Introduction
Methods
Selection and structuration of criteria for orphan drugs framework
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Updated version of EVIDEM framework (v.4): New considerations of the EVIDEM framework which is continually updated by the EVIDEM collaboration group to support pragmatic and reflective healthcare decision-making [8]
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Systematic Literature Review (SLR): Criteria from a SLR conducted by the Instituto Carlos III (ISCIII). The study identifies and analyses the information about the reimbursement criteria and pharmaceutical policies used for orphan drugs decision-making applied in the main countries of the European Union, Australia and Canada. Their search strategy covered literature published between to 2004 and 2015 [3].
Weighting of orphan drugs framework (value system elicitation)
Data analysis
Case studies – appraisal of three orphan drugs
Data analysis
Results
Selection and structuration of the criteria for orphan drugs framework
Criteria | Type of criteria | Source |
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Disease severity | Quantitative | Previous study [7] |
Size of affected population | Quantitative | Previous study [7] |
Unmet needs | Quantitative | Previous study [7] |
Comparative effectiveness | Quantitative | Previous study [7] |
Comparative safety/tolerability | Quantitative | Previous study [7] |
Comparative patients perceived health (PRO) | Quantitative | Previous study [7] |
Type of preventive benefit | Quantitative | Previous study [7] |
Type of therapeutic benefit | Quantitative | Previous study [7] |
Cost of orphan drug | Quantitative | Previous study [7] |
Other medical costs | Quantitative | Previous study [7] |
Non-medical costs | Quantitative | Previous study [7] |
Quality of evidence | Quantitative | Previous study [7] |
Expert consensus / clinical practice guidelines | Quantitative | Previous study [7] |
Population priorities and access | Qualitative | Previous study [7] |
Common goal and specific interests | Qualitative | Previous study [7] |
Opportunity costs and affordability | Qualitative | Previous study [7] |
System capacity and appropriate use of intervention | Qualitative | Previous study [7] |
Criteria | Type of criteria (quantitative/qualitative) | Source |
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Size of affected population | Quantitative | Previous study [7] |
Preventive benefit | Quantitative | Previous study [7] |
Therapeutic benefit | Quantitative | Previous study [7] |
Non-medical costs | Quantitative | Previous study [7] |
Budget Impact | Quantitative or qualitative | |
Rarity | Quantitative or qualitative | SLR [3] |
The rule of rescue | Quantitative or qualitative | SLR [3] |
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Size of affected population: The ethical basis of this criterion reflects an aspect of the utilitarianism principle (greatest good for greatest number). Orphan drugs target small populations. Then, this principle, albeit important, need to be considered as a low priority, in order to minimise differences between rare and ultra-rare diseases. It was agreed to exclude the criteria.
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Preventive benefit: the vast majority of rare diseases are of genetic origin and interventions are therefore symptomatic or curative rather than preventive. It was concerted to exclude the criteria.
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Therapeutic benefit: Based on its definition, the nature of the clinical benefit provided for patient-level intervention (i.e, symptom relief, prolongation of the life, healing), the criterion was maintained in the framework. However, it will be redefined so that it captures the therapeutic benefit in a broad and far-reaching way, including aspects such as reduction of risk factors, reduction in disease transmission, etc.
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Non-medical costs: Although non-medical expenses are highly relevant to rare diseases, the lack of information and the difficulty to quantify them makes them difficult to consider. It was agreed to exclude the criteria.
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Budget Impact: Relevant criteria for drug assessment in PHF process. It was agreed to include the criteria to the domain “feasibility contextual criteria” (Contextual tool). Furthermore, its inclusion supports the exclusion of the criteria “size of the population”, which would be covered with the financial/budgeting exercise.
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Rarity: The concept of common disease, rare or ultra -rare, is closely related with the number of patients affected. To be consistent with the exclusion of “size of affected population” criteria it was agreed not to include this criterion.
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The rule of rescue: The criterion describes the perceived duty to save endangered life whenever possible although the drug is not indicated or cost-effective. It was agreed to exclude the criteria.
MCDA Core Model | |
Domains | Criteria |
Disease Impact | Disease severity |
Unmet needs | |
Comparative outcomes of orphan drugs | Improvement of efficacy/effectiveness |
Improvement of safety/ tolerability | |
Improvement of patient perceived health/PRO | |
Type of therapeutic benefit | |
Economic consequences of intervention | Annual patient cost of treatment |
Other medical costs | |
Knowledge about intervention | Quality of evidence |
Expert consensus/clinical practice guidelines | |
MCDA Contextual Tool | |
Domains | Criteria |
Normative contextual criteria | Population priorities and access (principle of equity) |
Common goal and specific interests | |
Feasibility contextual criteria | System capacity and appropriate use of orphan drugs |
Opportunity costs and affordability (budget impact) |
Weighting of orphan drugs framework (value system elicitation)
Case studies – appraisal of 3 orphan drugs
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Disease severity of the alpha – 1 antitrypsin deficiency was considered high, reflecting the perception of their impact on mortality and morbidity. Alpha – 1 antitrypsin was not considered to have an added value versus standard of care in regards to efficacy, safety and quality of life (QoL). Regarding the type of benefit, alpha – 1 antitrypsin was considered as not providing an added therapeutic benefit, considering improvements on clinical variables or imaging abnormalities. Comparative treatment cost and other medical costs were assessed with a neutral score. Related to its inclusion in the international guidelines and quality of evidence for alpha – 1 antitrypsin was considered moderate, because of uncertainty in the methodology and results of the clinical trial publication.
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Gaucher disease was considered a very severe disease reflecting a high estimated mortality and co-morbidities because of impairment of relevant organs such as liver, spleen, bone marrow and bones. Some enzyme replacement therapies have been approved for Gaucher disease: imiglucerase, velaglucerase and miglustat. Eliglustat is an oral treatment that was considered similar to the previously approved drugs in regards to the therapeutic efficacy, but with the advantage of oral route despite a worst safety profile, although possibly better than the other oral alternative miglustat. The QoL outcomes were seen as translating this fact in a benefit for the patients. Treatment cost per patient and other medical costs were assessed with slightly positive score to eliglustat. Quality of evidence was considered low. Eliglustat was not included in the spansish recommendation about Gaucher disease [11] management since by the time of the guideline publication eliglustat was not yet approved by the European Medicines Agency (EMA).
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Autosomal dominant polycystic kidney disease was perceived as a very severe disease with an unfavourable prognostic based on reduced survival of these patients, and the lack of effective alternatives. It was observed that the efficacy of tolvaptan was moderately better than placebo although it is accompanied with a worst safety profile. There was no published data related to QoL, for this reason the score was considered neutral. Regarding the type of benefit tolvaptan was judged to provide a moderate therapeutic benefit. Comparative treatment cost was assessed with a negative score to tolvaptan and other medical costs with neutral score given the lack of available evidence related to these criteria. Quality of evidence was considered very low due to the poor external validity or applicability. The ERA-EDTA (European Renal Association and European Dialysis and Transplant Association) recommended tolvaptan with some clinical criteria of use.