page 24

25 Design Space (Validation Ranges) Internal Target/trending Knowledge Space Permitted changes Control Space Design Space Known range without impact on safety and efficacy Impact on safety and efficacy unknown Page 25

26 FDA View on QbD Product/process design and development QbD system Define desired product performance upfront; identify product CQAs Design formulation and process to reproducibly and robustly meet product CQAs Continually monitor and update process to assure consistent quality Identify and control sources of variability in material and process Understand impact of material attributes and process parameters on product CQAs Risk assessment and risk control Source: Christine More, ONDQA, CDER/FDA

27 GMP Inspections Based on Quality Risk Manufacturer s technical expertise and knowledge of FDA regulatory requirements, e.g. Good Manufacturing Practices (GMPs) Maturity of regulatory system in foreign home country Complexity/ contamination risk of product Level of exposure to US population

28 New Regulatory CMC Model Process Understanding ICH Q8 + Q9 Process Understanding Process Understanding CMC regulatory oversight cgmp regulatory oversight Company s Quality system Post approval change CMC regulatory oversight cgmp regulatory oversight Company s Quality system Post approval change CMC regulatory oversight cgmp regulatory oversight Company s Quality system Post approval change Risk Risk (P/R) Risk (P/R) ICH Q10 Source: Dr. Norman Schmuff(FDA) and Robert Baum(Pfizer), 2005 DIA

29 Conclusion Page 29

30 Conclusion Critical Path projects are designed to change the old drug development models. Pharmacogenomics and toxicogenomics will become integrated parts of an efficient drug development process. New models and designs will help streamline the clinical trials. Using biomarkers, personalized medicine can be incorporated from the early phase of clinical development. Utilization of QBD, risk-based quality system will bring the new manufacturing science into the process of new drug development. Many other projects are ongoing. Page 30

31 TPMT, 6TPMT (6-MP,MP, azathiopurine). Thiopurine S-methyltransferase (TPMT) is an enzyme that regulates the metabolism of azathioprine and 6-mercaptopurine (6-MP). UGT1A1 (irinotecan) UDP-Glucuronosyltransferase- estrogen metabolism gene; Mutation in UGT1A1 gene leads to reduced UGT1A1 activity CYP2C9/VKORC1 (warfarin) Cytochrome P450 CYP2D6 (Strattera) Cytochrome P450

32 Biomarker Go and No Go Point Go/NoGo point Specifications for sensitivity and specificity Specifications for reproducibility, Matrices and Sample volumes requirement Availability of reference protein