Health Technology Assessments and Systematic Reviews Marcia Reinhart, DPhil CMPP Principal, Tantalus Medical Communications

Health Technology Assessments Many definitions “Technology assessment in health care is a multidisciplinary field of policy analysis. It studies the medical, social, ethical, and economic implications of development, diffusion, and use of health technology.” – International Association of HTA (INAHTA) “A form of policy research that examines short- and long-term consequences of technology. . . safety, efficacy, patient-reported outcomes, real-world effectiveness, cost, and cost-effectiveness as well as social, legal, the application of a health-care ethical, and political impacts.” – International Society for Pharmacoeconomics and Outcomes Research (ISPOR)

Regardless of the technology assessed, HTAs include similar elements Clinical efficacy Safety Cost-effectiveness

HTAs are used to support many health care decisions Clinicians and patients Prescribing decisions Practice guidelines Public and private payers Drug plan formularies Level of coverage Hospitals Technology acquisition Hospital formularies

What is 'Market Access'? Governments/private insurers determine the price and availability of drugs via formulary designation Figure: Eichler GH et al. Nat Rev Drug Discov 2010;9:277-91.

Market Access around the world Just as health care systems vary worldwide, the payer assessment process differs from country to country

Who conducts and uses HTAs? National/regional government-based agencies Independent academic or consulting groups

How do HTAs fit into the decision-making process? HTAs as part of the market access continuum Manufacturer Conducts literature review, economic analysis, etc. Submits HTA-like document based on agency template submission HTA agency Assesses manufacturer submission May conduct independent review or rely on HTAs from 3rd parties Submits recommendation to payer report Payer Makes final decision on reimbursement and availability of drug or device    Payer often agrees with HTA agency, although may be influenced by additional factors     

Systematic review – an essential step of the HTA process Cochrane Collaboration definition: “… attempts to identify, appraise and synthesize all the empirical evidence that meets pre- specified eligibility criteria to answer a given research question. Researchers conducting systematic reviews use explicit methods aimed at minimizing bias, in order to produce more reliable findings that can be used to inform decision making.”

Systematic review: process Define research question Develop study inclusion/exclusion criteria Patients Intervention(s) Comparator(s) Outcomes Study type Develop literature search strategy Typically conducted across multiple databases Search strategies should be broad enough to capture all relevant publications, but narrow enough to avoid excessive irrelevant information Screen studies for inclusion and collect relevant data PICOS

Example – acupuncture for the treatment of fibromyalgia Define research question

Example – acupuncture for the treatment of fibromyalgia Define research question Develop study inclusion/exclusion criteria Patients Diagnostic criteria? Age? Disease severity? Comorbidities? Ethnicity?

Example – acupuncture for the treatment of fibromyalgia Define research question Develop study inclusion/exclusion criteria Patients Intervention(s) Frequency? Definition of acupuncture? Adjunct therapies?

Example – acupuncture for the treatment of fibromyalgia Define research question Develop study inclusion/exclusion criteria Patients Intervention Comparator(s) Placebo? No treatment? Drugs? Other TCM techniques? Physical therapy?

Example – acupuncture for the treatment of fibromyalgia Define research question Develop study inclusion/exclusion criteria Patients Intervention(s) Comparator(s) Outcomes Pain reduction? Physical function? Quality of life? Days off work? Adverse events? Fatigue?

Example – acupuncture for the treatment of fibromyalgia Define research question Develop study inclusion/exclusion criteria Patients Intervention(s) Comparator(s) Outcomes Study type RCTs? Real-world evidence? Non-RCTs? Economic evaluations? Quasi-randomized?

Small group exercise – develop PICOS criteria

Example – acupuncture for the treatment of fibromyalgia Develop literature search strategy Use both indexing terms (e.g. MeSH) and plain text terms Draft searches to identify studies in categories (e.g. disease terms, intervention terms), combined at end Disease terms

Example – acupuncture for the treatment of fibromyalgia Develop literature search strategy Combined Therapy terms

Example – acupuncture for the treatment of fibromyalgia Develop literature search strategy Medline Embase Cochrane congress abstracts ALL COMBINED (duplicates removed) Other sources?

Example – acupuncture for the treatment of fibromyalgia Screen studies for inclusion

Data extraction and synthesis: The meta-analysis Multiple studies are combined statistically to reveal the overall effect of an intervention A summary (pooled) effect estimate is calculated as a weighted average of the effects estimated in the individual studies Individual studies Box represents estimated effect Lines represent 95% CI Size of box represents weighting Summary intervention effect

Example – acupuncture for the treatment of fibromyalgia Meta-analysis for mean difference in pain

Risk of bias A bias is a systematic error, or deviation from the truth, in results or inferences Selection, performance, detection, attrition, reporting Several tools have been developed to assess bias

Role of medical writers in HTAs NICE single technology appraisal (STA) Section A – Decision problem Description of technology under assessment Context Equality Innovation Statement of decision problem May include >1 research question

Role of medical writers in HTAs Systematic review Meta-analysis Non-RCT evidence Safety data NICE single technology appraisal (STA) Section B – Clinical and cost effectiveness Clinical evidence Cost effectiveness Section C – Implementation Assessment of factors relevant to NHS/other parties References Appendices Related procedures for evidence submission Systematic review for published analyses Report and interpret results of own economic model(s)

Example – new class of drug to treat rheumatoid arthritis Section B – Clinical and cost effectiveness Clinical evidence

Example – new class of drug to treat rheumatoid arthritis Section B – Clinical and cost effectiveness Clinical evidence Results from the systematic review: Phase III clinical trial of new drug (B) vs placebo (A) Phase II clinical trial of new drug (B) vs placebo (A) 3 RCTs of competitor (C) vs placebo (A) 2 RCTs of competitor (C) vs other competitor (D) 3 single-arm non-RCTs How do we use this information to compare the new drug (B) to competitors C and D??

Network meta-analyses/indirect treatment comparison Network meta-analysis can be used to infer the comparative effectiveness of treatments of interest that have not been directly compared in trials

Example – new class of drug to treat rheumatoid arthritis Section B – Clinical and cost effectiveness Clinical evidence Safety data AEs from RCTs and non-RCTs Post-marketing surveillance data (if available) Other sources of real-world evidence

Example – new class of drug to treat rheumatoid arthritis Section B – Clinical and cost effectiveness Clinical evidence Cost effectiveness

The cost-effectiveness plane A new treatment can be compared with an existing therapy based on its effect on cost and effect differences Cost difference (+) Cost difference (−) Effect difference (+) Effect difference (−) Dominated Dominant Trade-off SC SC = standard care

Key concept: QALYs In cost-utility analyses, effectiveness is measured in quality-adjusted life years (QALYs) QALYs incorporate both quality and quantity of life gained from an intervention Improvement of quality of life with new treatment Estimated using utility values Improvement of quantity of life with new treatment QALYs without new treatment (standard care) Time QoL Figure: adapted from McCabe C. Hayward Group Ltd. 2009

Key concept: ICER = ICER Incremental cost-effectiveness ratio “costs per outcome” (cost-effectiveness analysis) or “costs per QALY” (cost-utility analysis) CostsTreatment – CostsStandard care QALYsTreatment – QALYsStandard care = ICER

Life-years gained (LYG) cost, Treatment vs Std. Care Key concept: ICER CostsTreatment – CostsStandard care QALYsTreatment – QALYsStandard care = ICER Total costs Life-years gained (LYG) Utility for LYG QALYs Treatment $20,000 7 0.5 3.5 Standard Care $10,000 5 0.6 3.0 Incremental cost, Treatment vs Std. Care life-years cost/LYG QALYs ICER cost/QALY $10,000 2 $5000/year 0.5 $20,000/ QALY

Optional group exercise – calculate the ICER of our new arthritis drug

Economic analysis: “willingness to pay” threshold Some countries/health care systems use an official or unofficial threshold of acceptable ICERs for new technology assessments Cost difference (+) Cost difference (−) Effect difference (+) Effect difference (−) Reject Accept WTP threshold SC

Example – new class of drug to treat rheumatoid arthritis An economic model determines that the ICER for the new drug is $40,000/QALY If the WTP was $50,000/QALY, this drug would fall into the range of acceptable cost/QALY Cost difference (+) Cost difference (−) Effect difference (+) Effect difference (−) Reject Accept WTP threshold SC X

Cost-utility: sensitivity analysis Calculating costs per QALY requires estimation of several parameters utility values cost of treatment duration of treatment/patient lifespan (“time horizon”) Base case = best estimate of all parameters Sensitivity analyses test alternative parameter estimates to assess the range of possible results

One-way sensitivity analysis Each parameter varied one-at-a-time over plausible range base case Tornado diagram ICER ($thousand/QALY) Figure: Reynolds MR et al. Circ-Arrhythmia Elec 2009;2:362–69.

Example – new class of drug to treat rheumatoid arthritis Sensitivity analysis shows that the new drug may rise above the WTP threshold in certain circumstances Cost difference (+) Cost difference (−) Effect difference (+) Effect difference (−) Reject Accept WTP threshold SC X X X X X X X

Other sensitivity analyses used in HTA Scenario analysis Similar to a one-way sensitivity analysis, however, assessments are made by varying multiple parameters at the same time Example = best-case and worst-case analyses Probabilistic sensitivity analysis “Drug X has a 86% probability of falling within the WTP threshold of $50,000/QALY” More statistically complex; assesses distributions of data for multiple inputs over the course of multiple simulations

Cost-utility is not the only economic analysis used in HTAs Cost-consequences analysis Estimates cost and value of interventions, but leaves it to the reader to draw conclusions Cost-minimization analysis Compares input costs, but assumes outcomes are equivalent (e.g., bioequivalent drug comparisons) Cost-effectiveness analysis Measures costs in dollars and reports outcomes in natural health units (e.g., mmHg reduction) or ratios (differences in cost/difference in outcomes) Cost-utility analysis Measures outcomes based on years of life and quality of life obtained with treatment Cost-benefit analysis Enumerates and compares costs and benefits achieved in monetary terms Budget impact analysis Estimates effect of intervention on overall cost to organization or health plan

Desirable qualities in HTA medical writers Well-versed in literature searching Experience with multiple databases and multiple interfaces (e.g. PubMed vs Ovid) Attention to detail – screening and data extraction Understanding of evidence grading systems Knowledge of statistical methods (e.g. meta- analysis, NMA, sensitivity analyses) Understanding of health economic models Excellent writing skills

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