Transcript Subgroups for regulatory vs HTA – methods and perspectives

Subgroups for Regulatory vs
HTA – Methods and Perspectives
Chrissie Fletcher Amgen Ltd
HTA 1-day scientific meeting
25th Sept 2014 Bayer, Berlin
Disclaimer (Chrissie Fletcher)
 The views expressed herein represent those of the
presenter and do not necessarily represent the views
or practices of Amgen or the views of the general
Pharmaceutical Industry.
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Outline
 Who is interested in subgroup analyses?
 Challenges with subgroup analyses
 Guidance on methods and perspectives from
regulators
 Guidance on methods and perspectives from HTA
agencies (effectiveness and cost-effectiveness)
 Trends in R&D and market access influencing use of
subgroup analyses
 Recommendations for optimising use of subgroups in
drug development
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Who is interested in subgroup analyses
 Pharmaceutical Industry
– Demonstrating the benefit-risk profile supports the
proposed population
 Regulatory agencies
– Is the evidence supporting benefit-risk acceptable to grant
approval for the proposed population
 Reimbursement agencies
– Is the incremental balance of benefit-risk better than
existing standard of care (e.g. IQWiG)
– Is the incremental balance of benefit-risk worth paying for
(e.g. NICE)
 Patient
– Will I benefit from the treatment and what potential side
effects may I experience?
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What questions can be addressed by
subgroup analyses?
 Does the drug work in a particular subset of patients?
 Is the drug effect consistent across different patient
subsets?
 Is the drug effect (or balance of benefit-risk) more
pronounced in a particular subset of patients?
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Subgroup analyses have numerous
challenges
 Subgroup analysis definition and pre-specification
 Consistency of effects and subgroup by treatment
interactions
 Multiplicity and replication
 Presenting and interpreting subgroup results
 Meeting needs for regulators and reimbursement
agencies
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Guidance on methods and perspectives
from regulators
 Subgroup analyses are covered in numerous
regulatory guidance documents
– ICH
– EMA draft ‘Guideline on the investigation of subgroups in
confirmatory clinical trials
– FDA
– + other countries (e.g. Switzerland, Australia, Canada)
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ICH relevant guidelines
 ICH E9 Statistical Principles for Clinical
Trials
 ICH E5 Ethnic Factors in the Acceptability of Foreign
Clinical Data
 ICH Gender Considerations in the conduct of clinical trials
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ICH E9 Statistical Principles for Clinical
Trials
 Subgroup effects should be pre-specified in the
protocol as part of the planned analyses
 In most cases, subgroup analyses are exploratory,
e.g. explore uniformity of treatment effects
 When exploratory, results should be interpreted
cautiously
 A conclusion of treatment efficacy/safety (or lack of)
based solely on exploratory subgroups unlikely to be
accepted
 Dangers of over-interpretation of unplanned subgroup
analyses are well known
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EMA draft guideline on subgroups in
confirmatory clinical trials
 Pre-agreement with regulatory authorities on important
subgroups prior to starting trials (key vs exploratory)
 Subgroup characteristics should be easy to measure and scale
is important
 Defining how to assess consistency of effect difficult
 Interaction tests are a possible way of approaching subgroup
analyses and should be presented with estimates of size of
effect in addition to p-values.
 Replication across >1 trial can help with interpretation
 Analyses depend on heterogeneity in target population
 Forest plots are useful for visual display
 Bayesian approaches may be potentially useful in some
situations
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EMA draft guideline on subgroups in
confirmatory clinical trials – Industry views
 EFSPI/PSI submitted comments (~ 18 pages), for
example further clarification regarding:
− Rare diseases
− Subgroups for reimbursement
− Dose adjustment for different subgroups… and the impact on
benefit/risk
− Use of subgroups in adaptive designs
− Role of Bayesian methods
− Confirmatory subgroups vs exploratory subgroups
 EFPIA submitted comments (~ 42 pages), for example
further clarification regarding:
−
−
−
−
Assessing safety in subgroups (+ benefit-risk)
Pre-specification and labelling
Multiplicity, credibility, replication….
Guideline for assessors and Industry or just assessors?
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FDA
 Guideline for the Format and Content of the Clinical and
Statistical Sections of New Drug Applications emphasized
the importance of conducting subset analyses on data
from clinical studies submitted in new drug applications
(NDAs) – focus on race and ethnicity
 Guideline for the Study and Evaluation of Gender
Differences in the Clinical Evaluation of Drugs. The
guidance specifically called for analyzing trials by gender
and for evaluating pharmacokinetics in women.
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FDA Guideline for the Format and Content of the
Clinical and Statistical Sections of New Drug
Applications
 Evidence to support labeling for specific subgroups (for
example, pediatrics, geriatrics, patients with renal failure)
 Subgroup hypotheses should be stated explicitly. It should be
noted whether the objectives were pre-planned or formulated
during or after completion of the study.
– Not pre-planned, usually not considered adequate for definite conclusions
 If the size of the study permits, relevant demographic or baseline
value-defined subgroups should be examined for unusually large
or small responses and the results presented, e.g., comparison
of effects by severity groups, by age, sex, or race, or by history
of prior treatment with a drug of the same class.
– not intended to “salvage” an otherwise non-supportive study
– may suggest hypotheses worth examining in other studies or
– refining labelling information, patient selection, dose selection, etc.
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Guidance on methods and perspectives
from HTA agencies
 Subgroup analyses are covered in numerous HTA
agency guidance documents
–
–
–
–
EUnetHTA (network of HTA agencies across Europe)
NICE (England/Wales)
IQWiG (Germany)
+ other countries (e.g. France, Australia, Canada)
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EUnetHTA Applicability of evidence in the context of a
relative effectiveness assessment of pharmaceuticals
 “Metaregression, subgroup analysis, and/or separate
applicability summary tables may help reviewers, and
those using the reports see how well the body of evidence
applies to the question at hand.”
 “In large clinical trials it is possible to have reliable
subgroup analyses which may help prescribers to relate
the trial’s findings more closely to patients for whom they
are trying to select appropriate therapies”
 “Moderators: Are there any analyses of moderator
effects—including different subgroups of participants and
types of intervention — to assess robustness versus
specificity of effects? ”
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NICE
 Require estimates of clinical and cost effectiveness
by subgroups
 Clearly defined subgroups ideally identified based on
expected differential clinical or cost effectiveness
because of known biological/other justified factors
– Biological plausibility for why subgroups may differ
 Ideally pre-defined (e.g. at scoping stage) with
rationale for expected subgroup effects,
– subgroups could be identified later (post-scoping)
– ‘relevant subgroups may be identified in terms of differences
in 1 or more contributors to absolute treatment effects’
– ‘post-hoc data dredging in search of subgroup effects should
be avoided and will be viewed sceptically’
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NICE
 Careful consideration for choice of scale
 Statistical precision of all subgroup effects reflected
in analysis of parameter uncertainty
 Differences in relative effects between subgroups due
to chance could be high when multiple subgroups
reported
 Credibility will be enhanced when expected subgroup
effect has pre-specified rationale and consistent
across studies)
– Quality of analysis, representativeness of evidence and
relevance to decision problem important
 Subgroups not considered based solely on differential
treatment costs
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IQWiG
 Pre-specification
– Subgroup analyses rarely planned a priori
– Post-hoc results cannot be regarded as confirmatory
 Multiplicity
– Caution with interpreting results from several subgroups
 Lack of power
– Subgroup sizes often too small to detect moderate differences
(unless included in sample size calculations)
 Testing for homogeneity
 Despite limitations, subgroups may represent best scientific
evidence
 Written into law “show a therapeutically relevant added benefit”
in patient subgroups
– Gender, age, disease severity and disease state required
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Comparing regulatory and HTA agency
method guidelines
Similarities
 Prospectively defined
and statistically
powered (ideal)
Differences
 Important subgroups
could be identified
post-design (HTA)
 Biologic rationale
 Advice on required
subgroups from
regulators and HTA
agencies available at
different stages
 Small number of
subgroups tested
 Assessment of
heterogeneity
 Robustness
(sensitivity) and levels
of uncertainty (HTA)
 Replication
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Trends in R&D and market access
influencing use of subgroup analyses
 Personalised/stratified medicine
– Biomarkers
 Adaptive licensing
– Accumulating evidence
 Increased data transparency
– Evaluating new subgroups
 Real world data
– Evaluating effectiveness
 Economic pressures in healthcare systems
– Rationalising treatment decisions
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Principles and best practices for
subgroup analyses (Paget et al)
 Subgroups
pre-specification & definition
 Subgroup by treatment interaction
 Multiplicity issues
 Sensitivity analyses
 Replication
 Source of evidence
 Presenting and reporting subgroup
results
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Relevance for cost-effectiveness
subgroup analyses (Fletcher et al)
Clinical effectiveness
Cost-effectiveness
 Sensitivity analyses
Extremely important
 Presenting and reporting
 Replication
Important
 Source of evidence
All data sources
 Subgroups prespecifications
Desirable
 Multiplicity issues
 Subgroup by trt interaction
trt: treatment
Transparency
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Less
important
Recommendations for optimal use of
subgroups in drug development
 Subgroup analyses remains a difficult area
 Plan for subgroups in design and analysis
− Individual RCTs
− Across product development program
− Benefit-risk assessments
 Present and interpret subgroup results appropriately
 Discuss subgroup analysis strategies with regulatory
agencies and reimbursement agencies
− Assess if different strategies are needed in different
regions/countries
− Understand how each stakeholder will view subgroup results
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Conclusions
 Subgroup analyses are important for regulatory and
HTA decision making
 Variety of guidance on methods for subgroup
analyses from regulatory and HTA agencies
 Whilst there is agreement on key principles, there are
differences in perspectives between these
stakeholders
 Discussing subgroup strategies with regulators and
HTA agencies should be a priority (via scientific
advice and early dialogue)
 Statisticians add strategic value in optimising the use
of subgroup analyses for regulatory and HTA decision
making
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References

ICH E9 Statistical principles for clinical trials
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9_Guid
eline.pdf

ICH E5 Ethnic Factors in the Acceptability of Foreign Clinical Data
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E5_R1/Step4/E5_R
1__Guideline.pdf

ICH E7 Studies in support of special populations: geriatrics
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E7/Step4/E7_Guid
eline.pdf

ICH E11 Clinical investigation of medicinal products in the pediatric population
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/Step4/E11_Gu
ideline.pdf

ICH Gender considerations in the conduct of clinical trials:
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC5000598
87.pdf

E17: General principle on planning/designing Multi-Regional Clinical Trials
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E17/E17_Final_Co
ncept_Paper_July_2014.pdf

EMA draft ‘Guideline on the investigation of subgroups in confirmatory clinical trials’
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/02/WC5001605
23.pdf).
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References

FDA Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug
Applications http://www.fda.gov/downloads/Drugs/Guidances/UCM071665.pdf

FDA Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of
Drugs. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126835.pdf

EUnetHTA (network of HTA agencies across Europe) Guidelines for Rapid Relative Effectiveness
Assessment of Pharmaceuticals: http://www.eunethta.eu/eunethta-guidelines

NICE (England/Wales) Methods guide to Health Technology Assessment:
http://www.nice.org.uk/article/pmg9/resources/non-guidance-guide-to-the-methods-of-technologyappraisal-2013-pdf

IQWiG (Germany) General Methods (Version 4.1)
https://www.iqwig.de/download/IQWiG_General_Methods_Version_%204-1.pdf

Questioning Patient Subgroups for Benefit Assessment: Challenging the German Gemeinsamer
Bundesausschuss Approach : http://www.ispor.org/VIH/commentary_benefit-assessment.PDF

Paget, Chuang-Stein, Fletcher, Reid. Subgroup analyses of clinical effectiveness to support health
technology assessments. Pharmaceut. Statist. 2011, 10 532–538

Fletcher C, Chuang-Stein C, Paget MA, Reid C, Hawkins N. Subgroup analyses in costeffectiveness analyses to support health technology assessments. Pharm.Stat. 2014 JulAug;13(4):265-74
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