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Current Challenges in Oncology:
The New EMA Guideline on
Evaluation of Anticancer
Medicinal Products in Man
Wednesday, 29 May 2013
About ICON
• ICON plc is a global provider of outsourced development
services to the pharmaceutical, biotechnology and medical
device industries.
• The company specializes in the strategic development,
management and analysis of programs that support clinical
development - from compound selection to Phase I-IV
clinical studies.
• ICON currently operates from 79 locations in 37 countries
and has approximately 10,045 employees.
• Further information is available at www.iconplc.com
ICON Signature Series
• ICON Signature Series is our thought leadership
program that offers expert insights into value-driven
strategies for clinical development.
• The program features ICON and external experts in all
aspects of clinical development and post-approval
product value strategies.
• For a list of featured topics and upcoming events go
to: http://www.iconplc.com/icon-views/
• ICON Signature Series is our thought leadership
program that offers expert insights into value-driven
strategies for clinical development.
• The program features ICON and external experts in all
aspects of clinical development and post-approval
product value strategies.
• For a list of featured topics and upcoming events go
to: http://www.iconplc.com/icon-views/
Upcoming Webinars
• Cardiovascular Outcomes Trials - State of the Art
4th June, 2013, 11:00 a.m. – 12:00 p.m. EST
• Biosimilar Availability and Price & Access Implications
12th June 2013, 11:00 a.m. – 12:00 p.m. EST
• Circulating Tumor Cell Testing
13th June, 2013, 11:00 a.m. - 12:00 p.m. EST
• To register visit: http://www.iconplc.com/news-events/events/webinars/
Introductions
Tim Clark
Vice President Scientific Affairs
ICON Clinical Research
Andreas Dreps, PhD
Senior VP, Drug Development Services, ICON
20 years of industry experience
• BMS - 4 years as Medical Scientist, 1992-1995
• Clinical development of Taxol®
• Aventis Medical – Director, 1995-2000
• Clinical development of Taxotere®, Campto® and Gliadel®
• Merck/Serono, BU Oncology Director, 2000-2004
• Clinical development of different target therapies including 2 EGF-R
antibodies (Erbitux® and EMD 72.000), angiogenesis inhibitors (Cilengitide)
and vaccines
Development experience includes:
• Chemotherapy agents
• Monoclonal antibodies
• Tumor Vaccines
• Angiogenesis inhibitors
• Tyrosine Kinase Inhibitors
Introductions
Tim Clark
Vice President Scientific Affairs
ICON Clinical Research
James Wachholz, BS, MBA
Vice President, Scientific Affairs, Regulatory, ICON Clinical Research
Industry Experience
• Over 30 years experience in pharmaceutical new product
development including oncology, CNS, cardiovascular imaging and
therapy, antivirals and oncologic vaccines.
• Senior Manager with Baxter International, Searle Pharmaceuticals,
Sunovion, Molecular Insight in areas ranging from Regulatory
Affairs, Regulatory Compliance to Quality Assurance and
Technical Operations.
Indication Experience
• Negotiated all phases of clinical development of new oncology
therapies with FDA/DOP I and II and with EU CAs/ EMA
Areas of Expertise
• Regulatory strategic planning and development
Agenda
• Introduction
• Pharmacokinetics
• Biomarkers
• Early Clinical Development (Phase I & II)
– Cytotoxic and Non cytotoxic compounds
• Phase III confirmatory trials
- Randomization and blinding
- Endpoints
- Methodology (adaptive designs, interim analyses, non- inferiority)
• Special Populations
Introduction
• Guidelines for the clinical development of anticancer agents are
changing rapidly
• Development of new Oncology Products are the subject of the
highest number of Scientific Advice Requests received by EMA
Agenda
• Introduction
• Pharmacokinetics
• Biomarkers
• Early Clinical Development (Phase I & II)
– Cytotoxic and Non cytotoxic compounds
• Phase III confirmatory trials
- Randomization and blinding
- Endpoints
- Methodology (adaptive designs, interim analyses, non- inferiority)
• Special Populations
Pharmacokinetics
• Same recommendations are valid for anticancer products as for other medicinal products
• Human mass-balance studies are strongly recommended (in vivo studies investigating the fate of a radio labeled dose in plasma and excreta)
• Food interaction studies should be performed prior to phase III
• Assessment potential for drug-drug interactions (in vivo if possible)
• PK population analysis to valuate the influence of intrinsic factors. Both sparse (few samples per patient) and rich data (full plasma concentration-time profiles) can be used.
• Exposure-efficacy and exposure-safety analysis/modeling is encouraged in the Phase II randomized trials to provide PK/PD information and to support Phase III dose selection.
Biomarker Utility
• Use of biomarkers in all phases of clinical drug development may accomplish identification of target population
• Essential to identify the proper target population for therapy to optimize benefit/ risk
• Uses in oncology development:
– Prospective stratification of clinical subjects by biomarker status
– Determination of the biologically effective dose
– Early proof of mechanism or concept
– Assessment of toxicity Mapping of the course of disease
Biomarker Validation
• Biomarker development should be planned early in development
– Allows maximization of clinical data employing the technology
• Careful and rigorous validation are essential, following systematic
evaluation in clinical trials – (reference “reflection paper on methodological issues associated with
pharmacogenomic biomarkers…clinical development and patient
selection”- EMA/CHMP/446337/2011)
• This EMA guideline introduces the possibility of retrospective
validation through replication of findings
• At time of licensure, a diagnostic assay in compliance with IVD
Directive 98/79/EC (the “IVD Directive”) should be available
Agenda
• Introduction
• Pharmacokinetics
• Biomarkers
• Early Clinical Development (Phase I & II)
– Cytotoxic and Non cytotoxic compounds
• Phase III confirmatory trials
- Randomization and blinding
- Endpoints
- Methodology (adaptive designs, interim analyses, non- inferiority)
• Special Populations
Phase I – Cytotoxic Compounds (1)
• Applies to compounds that induce irreversible lethal cell damage or to
targeted cytotoxics, eg., monoclonal antibody coupled toxins
– Tumor antigen expression and pro-drug activating pathways also need to be considered for such compounds
• Toxicity is an accepted endpoint for initial dose-finding and dose
selection decision
• Maximal tolerated dose (MTD) and dose limiting toxicity should be
defined
• Relationship between main side effects/ target organs and dose and
schedule should be defined
• Recommended dose for phase II is usually one dose level below the MTD
Phase I – Noncytotoxic Compounds (1)
• “Noncytotoxic” compounds; do not induce direct damage to DNA or inhibit essential pathways needed for DNA replication, transcription or repair as their main mechanism of action (CHMP)
– Vaccines, angiogenesis inhibitors, growth signal blockers etc
• Toxicity may not be an appropriate endpoint to select dose for further testing. PD readouts
– Receptor saturation, target inhibition may be more informative endpoints
• If justifiable based on preclinical toxicology data, healthy volunteer trials are acceptable in the early development phase of these agents.
• Even if sufficient PD activity ( e.g complete target inhibition ) is reached at certain doses, investigation of higher dose levels ( if permitted by side effects) is recommended
– Evaluate safety margins and non-linear pharmacokinetics. Not necessary to reach MTD.
Phase I – Cytotoxic Compounds (2)
• Eligible subjects-cancer patients with no treatment alternatives
(“Window of opportunity” mainly reserved for phase II)
• Healthy volunteer studies are in general not acceptable for cytotoxic
compounds
• BSA may be initially used to calculate dose.
– Appropriate modelling to justify BSA or weight to determine dose provided, as soon as meaningful PK data is available
• Repeated exposure ( at least 2 cycles) should be attempted for patients
treated at the dose level recommended for further testing
Cytotoxic Compounds-Evaluation of Activity
• Objective Response Rate (ORR) should be documented
• Assessment by International Standards (RECIST, Volumetric RECIST
or WHO criteria) unless modification is justified
• External independent review of tumor response is recommended,
depending on the trial’s objective
• Additional parameters to collect and report: – Duration of response
– TTP/PFS, confirmed ORR and available data on OS
• Adhere to Intent To Treat (ITT) principle – In single arm trials ORR in per protocol set may be reported as a primary
outcome measure
Cytotoxic Compounds-Evaluation of Toxicity
• Preclinical observations are used to guide the choice of assessments:
Minimum requirements- – Assessment of symptoms
– Physical exam/ECG/blood and urine analyses
– Radiologic assessment
• Assessment of potential for QTc prolongation from the preclinical studies
determines whether a thorough QT study is indicated
• Even when no preclinical signal is present, routine ECGs are recommended
• Record local toxicity at site of administration by generally recognized system
(eg., CTCAE)
• Explore related toxicity factors such as organ dysfunction and effects of
concomitant therapy to form basis of further study in Phase II/III
Phase II – Cytotoxic Compounds
• Primary objective: Assess, whether drug shows promising activity in a defined patient population, alone or in combination
• Secondary objectives: Detection of less common side effects and signs of cumulative toxicity. PK profiles should be further characterized and exposure / side effect relations explored
• Objective tumour responses: Acceptable endpoint for single agent studies. When referenced to historical data, differences in the response-definitions ( WHO vs. RECIST ) need to be recognized
• ITT population: Most appropriate target population. If others ( e.g. per protocol ) are used to assess response rates, justification needed.
• Single arm studies: Appropriate to detect signs of activity. But level of activity relative to standard treatments may be difficult to assess in a non-controlled trial
Phase I-Noncytotoxic Compounds (2)
• Inclusion criteria usually established to require patients who are refractory to
available therapy
• Window of Opportunity studies may be considered based on risk/ benefit
• Whenever appropriate, measure the expression of the drug’s target activity
• Population PK/PD studies are encouraged
• If compound is poly-targeting, rather than single main target, pharmacologic
rationale is to be investigated in exploratory development (e.g., biomarkers
selected to identify the proper target population for treatment)
Phase II – Noncytotoxic Compounds (1)
• Phase 2 initiates when association between dose/exposure range and activity has been defined (with or without DLT)
• Vast majority of these compounds do not produce early tumour shrinkage. Objective tumour response rate may not be an appropriate endpoint
• Time to tumour progression (TTP): Believed to be most informative endpoint for early evaluation of noncytotoxic compounds
• TTP used as the primary measure for activity, several points to consider:
– Documentation of tumour progression prior to inclusion into the trials should be required
– TTP/PFA are a function of underlying tumour growth rate. As growth rates are variable, TTP/PFS data can only be interpreted in the context of a randomized controlled trial.
– Single arm studies with TTP as primary endpoint and historical controls as reference have
been consistently misleading !
Phase II – Noncytotoxic Compounds (2)
• Randomized phase II studies with TTP as primary endpoint most appropriate design for early evaluation of activity of noncytotoxic compounds.
• Possible phase II designs are:
– Comparison against best available treatment
• Late stage/refractory disease BSC or investigator`s choice acceptable comparators
• Caveat: TTP may favour purely growth inhibitory treatments over treatment which induces significant tumour shrinkage, since smallest tumour volume is used as reference to define progression
– Within Patient Comparison
• Compare TTP on last prior therapy to investigational drug
• Caveat: Tumor growth rate over time may not be constant. Recruit patients with secondary as well as primary resistance.
PHASE II Noncytotoxic (3): Accepted Study Designs
• Randomized discontinuation trials
– Design acceptable from regulatory view; however, often difficult to accept for patients and ECs
– Caveat: Carry over effects -inherent risk which give false negative outcome
• Randomized dose comparative trials
– Well designed, trials give relative signs of activity (not in absolute terms)
– Caveat: may produce false negative results for compounds with no/weak dose-effect relation
• TTP/PFS and CBR
– Can be performed without internal reference
– Caveat: accepted when “more refined techniques are not applicable”
Agenda
• Introduction
• Pharmacokinetics
• Biomarkers
• Early Clinical Development (Phase I & II)
– Cytotoxic and Non cytotoxic compounds
• Phase III confirmatory trials
- Randomization and blinding
- Endpoints
- Methodology (adaptive designs, interim analyses, non- inferiority)
• Special Populations
Phase III – Confirmatory Trials
• Granting of a marketing authorization is based on demonstration of direct patient benefit
• In clinical oncology practice well established alternative regimens, showing major differences in anti-tumor activity and side effect profile are available
• Expected tolerability/toxicity profile of the experimental regimen will drive selection of reference regimen if several alternative established regimens are available.
• EMA guidance provides three categories
– Reduced or similar toxicity
– increased toxicity
– major increase in toxicity
• Categorization provides advice on regulatory expectations with respect to
study outcome measures in order to enable a proper benefit – risk
assessment.
Phase III – Confirmatory Trials
• Use of biomarkers provide guidance to selection of “right“ patient population in order to optimize benefit – risk perspective
• Local / regional biomarker assessments should be complemented with a central assessment of the biomarker
• For target indications with very small groups of patients, “exceptional circumstances” might apply
– Unless the target for activity is expressed only in these rare conditions, Sponsors are in general advised to undertake studies in these small patient groups in parallel to or when benefit – risk is established in indications allowing a more comprehensive evaluation, especially with respect to safety
Phase III – Selection of Reference Therapy
• Select best available, evidence-based therapeutic options
– “best available, evidence-based” is a widely used, but not necessarily licensed regimens, as long as randomized trials documented a favorable benefit-risk
• Regionally preferred standards can be considered when reference is evidence based
• Select regimens with similar cycle lengths recommended
• Without a well documented reference regimen, BSC is acceptable, however an active comparator is preferable
– investigator’s best choice is an option. In these cases reference regimens with low toxicity are favored and superiority in terms of patient relevant endpoints should be demonstrated.
Agenda
• Introduction
• Pharmacokinetics
• Biomarkers
• Early Clinical Development (Phase I & II)
– Cytotoxic and Non cytotoxic compounds
• Phase III confirmatory trials
- Randomization and blinding
- Endpoints
- Methodology (adaptive designs, interim analyses, non-inferiority)
• Special Populations
Endpoints
• Endpoints accepted as indicators for patient benefit: – Cure Rate
– Increased overall survival*
– Increased progression free / disease free survival*
– Increased rate of complete responses (mainly for leukaemia's)
– Relief of tumour related symptoms
– Substantial reduction in side effects while maintaining clinical efficacy
* If PFS/DFS is the selected primary endpoint, OS should be reported as a secondary and vice versa
Regular approval - Endpoints
• Increasing overall survival - strongest endpoint for a marketing authorisation of a cancer drug.
• Demonstrating differences in overall survival may be difficult/ impossible in certain situations:
– Long time interval between progression of disease and death
– Availability of established subsequent treatments with documented effects on survival
– Proven efficacy of the investigational drug in later stages of disease, making cross over necessary from an ethical point of view
Regular approval – Endpoints PFS/TTP (I)
• Prolongation of progression free survival (PFS) or time to progression (TTP) accepted as basis for marketing authorisation by FDA and EMA
• To produce convincing data, specific requirements for trial design and data collection are necessary:
– PFS and TTP extremely sensitive to evaluation intervals. Comparability in terms of evaluation visits and times of evaluation between arms an absolute must.
– PFS/TTP data must be confirmed by independent review. IRC charter should be prospectively designed and images must be collected
Outcomes
• Preferred: Convincingly demonstrated favorable effects on overall
survival (OS) are from both a clinical and methodological perspective
the most persuasive outcome of a clinical trial
• Accepted: Prolonged progression-free or disease-free survival
(PFS/DFS), are in most cases considered relevant measures of
patients benefit
• The magnitude of the treatment effect should be sufficiently large to
outbalance toxicity and tolerability problems.
• In order to capture possible negative effects on the activity of next-line
therapies and also treatment related fatalities, informative data on
overall survival compatible with a trend towards favorable outcome
are normally expected at time of submission.”
Special Populations
Elderly and frail:
• If the drug is expected to be used in the elderly, the development program
should strive to enroll adequate numbers to allow a risk-benefit analysis in the
elderly subset population
• Product labeling may reflect the lack of data for the analysis, and Post-approval
studies may be required if the study population does not provide adequate
numbers for a definitive conclusion regarding safety and efficacy
Gender
• The proportion of males and females in the clinical database should reflect the
prevalence of the disease
– Exploratory subgroup analyses by gender should be provided
• If there is a likely treatment by gender interaction the study design should
reflect the imbalance
Special Populations-Safety
• Data should be collected to allow reporting and analysis of:
– Effects of preventive measures such as anti-emetics or use of growth factors
– Acute, subacute, chronic and late toxicities
– Safety by treatment cycle
– Timing, duration and grade of common events such as diarrhoea, mucositis or cytopenias
– For immunosuppressive therapies-probable or proven infections, frequency or type (viral, bacterial, fungal)
• Monitoring for 1 year post-therapy should be considered
Special Populations-Safety (2)
• For curative therapies-Long term monitoring for late toxicities in
survivor population
• Patients regarding radiation therapy should normally be withdrawn, if
not:
• Collect safety data regarding concomitant or sequential use of
radiotherapy throughout the clinical program
– Include data on radiation recall
• If the clinical objective is to demonstrate comparative improved safety,
it is not acceptable to focus on one side effect only
– Outcome measurements should provide unbiased information on overall tolerability
– Review study design with regulatory agencies
References
Nonclinical evaluation for anticancer pharmaceuticals EMEA/CHMP/ICH/646107/2008 (ICH
S9)
Clinical Investigation of the Pharmacokinetics of Therapeutic Proteins
CHMP/EWP/89249/2004
Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Hepatic
Function - CPMP/EWP/2339/02
Guideline on the investigation of drug interactions, CPMP/EWP/560/95/Rev. 1
Points to Consider on Adjustment for Baseline Covariates - CPMP/EWP/2863/99
Points to Consider on Multiplicity Issues in Clinical Trials - CPMP/EWP/908/99
Guideline on the choice of non-inferiority margin - CPMP/EWP/2158/99
Reflection paper on methodological issues associated with pharmacogenomic biomarkers in
relation to clinical development and patient selection EMA/CHMP446337/2011
References (2)
Qualification of novel methodologies for drug development: guidance to applicants
EMA/CHMP/SAWP/72894/2008 Rev.1
Reflection paper on methodological issues associated with pharmacogenomic biomarkers in
relation to clinical development and patient selection EMA/CHMP446337/2011
Reflection paper on pharmacogenomics in oncology EMEA/CHMP/PGxWP/128435/2006.
Guideline on clinical trials in small populations-CPMP/EWP/83561/2005
Choice of Control Group in Clinical Trials CHMP/ICH/364/96 (ICH E10)
Guideline on clinical evaluation of diagnostic agents - CPMP/EWP/1119/98
Note for guidance on clinical safety data management: data elements for transmission of
individual case safety reports - CPMP/ICH/287/95 (ICH E2B)
Points to consider on application with 1. Meta-analyses 2. One pivotal study -
CPMP/EWP/2330/99
Reflection paper on methodological issues in confirmatory trials planned with an adaptive
design – CHMP/EWP/2459/02
