Table 2.
Evidence and evaluation criteria considered in HTAs
| France (HAS/CEESP) |
Germany (IQWiG) |
Sweden (TLV) |
England (NICE) |
Italy (AIFA) |
Netherlands (ZIN) |
Poland (AOTMiT) |
Spain (RedETS/ISCIII or ICP) |
|
|---|---|---|---|---|---|---|---|---|
| Burden of disease | ||||||||
| Severity | Yes, as part of SMR | Yes, as part of added benefit assessment | Yes (impact on WTP threshold)a | Yes (mainly as part of EoL treatments) | Yes (implicitly) | Yesb | Yesc | Yes |
| Availability of treatments (i.e. unmet need) | Yes (binary: Yes/No) | True for other technologies rather than pharmaceuticalsd | Yes, indirectly (captured by severity) | Yes (clinical need as a formal criterion) | Yese | Yesf | Yesg | Yes |
| Prevalence (e.g. rarity) | Yes, informally | As part of G-BA’s decision-making processh | Yes | Yes | YesI | Yes | Yesj | Yes |
| Therapeutic and safety impact | ||||||||
| Efficacy | Yes (4 classifications via SMR, 5 via ASMR)k | Yes (6 classifications)l | Yes | Yes | Yes | Yes | Yesm | Yes |
| Clinically meaningful outcomes | Yes (preferred) | Yes (preferred) | Yes | Yes (preferred) | Yes | Yes | Yesn | Yes |
| Surrogate/intermediate outcomes | Considered | Considered | Considered | Considered | Considered | Considered | Consideredo | Considered |
| HRQoL outcomes | Generic; disease-specific | Generic; disease-specificp | Generic (preferred); disease-specific | Generic; disease-specific | Generic; disease-specific | Yes | Yesq | Yes (including patient well-being) |
| Safety | Yes | Yesr | Yes | Yes | Yes | Yes | Yess | Yes |
| Dealing with uncertainty | Implicitly (preference for RCTs), explicitly (robustness of evidence) | Explicitly (classification of empirical studies and complete evidence) | Implicitly (through preference for RCTs) | Explicitly (quality of evidence), implicitly (preference for RCTs), indirectly (rejection if not scientifically robust) | Yes, registries and MEAs are used to address uncertainty | Implicitly (if included in the assessment studies) | Not | Can be considered as part of economic evaluation |
| Innovation level | ||||||||
| Clinical novelty | Yes (as part of ASMR) if efficacy/safety ratio is positive | Implicitly as part of added therapeutic benefit considerationu | Yes, but only if it can be captured in the CE analysis | Yes | Yes | Yes | Yesv | Yesw |
| Ease of use and comfort | Not explicitly, in some casesx | Only if relevant for morbidity/side effects, not explicitly considered for benefit assessmenty | Yes (to some extent) | Not explicitly | No | Not standard, case-by-case basis | Noz | Not explicitly, indirectlyaa |
| Nature of treatment/technology | Yes (3 classifications)ab | Not explicitly considered for benefit assessment | Not explicitly | Yes (when above £20,000) | No | Implicitly | Yesac | Yes (through the degree of innovation criterion) |
| Socio-economic impact | ||||||||
| Public health benefit/value | Yes, rarely via “intérêt de Santé Publique”ad | Noae | Yes, indirectlyaf | As indicated in guidance to NICE to be considered in the evaluation processag | Implicitly | Yes (explicit estimates) | Yesah | Social utility of the drug and rationalisation of public drug expenditures |
| Social productivity | Not explicitlyai | Yesaj | Indirect costs considered explicitly (to some extent) | Productivity costs excluded but informal “caregiving” might be considered | Direct costs onlyak | Yes | Noal | Yes, either explicitly or implicitly |
| Efficiency considerations | ||||||||
| Cost-effectiveness | Yesam | Optional (cost-benefit)an | Yes (cost-efficiency as a principle) | Yes | Yes | Yes | Yes, mandatory by law | Yes (not mandatory) |
| CBA/BIA | Not mandatory but BIA is highly recommendedao | BIA (mandatory) | Cost only considered for treatments of the same condition; BIA not mandatory | BI to NHS, PSS, hospitals, primary care | Yes | Yes | Yes, payer affordability mandatory by law | Yes (BI to NHS) |
| Other evidence and criteria | ||||||||
| Place in therapeutic strategy | Yesap | Evaluation usually specifies the line of treatment | Evaluation usually specifies the line of treatment | Broad clinical priorities for the NHS (by Secretary of State) | Yes | Not explicitly | No | Yesaq |
| Conditions of use | Yes (e.g. the medicine is assessed in each of its indications, if several) | No, drug is in principle reimbursable for the whole indication spectrum listed on its authorisationar | Yes, coverage can be restricted based on evidence at sub-population level | Yes, coverage can be restricted based on evidence at sub-population level | Implicitly | Yes, indications | Yes, coverage can be restricted to strictly defined sub-populations | Yes (several medicines are introduced with Visado—Prior Authorization Status) |
| Ethical considerations | Not incorporated in assessmentas | Sometimes (implicitly) | Yes | Yesat | Implicitly | Yes, explicitly (e.g. solidarity and affordability)au | Considered on the basis of HTA Guidelines | Not explicitly |
| Weights/relative importance of different criteria | Not transparent | Not transparent | “Human dignity” usually being overridingav | Not transparent | Not transparent | Therapeutic value is the most important criterion | Not transparent | Not transparent and not consistent across regionsaw |
| Accepted data sources (for estimating number of patients, clinical benefits and costs) | Clinical trials, observational studies, national statistics, clinical guidelines, surveys, expert opinions | RCTsax, national or local statistics, clinical guidelines, surveys, price lists, expert opinions (including patient representatives) | Clinical trials, observational studies, national statistics, clinical guidelines, surveys, expert opinions | Clinical trials, observational studies, national or local statistics, clinical guidelines, surveys, expert opinions | Clinical trials, observational studies, national statistics, clinical guidelines, surveys, expert opinions, scientific societies‘ opinion | Clinical trials, clinical guidelines, expert opinions | Clinical trials, observational studies, national or local statistics, clinical guidelines, surveys, expert opinions | Clinical trials, observational studies, national statistics, clinical guidelines, surveys, expert opinions |
Source The authors (based on literature review findings and expert consultation)
SMR Service Médical Rendu, ASMR Amélioration du Service Médical Rendu, RCT randomised clinical trial, HRQoL health-related quality of life, MEA managed entry agreement, EoL end of life, WTP willingness to pay, BIA budget impact analysis, NHS National Health System, PSS personal social services
aSeverity can be defined on the basis of several elements of the condition, including the risk of permanent injury and death
bBoth explicitly and implicitly; more recently they tend to explicitly take into account “burden of disease” measures
cRegulated by law: the Act of 27 August 2004 on healthcare benefits financed from public funds
dIn evaluations performed by the G-BA to determine the benefit basket (i.e. not drugs, which are covered automatically after marketing authorization and value assessment plays a role for the price) availability or lack of alternatives and the resulting medical necessity are considered to determine clinical benefit
eExplicitly stated in the legislation as a criterion to set price
fEstimate the number of treatments that is considered necessary and compared that with the actual capacity
gNot obligatory by law; considered in the assessment process of AOTMiT on the basis of HTA guidelines (good HTA practices)
hLower accepted significance levels for P values (e.g. 10% significance levels) for small sample sizes such as rare disease populations; acceptance of evidence from surrogate endpoints rather than only ‘hard’ or clinical endpoints
IDecisions on price and reimbursement of orphan drugs are made through a 100-day ad-hoc accelerated procedure, although criteria for HTA appraisals do not differ from non-orphan drugs
jCommonness, but not rarity, regulated by law (the Act on healthcare benefits); rarity is considered in the assessment process in AOTMiT on the basis of HTA guidelines
kSMR, 4 classifications for actual clinical benefit: Important/High (65% reimbursement rate), Moderate (30%), Mild/Low (15%), Insufficient (not included on the positive list); ASMR, 5 classifications for relative added clinical value: Major (ASMR I), Important (ASMR II), Moderate (ASMR III), Minor (ASMR IV), No clinical improvement (ASMR V)
lThe possible categories are: major added benefit, considerable added benefit and minor added benefit. Three additional categories are recognized: non-quantifiable added benefit, no added benefit, and lesser benefit
mRegulated by law: the Act of 27 August 2004 on healthcare benefits financed from public funds
nRegulated by law: the Act on the reimbursement
oWeak preference; if no LYG/QALY data available
pConsidered if measured using validated instruments employed in the context of clinical trials
qRegulated by law: the Act on reimbursement
rBased on the following ranking relative to comparator: greater harm, comparable harm, lesser harm
sRegulated by law: the act on healthcare benefits; the act on reimbursement
tNot obligatory by law; considered in the assessment process of AOTMiT on the basis of HTA guidelines (good HTA practices)
uNot a criterion per se, implicitly considered if patient benefit is higher than that of existing alternatives
vThe Act on healthcare benefits considers the following classifications: saving life and curative, saving life and improving outcomes, preventing premature death, improving HRQoL without life prolongation
wIncremental clinical benefit is considered as part of the therapeutic and social usefulness criterion
xOnly considered in the ASMR if it has a clinical impact (e.g. through a better compliance)
yThe IQWiG’s general methodology (not specifically for new drugs) states that patient satisfaction can be considered as an additional aspect, but it is not adequate as a sole deciding factor
zNot obligatory by law (unless captured in HRQoL/QALY); considered in the assessment process of AOTMiT on the basis of HTA guidelines
aaThrough the therapeutic and social usefulness criterion
abRanking includes the following classifications: Symptomatic relief, Preventive treatment, Curative therapy
acRegulated by law: the Act on healthcare benefits considering the following classifications: saving life and curative, saving life and improving outcomes, preventing the premature death, improving HRQoL without life prolongation; thus no “innovativeness” per se
adPublic health interest (interêt santé publique; ISP) is incorporated into the SMR evaluation. ISP considers 3 things: whether the drug contributes to a notable improvement in population health; whether it responds to an identified public health need (e.g. ministerial plans); and whether it allows resources to be reallocated to improve population health
aeHowever, manufacturer dossiers need to include information on the expected number of patients and patient groups for which an added benefit exists as well as costs for the public health system (statutory health insurance)
afThe following principles are considered: human dignity, need/solidarity, cost-efficiency, societal view
agFactors include cost-effectiveness, clinical need, broad priorities for the NHS, effective use of resources and encouragement of innovation, and any other guidance issued by the Secretary of State
ahRegulated by law: the Act on healthcare benefits considering: impact on public health in terms of priorities for public health set; impact on prevalence, incidence—qualitative assessment rather than quantitative
aiOnly potentially as part of economic evaluations
ajProductivity loss due to incapacity as part of the cost side, productivity loss due to mortality as part of the benefit side (no unpaid work, e.g. housework)
akIndirect costs can be taken into account in a separate analysis
alNo social perspective obligatory by law; may be provided but problematic to use for recommendation/decision
amAlready implemented but analysis conducted separately by the distinct CEESP. The health economic evaluation does not impact the reimbursement decision
anCBA is not standard practice in the evaluation but, rather, can be initiated if no agreement is reached between sickness funds and manufacturer on the price premium or if the manufacturer does not agree with the decision of the G-BA regarding premium pricing (added benefit)
aoASMR V drugs should be listed only if they reduce costs (lower price than comparators or induce cost savings)
apThe commission will also make a statement if a drug shall be used as first choice or only if other existing therapeutics are not effective in a patient
aqIn the form of the new IPT—Informes de Posicionamiento Terapéutico/Therapeutic Positioning reports.
arSub-groups are examined as part of benefit assessment but in order to guide pricing, not reimbursement eligibility. If a drug has an added benefit for some groups but not for others, a so-called “mixed price” is set that reflects both its added benefit for some patients and lack thereof for others
asThe assessment in France is purely ‘scientific’ i.e. focuses on the absolute and comparative merits of the new therapy and its placement in the therapeutic strategy
atNICE principles include fair distribution of health resources, actively targeting inequalities (SoVJ); equality, non-discrimination and autonomy
auAlso indirectly through a seat for an ethicist in the Committee
avNo clear order between “need and solidarity” and cost-efficiency. In the entire health system a more complete ordering is seen where human dignity takes precedence over the principles of need and solidarity, which takes precedence over cost-efficiency
awNot all regions have either HTA agencies or regional committees for drug assessment. However, at regional level drug assessment is limited to prioritizing (or not) its use by means of guidelines or protocols together with some type of incentives to promote savings
axFor therapeutic benefit, other designs such as non-randomised or observational studies might be accepted in exceptional cases if properly justified, e.g. in the case that RCTs are not possible to be conducted, if there is a strong preference for a specific therapeutic alternative on behalf of doctors or patients, if other study designs can provide sufficiently robust data, etc