HTA EXPERIENCES IN DIFFERENT SETTINGS: COMMONALITIES AND CONTRASTS

Part 2

2.30-3.30 pm

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Cross-country differences in HTA recommendations

• Differences across countries exist (Nicod 2012) • 47% of 287 recommendations issued between 2007-2009 in 5

countries were homogeneous • Expectations in terms of relative effectiveness differ depending

on the disease and drug characteristics

• Differences may be a consequence of: • Each country sets its own objectives reflecting values, preferences (e.g.

population disease profile) and constraints (e.g. budget constraints, structure of the health care system) (Banta 2003)

• HTA processes (topics appraised, timing, level of stakeholder involvement, type of HTA body)

• Consequence of the application of HTA

⇒Differences are inevitable and often legitimate

2 Sources: Nicod, E., & Kanavos, P. (2012). Commonalities and differences in HTA outcomes: A comparative analysis of five countries and implications for coverage decisions. Health Policy, 108(2-3), 167-177; Banta, D. (2003). The development of health technology assessment. Health Policy, 63(2)

Comparison of the assessment of benefit in Germany (FJC) and France

3 Source: Ruof J et al. (2014). Early benefit assessment (EBA) in Germany: analyzing decisions 18 months after introducing the new AMNOG legislation. European Journal of Health Economics. 15:577-589

Comparisons of FJC decisions with NICE and SMC’s (2011-2014)

NICE and FJC decisions Agreement for 40% of 55 decisions

SMC and FJC decisions Agreement for 47.6% of 166 decisions

NICE and FJC comparative effectiveness Agreement for 52.7% of 55 decisions

SMC and FJC comparative effectiveness Agreement for 64.5% of 166 decisions

Source: Fischer KE, et al. Health benefit assessment of pharmaceuticals: An international comparison of decisions from Germany, England, Scotland and Australia. Health Policy (2016), http://dx.doi.org/10.1016/j.healthpol.2016.08.001

• Agreement in the endpoints: • Adverse events (92% for FJC-NICE, 77% for FJC-SMC) • Quality of life (85% forFJC-NICE, 89% for FJC-SMC) • Mortality (71% for FJC-NICE, 83% for FJC-SMC) • Morbidity (52% for FJC-NICE, 60%for FJC-SMC)

• Agreement in the comparators • 71% of decisions for NICE • 56% for SMC

⇒Extent of differences, even when focusing on comparative effectiveness only

⇒Same evidence-based

⇒Consequences of decisions differ in terms of patient access

⇒Differences: ⇒Accepting surrogate progression-free survival endpoints ⇒Disease-specific mortality over overall mortality ⇒Comparators ⇒Handling lack of evidence

Comparisons of FJC decisions with NICE and SMC’s (2011-2014)

Source: Fischer KE, et al. Health benefit assessment of pharmaceuticals: An international comparison of decisions from Germany, England, Scotland and Australia. Health Policy (2016), http://dx.doi.org/10.1016/j.healthpol.2016.08.001

Drug Indication NICE England

SMC Scotland

TLV Sweden

HAS France

SMR (Coverage rate %)

ASMR (Pricing scheme)

Eltrombopag Thrombocytopenic purpura Reject Restrict Restrict important (65%) II (EU)

Ofatumumab Chronic lymphocytic leukemia Reject Reject na moderate (30%) V (comp)

Mannitol dry Cystic fibrosis Restrict Reject na weak (15%) V (comp) Everolimus Renal cell carcinoma (2nd line,

advanced) Reject Reject List important (100%) IV (comp)

Azacitidine Myelodysplastic syndrome Restrict Restrict na important (65%)* II (EU)

Lenalidomide Multiple myeloma (2, 3rd line) Restrict Restrict List important (65%)* III (EU)

Mifamurtide Osteosarcoma Restrict Restrict List insufficient (0%) Reject

Trabectedin Soft tissue sarcoma Restrict Reject na important (65%)* V (comp)

Imatinib Gastro-intestinal stromal tumours (adj. unresectable and/or metastatic)

Reject Restrict na important (100%) III (EU)

Romiplostim Thrombocytopenic purpura Restrict Restrict Restrict important (65%) II (EU)

* not explicitly stated in HTA decision; EU: European price levels and price negotiation; comp: price equal or lower than comparators.

Comparison of 10 orphan drugs decisions in England, Scotland, Sweden and France

6 Homogeneous recommendations

Rejected only by NICE and not the others

Rejected by SMC, ASMR V and not by NICE

Restricted by NICE and SMC, rejected by HAS

Source: Nicod, Elena (2016) Why do health technology assessment coverage recommendations for the same drugs differ across settings? Applying a mixed methods framework to systematically compare orphan drug decisions in four European countries. The European Journal of Health Economics . ISSN 1618-7598 (In Press)

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The decision process to assessing value

Scientific value judgments acceptability of

imperfect/ incomplete evidence

(non-quantified)

Social value judgments

social values (elicited or non-

elicited)

E.g. elicited societal preferences: End-of-life criteria, England (NICE) SMC modifiers, orphan drugs, Scotland (SMC)

Clinical and/or cost-effectiveness

Incomplete imperfect

Value judgments about

uncertainty

Influenced by stakeholder input

and other considerations

List/restrict/reject

Source: Nicod & Kanavos (2016)Developing an evidence-based methodological framework to systematically compare HTA coverage decisions: a mixed methods study Health Policy, 120 (1). 35-45. ISSN 0168-8510

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Mixed methods methodological framework

⇒ To systematically identify & compare HTA decision processes across countries and drugs ⇒ To understand how value is assessed in each setting and the reasons for cross-national

differences

Interviews to obtain insights from HTA bodies on cross-country differences

Source: Nicod & Kanavos (2016)Developing an evidence-based methodological framework to systematically compare HTA coverage decisions: a mixed methods study Health Policy, 120 (1). 35-45. ISSN 0168-8510

Differences in the HTA recommendations explained for a sample of 10 orphan drugs undergoing the traditional HTA processes

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(1) Evidence

(2) Interpretation of the evidence: value judgments

(3) Decision modulators (4) HTA approach

Dealing with rare conditions

Source: Nicod, Elena (2016) Why do health technology assessment coverage recommendations for the same drugs differ across settings? Applying a mixed methods framework to systematically compare orphan drug decisions in four European countries. The European Journal of Health Economics . ISSN 1618-7598 (In Press)

Similar evidence: similar, but not without uncertainty…

Primary trial Trial type Subgroup/trial population # trial participants

Eltrombopag RAISE Phase III Total 197 Subgroup (splenectomised) 1/3 (= 66)

Subgroup (non-splenectomised) 2/3 (= 131)

Romiplostim Study 105 Phase III Splenectomised 105 Study 212 Phase III Non-splenectomised 212

Everolimus Record-1 Phase III Total 416 Lenalidomide MM-009 Phase III Same design/different location. 353

MM-010 Phase III 351 Mifamurtide INT-0133 Phase III Posthoc analyses of different

treatment regimens 678

Azacitidine AZA-001 Phase III Total 358 Imatinib ACOSOG-Z9001 Phase III Total 713

Subgroup (by risk groups) 566

Mannitol dry DPM-CF-301 Phase III Subgroup (receiving or not rhDNase, enzyme therapy)

190 adults DPM-CF-302 Phase III 151 adults

Ofatumumab Hx-CD20-406 Phase II, prospective, non-randomised, non-comparative

Total 154 Subgroup (refractory to other treatments)

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Trabectedin STS-201 Phase II, randomised Total 270

What do we see… • Same primary trials

• All phase III except:

• Ofatumumab: phase II, prospective, nonrandomised, noncomparative (conditional marketing approval)

• Trabectedin: phase II, randomised (exceptional marketing approval)

• 5/10 drugs relied on subgroups

• 9/10 drugs relied on surrogate outcomes

• 8/14 trials enrolled < 300 patients

⇒ Same trials, different ways of reporting outcomes

Different evidence-based used

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Endpoints reported from the same trials

Clinical endpoints of interest

Non-primary evidence

Economic models and comparators

Trabectedin Soft Tissue Sarcoma

Lack of comparative data following

early conditional marketing authorisation (different dosages compared)

Registry data as historical controls (NICE)

Not accepted by the other agencies

Differences in the HTA recommendations explained

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(1) Evidence

(2) Interpretation of the evidence: value judgments

(3) Decision modulators (4) HTA approach

Dealing with rare conditions

Scientific value judgments: dealing with uncertainty

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Different types of concerns (raised by some and not by others)

trial duration, benefit (survival and

quality of life), resource use, safety, comparative data, generalisability

Different ways of dealing with the same concerns

Means to address uncertainty: (1)

stakeholder input, (2) orphan status or investigational nature, (3) “other considerations”, (4) other study, (5)

judgment during deliberation

e.g. Mannitol dry (cystic fibrosis)

No improvement in HRQol NICE (patient experts)

× HAS Not raised by SMC

14.5% of 114 concerns commonly raised across all 4 countries

Proportion of cases that accounted for other considerations (N 125), by cluster

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0% 20% 40% 60% 80% 100%

Adverse events manageable/non significant

Indirect benefits from the treatment

Innovative nature of the treatment

Clinical benefit and type of benefit

Complex pathway, no best practices or advances

Issues around current treatment alternatives

Rarity, orphan status, small patient population

Unmet need

Disease nature affecting the patient

TREA

TMEN

TD

ISEA

SE

NICEN = 10

SMCN = 10

TLVN = 4

Social value judgments: elicited and non-elicited

Source: Nicod et al. 2016

Elicited versus non-elicited value judgments (NICE)

Elicited versus non-elicited value judgments (SMC)

Social value judgments: innovation, unmet need, severity

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Innovation • Treatment benefits (ICER or deliberative process) • Intrinsic to decision • New mode of action / Covers an unmet need

Unmet need • Consequence of the decision (disease severity) • Lack of available treatment options (no differentiation of severity) Disease severity • Consequence of the decision (unmet need) • Intrinsic to the decision • Severe, life-threatening, short life-expectancy, affects quality of life, etc. ⇒ Deliberative process ⇒ Elicited or not, overlap of terminologies ⇒ Consistency ⇒ Accountability for reasonableness

Stakeholder input: patient input (NICE)

Disease characteristics Disease symptoms • Fatigue

Impact of disease on quality of life • Patients, carers, family, friends • Limiting life style choices (daily or leisure activities) • Functional capacity

Disease severity

Other effects from the disease • Social stigma (e.g. from bruises) • Anxiety of symptoms, relapse, or surgery • Stress at work

Unmet need • lack of alternatives • need for options (relapse)

Issues around current treatments • Negative effects (e.g. taste) • Adherence issues • Dependence on rescue therapy, blood transfusions

Treatment characteristics Adverse events from the treatment • Well tolerated, tolerable • Safe • Relief from fatigue • Adverse event preferences

Disease management • decreased need for rescue therapy • Preference for oral therapy versus transfusions

Quality of life improvements • Functional capacity • Patients, carers, family, friends

Measures of quality of life • Do not capture the consequences of living with the disease

Differences in the HTA recommendations explained

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(1) Evidence

(2) Interpretation of the evidence: value judgments

(3) Decision modulators (4) HTA approach

Dealing with rare conditions

Context-specific decision modulating factors (societal preferences)

Agency-specific NICE End-of-life (EoL) SMC modifiers (modifiers) Temporary authorization scheme? (ATU)

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Process-specific Patient access schemes (PAS) Lower discount rate (1.5%, 3%) Restrictions (restrict) Re-assessments (re-assess)

Drug NICE

England SMC

Scotland HAS

France Eltrombopag restrict ATU, re-assess

Ofatumumab PAS ATU

Mannitol dry restrict Everolimus EoL, PAS ATU

Azacitidine EoL, PAS modifiers, PAS ATU

Lenalidomide EoL, PAS modifiers ATU

Mifamurtide PAS, 1.5% PAS, 1.5% Trabectedin EoL, PAS PAS ATU Imatinib modifiers, restrict ATU, re-assess

Romiplostim PAS, restrict modifiers, restrict ATU, re-assess

Color legend: rejected listed/restricted, ASMR I-IV

Differences in the HTA recommendations explained

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(1) Evidence

(2) Interpretation of the evidence: value judgments

(3) Decision modulators (4) HTA approach

Dealing with rare conditions

HTA approach: clinical benefit versus cost-effectiveness

Positive clinical benefit + cost-ineffective Important SMR (65%-100% coverage)

eltrombopag (× NICE), everolimus (× NICE, SMC), imatinib (× NICE) ASMR I-III (European price levels)

eltrombopag (× NICE), imatinib (× NICE)

Lack of comparative data No comparative data (different dosages, non-comparative) for mannitol dry,

ofatumumab, trabectedin ⇒Early marketing authorization or scientific advice ⇒× Rejected/ASMR V restricted by NICE (mannitol dry, trabectedin)

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(1) Evidence

(2) Interpretation of the evidence: value judgments

(3) Decision modulators (4) HTA approach

Dealing with rare conditions

CASE STUDY HTA DECISION IN ENGLAND,

SCOTLAND AND FRANCE COMPARED ELTROMBOPAG- Treatment for chronic idiopathic

thrombocytopenic purpura

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Natural history & definition

= rare disease, low platelet count (thrombocytopenia), with normal bone marrow, and absence of other causes of thrombocytopenia

The platelets are the cells that help our blood to clot.

Idiopathic thrombocytopenic purpura (ITP)

ITP is an autoimmune disease, where antibodies produced by the immune system attach themselves to the platelets, marking them for destruction. The spleen, which helps the body fight infection, recognizes these antibodies and removes them. Causes are unknown, hence “idiopathic” = “unknown cause”. Acute versus chronic: • acute in children (infection and spontaneous resolution within 2 months) • chronic in adults (persists longer than 6 months without a specific cause)

150,000 Platelet count per microliter of blood

20,000

ITP

thrombocytopenic normal

Sources: (a) Ghanima W, Godeau B, Cines DB, Bussel JB. How I treat immune thrombocytopenic purpura: the choice between splenectomy or a medical therapy as a second-line treatment. 2011 Blood online,12-309153. (b) Mayo clinic website www.mayoclinic.org. © http://www.patient.co.uk/doctor/idiopathic-thrombocytopenic-purpura (d) Terrell DR, Beebe LA, Vesely SK, et al. The incidence of immune thrombocytopenic purpura in children and adults. Am J Hematol. 2010;85(3):174-80.; (e) Schoonen M, Kucera G, Coalson J, Li L, Rutstein M, Mowat F, Fryzek J, Kaye JA. Epidemiology of immune thrombocytopenic purpura in the General Practice Research Database. British Journal of Haematology. 2009;145(2):235-44.

Epidemiology

Incidence of childhood ITP 2.2-5.3 per 100,000 per year, and of adults 3.3 per 100,000 per year => recognized as a rare disease by the European Medicine Agency

70% of childhood cases will end up in remission, and is of 20-40% in adults

Age and sexe: the median age for ITP is between 50-60 years, and the male:female ratio ranges from 1:2 to 1:7

The mortality rate compared to healthy population per age and gender matched groups: 60% higher in Great Britain. Higher mortality rates in individuals 45 and older.

ITP symptoms & diagnosis

Low platelet count

(< 20,000 microliter)

• Spontaneous formation of bruises (purpura) and petechiae (tiny bruises) especially on the extremities,

• bleeding from the nostrils or gums,

• menorrhagia (excessive menstrual bleeding)

Very low count

(< 10,000 microliter)

• Spontaneous formation of hematomas (blood masses) in the mouth or on other mucous membranes,

• prolonged bleeding time from minor lacerations or abrasions

Extremely low count

(< 5,000 microliter)

• => Serious and possible fatal complications

• subarachnoid or intracerebral hemorrhage (bleeding inside the skull or brain),

• lower gastrointestinal bleeding or other internal bleeding,

• bleeding caused by blunt abdominal trauma (e.g. car crash).

Diagnosis: blood test (blood count) & other investigations (e.g. bone marrow biopsy) to exclude other causes of thrombocytopenic purpura

Treatment depends on symptoms (e.g. bleeding), age and platelet count (< 20,000 microliters). Aim of treatment is to increase platelet count and prevent bleeding complications

Corticosteroids Medicines that suppress the immune system. Once

platelet count improves, dose of treatment reduced, but risk of relapse (60-90%).

Long-term effects of treatments include osteoporosis, cataracts, diabetes.

Surgery (splenectomy) Removal of the spleen.

Used if corticosteroids do not work.

Risk of significant bleeding during surgery and infection. Durable remission: 72% at 5 years

Thrombopoietin receptor agonists Medicines that stimulate the production of platelets:

Romiplostim (subcutaneous injection) or Eltrombopag (oral administration)

59-88% success rates, but life long treatments (relapses when discontinued)

Adverse events: headaches, joint or muscle pain, dizziness, nausea or vomiting, risk of blood clots

Anti-D Intravenous administration of Rho(D) immune globulin

that destroy red blood cells preferentially (although not well understood).

Adverse events: headaches, chills, fever.

Treatments

• Indication = chronic immune (idiopathic) thrombocyptopenic purpura : • in splenectomised adults whose condition is refractory to other treatments

(corticosteroids, immunoglobulins), or • as 2nd line treatment in non-splenectomised adults where surgery is contraindicated.

What happened with the assessment of eltrombopag in the four countries?

England NICE

Scotland SMC

Sweden TLV

France

Rejected Restricted to patients with severe

risk of bleeding

Restricted, planned re-assessment in 2

years

Important improvement in clinical benefit

(ASMR II)

We will try to understand why?

• By comparing how they were assessed in each country, in terms of: • Clinical evidence (clinical trials, quality of life, etc.)

• Economic evaluation (including costs and modelling of the clinical evidence to

extrapolate the long term effects of the treatment)

• Interpretation of the evidence:

… and how these led to the final recommendation…

• Data sources: the HTA reports publicly available

Understanding what happened

Let’s start by looking at the clinical evidence considered… Which trials were considered in the assessments?

Clinical trials: Pivotal trial “RAISE” • Phase III RCT, 197 participants • Comparator: standard care (steroids, non-selective immunosuppressant and rescue

medication as required) • 6 months duration Indirect comparison with romiplostim (= thrombopoietin receptor agonist) • Romiplostim indicated for the treatment of chronic ITP • In patients whose condition is refractory to standard active treatments and rescue therapies, or

• In patients who have severe disease and a high risk of bleeding that needs frequent courses of rescue therapy

Source: RAISE: Randomized Placebo-Controlled Idiopathic Thrombocytopenic Purpura (ITP) Study With Eltrombopag. http://clinicaltrials.gov/ct2/show/NCT00370331

Clinical endpoints (non-exhaustive list) RAISE trial

England NICE

Scotland SMC

Sweden TLV

France HAS

Platelet response (primary endpoint)

Rescue treatment

Bleeding events (WHO grades 1-4)

Bleeding events (WHO grades 2-4) =clinically significant bleeding

Bleeding events (WHO grades 3-4) Gross (grade 3) and debilitating (grade 4) blood loss

X

Main reduction in bleeding X grade 2

HRQOL (SF36) 4 domains X 6 domains

4 domains

Indirect comparison (RAISE) with romiplostim

Platelet response (primary endpoint) NR NR NA

Platelet response (splenectomised) X

Platelet response (non-splenectomised) X

Statistically significant; X not statistically significant Bleeding events World Health Organization grade 1 = petechiae; grade 2 = mild blood loss; grade 3 = gross blood loss ; grade 4 = debilitating blood loss; NR: not reported in HTA final report; NA: not applicable as not included in submission

Cost-effectiveness evidence

NICE England

SMC Scotland

TLV Sweden

Type of model Cost-utility analysis Cost-utility analysis Cost-minimisation analysis

Comparator “Watch and rescue” Romiplostim Romiplostim

Outcome Same clinical benefit and lower cost

- Splenectomised £104,000/QALY Savings £12,641 and 0.039 QALY gain => dominant

- Non-splenectomised £116,000/QALY Savings £2,094 and 0.028 QALY gain => dominant

=> Economic models not comparable (different comparators and models)

Discuss the clinical benefit of eltrombopag and modeling of the clinical evidence

• What clinical outcomes do you think are important in measuring the benefit of eltrombopag?

• How would you interpret the primary endpoint, bleeding events, quality of life data, or the group where the main reduction in bleeding was seen?

• Anything missing?

• Do these measures capture the full effects of the disease to the patient (and to society)?

• Any other considerations that could be accounted for (e.g. patient input)?

• What about the results from the indirect comparison?

• What about the different ways to model this evidence?

…. Let’s see what happened….

Interpretation of the evidence (non-exhaustive list) Clinical uncertainties Raise trial

NICE England

SMC Scotland

TLV Sweden

HAS France

Lack of comparator (based on RAISE) X X X X

Short duration of the trial (RAISE only 6 months) X X

Significant bleeding events (grade 3-4 bleeding & main reduction in bleeding)

X NA NA NA

Lack of quality of life data NA NA X

Indirect comparison (eltrombopag-romiplostim)

Uncertain nature of the indirect comparison (different populations enrolled, overall response not pre-specified in eltrombopag trial)

X X NA

uncertainty deemed acceptable; X uncertainty was a concern

Other considerations (non-exhaustive) NICE

England SMC

Scotland TLV

Sweden HAS

France

New class of drugs Clinicians X*

Benefit from oral administration X* X*

Unmet need for treatment alternatives Clinicians X* X* X

Life-threatening, serious condition Patients /clinicians

X* X

Impact on quality of life, functional capacity, daily activities

Patients /clinicians

X* X

Social stigma, limiting life-style choices Patients /clinicians

Orphan status X* X* X

Comparator unlicensed and associated with anxiety from adverse events

Patients

No routine standard pathway Clinicians Clinicians

Legend: patients/clinicians: input from patients or clinicians; * considered as one of the main reasons for the final recommendation

The decision NICE England

SMC Scotland

TLV Sweden

HAS France

Effect of eltrombopag

> Standard care, but uncertain

> Standard care, but uncertain

= romiplostim > Standard care, but uncertain Lack of comparative and long-term data

Cost of eltrombopag

< romiplostim

ICER Uncertain and high ICER

Uncertain ICER

WTP (France: relative improvement in clinical benefit)

ICER > WTP Not cost-effective

Greater uncertainty in ICER is acceptable given the orphan status, oral administration benefit, and that it offers additional treatment options

Cost-effective, given that eltrombopag has the same effect as romiplostim and is cheaper. Romiplostim was already considered cost-effective. And eltrombopag is an orphan drug, for a severe condition that impacts the patient’s quality of life

Considered similar to romiplostim until further evidence is provided (risk assessment plan) = ASMR II

LESSONS LEARNT • Different HTA recommendations for a same drug and indication exist • Objectives, values, preferences, constraints, processes • Application of HTA (approach used, value judgments) • Methodological limitations

• Awareness of (reasons for) cross-country differences • Accountability for reasonableness & transparency (value judgments) • Acceptable / preferred evidence • Dealing with uncertainty • Stakeholder involvement (incomplete evidence)

⇒ Implications for patient access from ⇒ Need for improved HTA processes (e.g. adaptive, re-assessments

when new evidence arises, stakeholder input, capturing a more comprehensive picture of the treatment’s value)

⇒ EU cooperation

THANK YOU FOR YOUR ATTENTION

Q&A elena.nicod@unibocconi.it