Table 1 HTA report with validated data for each component of decision of the framework (highly synthesized version)

Disease: Turner syndrome (TS)

Intervention: growth hormone (GH)

Setting: Canada

Drug class: Polypeptide hormone

Indication: treatment of short stature in girls with Turner Syndrome

Administration: subcutaneous injection 3 to 7 days a week

Intervention duration: not established; initiate treatment as soon as growth failure demonstrated until satisfactory height reached (in Canadian RCT, 6 years of treatment starting at 10 years)

Comparator(s): No treatment

Economic burden of illness: No data available

Intrinsic value components

(MCDA Value Matrix)

Quality of evidence

Q1

Adherence to requirements of decisionmaking body

Not applicable for case study

Low adherence

High adherence

Q2

Completeness and consistency of reporting evidence

Epidemiology: limited statistical information; Clinical data: limited reporting of AEs; PRO: i ncomplete reporting of questionnaire dimensions; Economic evaluation: some model features unclear; Budget impact: no sensitivity analysis reported

Many gaps/inconsistent

Complete and consistent

Q3

Relevance and validity of evidence

Epidemiology: study in one Canadian hospital with small sample size; Clinical data: uncertainty on final height gain, high attrition rate in key RCT; PRO: interim analysis of a subset of participants to a non blinded RCT; Economic evaluation: questionable outcome -cost per cm of final height, no adverse events costs, weak utility data; Budget impact: assuming all Canadian girls treated based on prevalence data

Low relevance/validity

High relevance/validity

Disease impact

D1

Disease severity

Female-specific genetic disorder characterized by short stature, cardiovascular defects, absence of puberty, infertility, increased risk of diabetes, defects in visuo-spatial organization and nonverbal problem-solving, and decreased life expectancy

Not severe

Very severe

D2

Size of population

Prevalence: 40/100,000 female adults

Very rare disease

Common disease

Intervention

I1

Clinical guidelines

International guidelines ( no Canadian guidelines): Consider GH treatment as soon as growth failure is demonstrated and potential risks/benefits have been discussed with patient/family. Treat until satisfactory height is reached

No recommendation

Strong recommendation

I2

Comparative interventions limitations

There is no other therapeutic intervention indicated to treat short stature in Turner syndrome

No or very minor limitations

Major limitations

I3

Improvement of efficacy/effectiveness

4 placebo controlled RCTs (2-year (toddlers) to 11-year treatments; N = 42 to 104, 1 in Canada, 3 in USA): Final height of treated patients = 147 cm to 150 cm (excluding toddlers); difference with untreated = 7 cm

Observational controlled studies (2-year to 8-year treatments, N = 26 to 123, 1 in Germany, 1 in Greece, 1 in Israel, 3 in Italy): Final height of treated patients = 148 cm to 151 cm; difference with controls = 2.1 to 6.8 cm

Lower than comparators

Major improvement

I4

Improvement of safety & tolerability

Common AEs (from RCTs -frequency at least twice of placebo): Surgeries (50%), ear problems (6% to 47%), joint (13.5%) and respiratory (11%) disorders, sinusitis (18.9%)

Serious AEs (from registries, no control data): Intracranial hypertension (0.2%), slipped capital femoral epiphysis (0.2 - 03.%), scoliosis (0.7%), pancreatitis (0.1%), diabetes mellitus (0.2 to 0.3%), cardiac/aortic events (0.3%), malignancies (0.2%)

Warnings: Scoliosis, slipped capital femoral epiphysis, intracranial hypertension, ear disorders, cardiovascular disorders, autoimmune thyroid disease, insulin resistance

Lower than comparators

Major improvement

I5

Improvement of patient reported outcomes

Inconclusive data:

1 RCT (2-year treatment data, N = 28, Canada): higher rating on questionnaire by GH treated patients versus untreated for some domains but not for others

2 observational studies: no significant differences on SF-36 dimensions in one study (5-year treatment, N = 568, France) and significant differences in another (7-year treatment N = 29, Holland); other questionnaires, non significant differences

Convenience: Subcutaneous injection 3 days a week or daily

Worse patient reported outcomes than comparators presented

Major improvement

I6

Public health interest

No data on risk reduction with GH treatment

No risk reduction

Major risk reduction

I7

Type of medical service

Goal of treatment: promote growth and improve psychosocial wellbeing (height gain 7 cm, patient reported outcomes data limited & inconclusive)

Minor service

Major service (e.g. cure)

Economics

E1

Budget impact on health plan

Average annual cost of drug per patient: CAN$28,525

Annual impact for Canadian public drug plans: $11.3 million (coverage for all 396 Canadian patients)

Substantial additional expenditures

Substantial savings

E2

Cost-effectiveness of intervention

Incremental cost per additional centimeter in final height: $23,630 (discounted at 5%);

Incremental cost per QALY gained $243,087 (discounted at 5%)

Not cost-effective

Highly cost-effective

E3

Impact on other spending

Incremental cost per patient: $1,166 (includes training by nurse, outpatient visits & X rays over 6 years - excludes drug cost, see E1)

Substantial additional spending

Substantial savings

Extrinsic value components

(Extrinsic Value Tool)

Ethical framework*

Goals of healthcare - utility*

Goal of healthcare is to maintain normal functioning which may be impacted by very short stature. Goals of GH treatment are to promote growth and improve psychosocial adaptation of individual with short stature. However, psychosocial functioning of individuals with short stature is largely indistinguishable from their peers.

Opportunity costs- efficiency*

Considering maximizing impact on health for a given level of resources at:

Patient level: resources allocated to GH treatment may be more beneficial if allocated to other interventions such as psychological support to cope with condition overall (not just short stature).

Society level: Significant cost/person but small population.

Population priority & access - fairness*

Prioritize worst off: applicable to patients with Turner Syndrome but maybe not to the short stature part of the disease; daily lot probably not improved with daily injections for several years, but maybe as adult with less short stature than without treatment.

Treat like cases similarly: should we treat differently short stature due to disease or due to genes?

Access to care/treatment: easier in big cities where specialists are available

Other components

System capacity and appropriate use of intervention

Optimal age for initiation of treatment has not been established. Appropriate follow up requires the intervention of skilled healthcare professionals

In Canada, any physician can prescribed GH; some of the provinces that reimburse GH require it is prescribed by an endocrinologist.

Stakeholder pressures

Pressure from parents, from clinicians, industry?

Political/historical context

Societal pressure on short stature?

Other components?