→ Patients need comprehensive care (= social aspects should also be taken care of) and patient empowerment should be enhanced (e.g. by enforceable patient participation, not only in their own treatment, but also in the way Centres operate and in initiatives on research and clinical trials). → develop systems for Early Temporary Access (ETA) and Early Temporary Reimbursement (ETR) (→ provide early access to patients) when there is an agreement on terms between the pharmaco and the authorities. → Specify conditions of (authorised) off-label use (when no alternative is available, along with scientific proof of effectiveness and safety and with clinical follow-up of results). → Ethics and governance: price transparency for orphan drugs (setting up rules?) and citizens consultations on ethical aspects (and reimbursement; cfr. NICE). Belgium plays a leading role in Europe for clinical trials, early access and collaboration between countries…

Transparency High prices and low cost-effectiveness
(Philippe Van Wilder, VUB & TiGenix)
Alternative title of talk: ‘How to deal with uncertainties in clinical benefit, budget impact and efficiency?’

The Belgian reimbursement criteria for OD’s are the same as for normal products, even if the procedure is different. In Belgium only the pharmaco’s can file for reimbursement; in the Netherlands any stakeholder can (eg. the hospitals).

In a study 25 OD submissions were compared to 25 Class1 submissions for the following characteristics (OD vs. Class1 submission):
• At least one RCT used (52% vs 84%)
• RCT with active therapy as control (12% vs 60%)
• Inclusion of dose finding studies (20% vs 92%)
• Adequate sample size (16% vs 92%)
• Adequate duration of exposure (48% vs 96%)
• Use of clinical endpoints (48% vs. 56%)

The ICER is often much higher than the usual thresholds (NB: the limit <30.000£ is the only clearly established limit by NICE, but Drummond doesn’t think the normal ICER approach should be applied.

The high prices of OD’s are due to rarity (lack of alternatives) and limited budget impact. The economic model is affected by uncertainties of (the lack of proof of) effectiveness.

Let’s think of an alternative approach→ PBRSA (Performance Based Risk Sharing Arrangement) : outcomes based schemes, risk-sharing agreements, coverage with evidence development, patient access schemes, pay-for performance programs… (CLICK HERE for the pdf on PBRSA)
 
1. data collection to reduce uncertainties about the expected effectiveness and cost-effectiveness or other relevant outcome or cost impact data.
2. Data collection during the time between the regulatory approval and the full diffusion and uptake
3. price and/or revenue is linked to the outcome of the data collection program or is renegotiated after a certain time.

Conclusions: clinical evidence is lower, but access is quicker than for normal products. The reason: high burden of disease (30 million patients in Europe) and low prevalence. More coordination between countries and (national) registries is necessary. The aim should be to increase effectiveness and efficiency and to improve the balance between the availability of treatments and the risk of exposing patients to ineffective / unsafe treatments.

Q&A
Europe is funding a network of centres of excellence. This initiative helps to identify the centres, coordinate their work (and knowledge) and already leads to cooperation and new clinical research.

It is not a question of ‘poor clinical evidence but ‘rare clinical evidence’.

EU perspectives on Market entry for OD
(Steven Simoens, KULeuven)

Incentives for development
• Very high variety of features / conditions between the EU countries.
• Belgium has no ‘institutional context’ (except for compassionate use).
• Consensus on statements → study: results shown.

Registration:
• Centralised procedure EMA → EMA and national authorities work on identical data for different purposes.
• The design of the registry (to collect data post market authorisation) is crucial to allow continuous research (international coordination) → funding of registries independent from industry.
• 10 year market exclusivity period: can be shortened if the product is “sufficiently” profitable. (But what is ‘sufficient’?)
• RCT’s should remain the standard.
• EPAR and SPC need to be systematically updated whenever new clinical data become available!

Pricing
• Price is the key element in the orphan drug equation!
• Small monopolies are created; no competitive incentives → there are no correction mechanisms in the market.
• Not all OD’s are innovative → not all cases are the same → high price is not automatic!
• Pricing should be coordinated at a EU level! Price justification should be based on investments and expected return. Risk sharing should be P4P, no-cure-no-pay or conditional reimbursement.

Reimbursement
• Efficacy → effectiveness data (best is to have data that are useable for both!)
• Comparison with standard treatment (if there is one, but often there is!)
• Budget impact should be based on registry data (prevalence → volume → budget).
• Standardised and more detailed cost data should be used in pharmaco-economic studies.
• New models: ‘Auction of Patents’, ‘Advance Purchase Commitments’, ‘Pay-as-you-go Schemes’ (= increase reimbursement after milestones in R&D are reached).

Market uptake
• 17 OD’s studied by IMS → 4 clusters
• Huge variation in access / availability of products, public expenditure per capita and share of total market sales per country.
• High GDP and strong IP law increases access and uptake.

Conclusions:
• A more transparent and evidence-based approach
• There is not one market for OD:
o a traditional market: high R&D cost and high prices
o questionable high prices: older drugs that are ‘re-used’
• Supply vs demand: Today it is a supply driven market (the pharmaco’s decide for which diseases OD’s are developed. The market should be more demand driven (cfr. the new models supra).

Q&A
OD’s can get protocol assistance (national or EMA), which will decrease costs and increase the chance of acceptance.

Misconceptions on OD’s
(Erik Tambuyzer, AbConsult, ex-Genzyme)

EU is taking the global lead on rare disease public policies. But with a weakness: At least 33 different European healthcare systems.

Only 10% of rare diseases have some kind of treatment → high medical need.
New business models have been developed for OD’s

Misconceptions:
• 1-2% of the population can be treated by OD’s (not the 7-8% that have a rare disease, but many of which are not (yet) treatable. (e.g. the estimated prevalence of Gaucher (5.000 in Germany) vs. the number of patients that are actually treated (only 250!) → the estimate was too high.
• Most R&D is done by industry (not academia). Spinoffs of universities are also pharmaco’s!
• A lot of very expensive but mostly ‘invisible’ failures have to be recouped by the (few) successes.
• Is ‘safety’ or are ‘patients needs’ to come first? In the USA it is safety; in the EU patient needs come first.
• Over the next 5-10 years some 10-12 new OD’s will be approved in EU.

Prices aren’t too high; otherwise every pharmaco would be developing them!

Q&A – discussion
Normal market mechanisms don’t apply.
Patient access is more than market authorisation (reimbursement is also needed). Models should go back to the basic question: what is the earliest moment when products could be made available to patients (= long before the end of the normal procedures of market access / registration and reimbursement). In case of immediate access, what (new) rules should guarantee sufficient safety for the patient? We should have the courage to rethink the whole model!

Patients are willing to take risks: if it is not helping them, it might help the next generation (remember that a lot of OD are hereditary / genetic)!

The Swedish model of early consultation: the earlier pharmaco’s consult with the Agency/NIHDI/EMA the better it is for everybody.

The highest level of collaboration was standardisation, not collaboration on the collection of data etc.
EMA is trying (in the EUNETA network) to develop a methodology to be able to combine effectiveness and efficacy studies (= “one study” for registration and pharma-economy).

We are going to live very different (budgetary) years, because we won’t be able to pay for everything anymore (and postpone the bill for future generations). This will change the way we have to approach the off-patent market and the way we will accept innovative treatments. OD’s can’t be addressed separately. And Europe will have to take it’s responsibility, also for reimbursement. (nvdr: or at least for assessment).

Public pharmacists should actively participate in the working groups. Otherwise there will only be distribution in hospital pharmacy.

Dirk Broeckx – 14 december 201-12-14
db@de7de.be