Chrissie Fletcher Amgen Ltd

HTA 1-day scientific meeting

25th Sept 2014 Bayer, Berlin

Subgroups for Regulatory vs HTA – Methods and Perspectives

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

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?

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 ClinicalTrials

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 ClinicalTrials

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)

Biologic rationale

Small number of subgroups tested

Assessment of heterogeneity

Replication

Differences Important subgroups

could be identified post-design (HTA)

Advice on required subgroups from regulators and HTA agencies available at different stages

Robustness (sensitivity) and levels of uncertainty (HTA)

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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

Relevance for cost-effectiveness subgroup analyses (Fletcher et al)

Clinical effectiveness

Sensitivity analyses

Presenting and reporting

Replication

Source of evidence

Subgroups pre-specifications

Multiplicity issues

Subgroup by trt interaction

Cost-effectiveness

Desirable

Less important

Extremely important

Important

All data sources

Transparency

trt: treatment 22

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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_Guideline.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_R1__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_Guideline.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_Guideline.pdf

ICH Gender considerations in the conduct of clinical trials: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500059887.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_Concept_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/WC500160523.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-technology-appraisal-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 cost-effectiveness analyses to support health technology assessments. Pharm.Stat. 2014 Jul-Aug;13(4):265-74