Oncology biomarkers for safety and efficacy

Oncology biomarkers for safety and efficacy
by
David Ross, M.D., Ph.D.
Office of Oncology Drug Products
Center for Drug Evaluation and Research
U.S. Food and Drug Administration

* Why biomarkers?
* Biomarkers for safety
* Biomarkers for efficacy
* Scientific and regulatory challenges
* FDA views pharmacogenomics and biomarkers as part of a new paradigm for oncology therapeutics development
* Developing new cancer treatments via biomarkers will require a coordinated public-private approach between academia, industry, government, and other stakeholders

Development issues in oncology – I

* Represents >100 diseases/indications
o Different natural histories
o Different etiologies/molecular biology
* Efficacy assessment is difficult
o Most investigational therapies fail to show efficacy
o Even promising agents may have small treatment effects
* Safety assessment is difficult
o most candidates (even targeted) are toxic
o underlying disease may confound safety assessment
* Investigational nature of discipline
o cancer centers, cooperative groups, NCI
* Multi-disciplinary approaches
o chemotherapy, biologics, surgery, radiation therapy, devices, supportive care, diagnostics

Development issues in oncology – II

* Life-threatening nature of diseases
* Potential for distant recurrences
* Drugs have multiple MOAs; used in combination
* Risk/benefit ratio--different perspective on serious adverse events; highly trained specialists using drugs rather than GP
* Off-label uses may be standard of care
* New technologies/concepts piloted in oncology

Research vs. results
The paradox of drug development

1. Clinical trials provide evidence of efficacy and safety at usual doses in populations
2. Physicians treat individual patients who can vary widely in their response to drug therapy

All patients with same diagnosis


Therapy C
Therapy B
Therapy A
Some respond to treatment
Some don’t
Some develop adverse reactions
Why the differences in response?

Standard therapy

Responders and Patients

Not Predisposed to Toxicity

All patients with same diagnosis

Alternate therapy
non-responders
and toxic responders
Responding to variability

Pharmacogenomics applied to oncology therapeutics development

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Evolution of pharmacogenomics

* Phenotypic variation known for >50 y
o Isoniazid rapid acetylators, G6PD-associated hemolysis
o Application required development of new assay for each phenotype
* Sequencing of entire human genome
* Genotype – drug response correlations
* Analytic biochemistry advances
o Development of bioinformatics
o Multiplex gene analysis platforms
o Application of fluidics and IC manufacturing techniques to gene chip fabrication
* Oncology therapeutic strategies
o Clinically relevant genotypes identified
o Development of validated assay for genotype
o Safety – correlation of clinical risk with genotype
o Efficacy – clinical benefit via genotype targeting

Irinotecan (Camptosar®)

* Irinotecan ~ proven 1st (5-FU and leucovorin) and 2nd line prodrug therapy for metastatic colon/rectal cancer
* Providers/patients face a clinical predicament ~ what is the optimal dose?
o Incidence of grade 3-4 neutropenia is 35%
o Nearly 70% of patients need dose reduction
o Toxicity associated with active drug exposure

Irinotecan metabolism
UGT1A1 gene structure

UGT1A1: promoter polymorphism and toxicity

* Prodrug (irinotecan) metabolized to SN-38 (active drug)
* Rate-limiting metabolic enzyme encoded by UGT1A1
* Five exons
* Promoter contains run of TA repeats; most common allele has 6 repeats; unusual allele has 7

Problem: accumulation of SN-38

* Exposure dependent on metabolism of camptosar by UGT1A1
o Wide interpatient variability in UGT1A1 activity
o Patients with *28 variant (7 TA repeats) have reduced enzyme activity
o Homozygous deficient (7/7 genotype) patients have the greatest risk of neutropenia
o Neutropenia matters to patients
* Original label was silent on UGT information; approved dose not optimized

UGT1A1 TA repeat→irinotecan neutropenia

Camptosar Label Revised and FDA Approved UGT Test

“Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele (see DOSAGE AND ADMINISTRATION). Heterozygous patients (carriers of one variant allele and one wild-type allele which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical results have been variable and such patients have been shown to tolerate normal starting doses.”

EGFR as a therapeutic target

o Epidermal growth factor receptor (EGFR) gene (erbB1) first sequenced in a four-member family of structurally related type or subclass 1 receptors known as tyrosine kinases.
o Critical for mediating the proliferation and differentiation of normal cell growth
o Widely expressed in epithelial, mesenchymal, and neuronal tissues
o Aberrant activation of the kinase activity of these receptors appears to play a primary role in solid tumor development and/or progression
o Breast, brain, lung, cervical, bladder, gastrointestinal, renal, and head and neck squamous cell carcinomas, have demonstrated an over expression of EGFR relative to normal tissue, which is associated with a poor clinical prognosis

Erlotinib (Tarceva®)

* Potent EGFR tyrosine kinase inhibitor
o MW 428 Da
o IC50 20 nM
* Pre-clinical anti-tumor activity
o Inhibits tumor cell line growth
o Activity in mouse xenograft models
* Increased RR, PFS, and OS in Phase 3

Current pharmacogenomic examples

* bcr/abl or 9:22 translocation—imatinib mesylate (Gleevec)*
* HER2-neu—trastuzumab (Herceptin)**
* C-kit mutations—imatinib mesylate (Gleevec)**
* Thiopurine S-methyltransferase—mercaptopurine and azathioprine*
* UGT1A1-irinotecan (Camptosar)**
* Cytochrome P-450 (CYP) 2D6—5-HT3 receptor antagonists and codeine derivatives*
* *-FDA package insert information
* *-FDA-approved device

Scientific challenges

* Biomarker/transcript profile selection
* Definition of response predictors
* Assay development
o Platform and reagent standardization
o Defining sensitivity
o Minimizing variability
* Pharmacodynamic modeling
* Biomarker validation
* Biomarker ≠ surrogate

Regulatory challenges

* Ensuring assay reliability/validity
* Addressing drug/diagnostic co-development
* Understanding physiologic, toxicologic, and clinical significance of biomarkers
* Defining criteria for biomarker validation
* Extrapolation across populations
* Endpoint definitions
* Addressing exclusion of patients without target
* Defining standards for transmission, processing, and storage of pharmacogenomic data
* Communication with diverse stakeholders

Platform standardization
Summary

* Biomarkers hold enormous promise
o Conventional oncology development - small benefit in a large patient population
o Targeted drug development – may define large benefit in smaller population
* The devil will be in the details
* New development structures must be built
o Flexible regulatory mechanisms
o Need for drug-device co-development paradigm
o Need for new partnerships between industry, government, academics

FDA Pharmacogenomic Guidances

March 2004, CDER:
Pharmacogenomic Data Submissions
http://www.fda.gov/cber/gdlns/pharmdtasub.htm

April 2005, CDER/CDRH/CBER/OCP:
Drug-Diagnostic Co-development Concept Paper http://www.fda.gov/cder/genomics/pharmacoconceptfn.pdf

February 2006, CDRH:
Multiplex Tests for Heritable DNA Markers, Mutations and Expression Patterns: Draft Guidance for Industry and FDA Reviewers http://www.fda.gov/cdrh/oivd/guidance/1549.pdf

Oncology biomarkers for safety and efficacy

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Working with FDA: Biological Products and Clinical Development

Working with FDA: Biological Products and Clinical Development
by
Eda T. Bloom, Ph.D.

Chief, Gene Transfer and Immunogenicity Branch
Office of Cellular, Tissue, and Gene Therapies
Division of Cellular and Gene Therapies
Center for Biologics Evaluation and Research
FDA

Outline

* FDA organization
* Products regulated
* Critical path issues in the development of cell based products

OCTGT Regulated Products

* Products with Cancer indications
o Cellular therapies
o Tumor vaccines
o Gene therapies
o Tissue and tissue based products
o Combination products
o Anti-idiotype antibodies
* Products generally not used for cancer
o Xenotransplantation products
o Devices used for cells/tissues

Therapeutic Biological Products Regulated by CDER

* Monoclonal antibodies for in vivo use.
* Proteins intended for therapeutic use
o Includes cytokines (e.g. interferons), growth factors, enzymes (e.g. thrombolytics), and other novel proteins, except for those that are specifically assigned to CBER (e.g., vaccines and blood products).
o Includes therapeutic proteins derived from plants, animals, or microorganisms, and recombinant versions of these products.
* Immunomodulators (non-vaccine and non-allergenic products intended to treat disease by inhibiting or modifying a pre-existing immune response).

FDA Perspectives (CMC)

* Greater product knowledge (mechanism of action, characterization, etc) will aid in developing meaningful assays and/or novel approaches for product characterization and comparability
o Potency and identity testing should provide meaningful information about the product prior to its release
* Control of manufacturing process is key to producing consistent biological products
* A flexible approach and open communication is needed by both regulators and product developers

Potential CMC Issues for
Biological Products

* Some unique concerns for cell/gene therapy products
o Replication competent viruses
o Oncolytic viruses
o Cell/tissue source

* Some unique concerns for protein products
o Post-translational issues
+ Isoforms
+ Glycosylation
o Aggregates

* Examples of cross-cutting concerns
o Immunogenicity
o Animal components
o Formulation, delivery, stability
o Identity, purity, potency, comparability

Key Points to Consider for Pharmacology/Toxicology Testing

* Preclinical testing paradigm is influenced by:
o Data from previous preclinical studies on all components and combination
o Data from previous clinical studies (pre- and post-marketing) on all components and combination
o Regulatory status of each component
* Provide safety and activity data for individual components and combination in appropriate animal models by intended clinical route of administration

Potential PT Issues for Biological Products

* Some unique concerns for cell/gene therapy products
o Insertional mutagenesis
o Alteration of germline
o Long-term toxicity
o Migratory potential

* Some unique concerns for protein products
o Immune-mediated problems
+ Immune complexes
+ Obfuscation of toxicity
+ Allergy
o Species specificity

* Examples of cross-cutting concerns
o Picking the relevant animal model
o Dosing, safety
o Biodistribution
o Toxicity, tumorigenicity
o Immunogenicity (rejection/elimination)

Science in Research and Review:
Critical Path Initiative

* Bring scientific advances to medical product development process (simulation models, validated biomarkers, new clinical trial designs)
* Stimulate development of applicable research programs in critical path scientific areas, aim to develop techniques that address challenges encountered during product development
* Regulatory guidance/practice and standards to reflect best available science, integrate FDA involvement

OCTGT Research Program Areas

* Virology
o Retroviruses, adeno, herpes, PERV
* Immunology
o Host-vector interactions, transplant rejection
* Cell biology
o Control of differentiation in animal models, stem cell biology
* Cancer biology
o Molecular biomarkers, animal models
* Biotechnology
o Microarray, flow cytometry

Cell Therapy Product Characterization

* Morphologic evaluation
* Unique biochemical markers
* Gene and protein expression analysis
* Cellular impurities profile
* Biologic activity/Potency
* Identity: HLA, other unique marker

Developmental Stages
Characterization
Gene expression profile, Antibodies, Enzymes,
In vitro differentiation
Manufacturing Concerns
Exogenous Influences
Cell-cell interaction
Growth factors
Lot Release
Identity
Potency
Safety
Viability
Manufacturing
Cell Banks
Cell Characterization
Testing and Screening
Donors, Viruses, Genetic defects?
Tumorigenesis
mutation
Apoptosis
Self renewal
Commitment
Differentiation

are covered in this presentation.

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Two Models of Medical Error Reduction Programs in Radiation Oncology

Two Models of Medical Error Reduction Programs in Radiation Oncology
by
Ed Kline
RadPhysics Services LLC
Albuquerque, NM, © RPS


Introduction

* This presentation describes the design, implementation, and results of two QA/medical error reduction programs
* Both programs are designed for
o Reducing preventable systems-related medical errors (i.e., sentinel events, “near misses”)
o Preventing violations of regulatory requirements (i.e., State/NRC)
o Ensuring compliance with recommended standards (i.e., JCAHO, ACR, ACRO, etc.)

History

* Institute of Medicine (IOM) report5
o Focused a great deal of attention on the issue of medical errors and patient safety
o 44,000 to 98,000 deaths per year in U.S. hospitals each year as the result of medical errors
o 10,000 deaths per year in Canadian hospitals
o Exceeds annual death rates from road accidents, breast cancer, and AIDS combined in U.S.


To Err is Human: Building a Safer Health System.


* Key legislation
o Patient Safety Quality Improvement Act9
+ Certifies patient safety organizations in each State to collect data and report on medical errors
o State Patient Safety Centers
+ In past 5 years, 6 states have enacted legislation supporting creation of state patient safety centers
+ 5 of the 6 states now operate patient safety centers
+ Separate mandatory reporting systems for serious adverse events
+ Centers are housed within state regulatory agencies



Reducing Medical Errors, Issue Module, Kaiser EDU.org, Accessed through www.kaiseredu.org.

* Patient safety centers include10
o The Florida Patient Safety Corporation
o The Maryland Patient Safety Center
o The Betsy Lehman Center for Patient Safety and Medical Error Reduction (Massachusetts)
o The New York Center for Patient Safety
o The Oregon Patient Safety Commission
o The Pennsylvania Patient Safety Authority


State Patient Safety Centers: A New Approach to Promote Patient Safety, The Flood Tide Forum, National Academy for State Health Policy, 10/04, Accessed through www.nashp.org.


* State reporting: mandatory vs voluntary11
o Mandatory reporting: Colorado, Florida, Kansas, Nebraska, New York, Ohio, Pennsylvania, Rhode Island, South Carolina, South Dakota, Tennessee, Texas, Washington
o Voluntary reporting: District of Columbia, Georgia, New Mexico, North Carolina, Oregon, Wyoming
o Considering new legislation: Arizona, California, Maine
o Mandatory reporting but considering new legislation: Massachusetts, New Jersey


National Conference of State Legislatures, National Academy for State Health Policy, 12/03, Accessed through www.nashp.org.


* JCAHO revises standards
o Patient safety standards effective 7/1/01
o Requires all JCAHO hospitals (5,000) to implement ongoing medical error reduction programs
o Almost 50 percent of JCAHO standards are directly related to safety


Patient Safety - Essentials for Health Care, 2nd edition, Joint Commission on Accreditation of

Healthcare Organizations. Oakbrooke Terrace, IL: Department of Publications, 2004.

* JCAHO’s sentinel event policy13
o Implemented in 1996
o Identify sentinel events
o Take action to prevent their recurrence
o Complete a thorough and credible root cause analysis
o Implement improvements to reduce risk
o Monitor the effectiveness of those improvements
o Root cause analysis must focus on process and system factors
o Improvements must include documentation of a risk-reduction strategy and internal corrective action plan
o Action plan must include measurements of the effectiveness of process and system improvements to reduce risk


Sentinel Event Policies and Procedures - Revised: July 2002, Joint Commission on Accreditation of Healthcare Organizations, Accessed through www.jcaho.org/accredited+organizations/long+term+care/sentinel+events/index.htm.

* JCAHO’s Office of Quality Monitoring
o Receives, evaluates and tracks complaints and reports of concerns about health care organizations relating to quality of care issues
o Conducts unannounced on-site evaluations
* JCAHO and CMS agreement14
o Effective 9/16/04
o Working together to align Hospital Quality Measures (JC’s ORYX Core Measures and CMS’7th Scope of Work Quality of Core Measures)


Joint Commission, CMS to Make Common Performance Measures, Joint Commission on Accreditation of Healthcare Organizations, Accessed through www.jcaho.org/accredited+organizations/long+term+care/sentinel+events.

* CMS quality incentives15
o Quality Improvement Organizations (QIOs)
+ Contracted by CMS to operate in every State
+ 67% of QIOs perform independent quality audits
o Premier Hospital Quality Initiative
+ 3-year demonstration project recognizes and provides financial reward
+ CMS partnership with Premier Inc., nationwide purchasing alliance
+ Hospitals in top 20% of quality for specific diagnosis get financial reward
# Top decile gets 2% Diagnosis Related Group (DRG) bonus
# 2nd decile get 1% DRG bonus
+ Hospitals performing below 9th and 10th decile baseline levels, DRG payments reduced 1% and 2%, respectively


Medicare Looks for Ways to Boost Quality Care Comments Sought on New Plan for Quality Improvement Organizations, Centers for Medicare & Medicare Services (CMS), Accessed through www.cms.hhs.gov.

* CMS quality incentives
o CMS consumer website
+ Beginning in 4/05, hospital quality data available at www.HospitalCompare.hhs.gov or 1-800-MEDICARE
o Data indicators16
+ In 2006, hospitals reporting quality data to Medicare receive 3.7% increase in inpatient payments
+ Non-reporters receive 3.3% increase
+ Data covers 10 quality indicators for cardiology
+ Plans are to expand into other disciplines

and more in this presentation

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