Table 3. Legislations, Regulations and Policies for Orphan Drugs by Country.
| Country Covered (Reference) | Orphan Drug Legislation | National Plan for Orphan Drugs/Rare Diseases | Orphan Drug Designation | Independent Orphan Drug Market Authorization | Market Exclusivity | Financial Incentives (Country specific) | Non-Financial Incentives (Country Specific) | Pricing | Reimbursement 1. Procedures and/or coverage 2. HTA Criteria |
|---|---|---|---|---|---|---|---|---|---|
| Australia [3, 12–14] | Yes | No | Yes | Yes | No | Yes—Fee Reduction for Marketing Authorization Approval | Pre-licensing access, Regulatory Assistance | Fixed | 1. Reimbursement under Australia’s life-saving drug programme, 2. Cost-effectiveness (Under consideration of Australia’s Life-Saving Drug Programme) |
| Austria [10, 15] | Yes (EU) | No | Yes (EU) | Yes (EU) | EU– 10 Years | No | Free scientific advice, free protocol assistance | Reference Pricing | 1. Physicians entitled to prescribe medicines in the Austrian Reimbursement Code–Orphan Drugs often require prior approval 2. Cost-effectiveness |
| Belgium [10, 16–18] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU-10 Years | Tax exemptions | No | Price negotiations | 1. Reimbursement drug decisions Ministry of Social Affairs and committee of doctors for orphan medicinal products 2. Therapeutic advantage, Budget Impact, importance in clinical practice |
| Bulgaria [19–22] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU-10 years | No | Pre-licensing access | Reference Pricing | 1. Orphan drugs reimbursed by the MoH or NHIF. 2. Cost-effectiveness |
| Canada [1, 3, 13] | No | No | No | No (Accelerated Review is Possible) | No | Yes (tax incentives, fee reductions for marketing authorization) | Pre-licensing access scientific advice- protocol assistance and/or development consultation, regulatory assistance | Reference pricing (regional negotiation) | 1. 80% to 100% reimbursement provided by the Public Service Health Care Plan, with 100% after a drug’s costs after the patient has reached a co-payment threshold of $Can3000 in a calendar year for approved orphan drugs. 2. Cost effectiveness, safety, therapeutic advantage |
| China [23] | No | No | No | No | No | No | Yes- Ability to conduct smaller clinical trials or waive the trial if necessary | Free | 1. Self-funded by patients ‘out of pocket’ with assistance from NGO’s or patient foundations. Reimbursement determined by the National Reimbursement Drug List–Set by the NDRC, CFDA, Ministry of Human Resources & Social Security & the Ministry of Finance 2. Cost-effectiveness |
| Czech Republic [10, 21] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU- 10 Years | No | None | Fixed (Maximum reimbursed price set at 70–99% of the public price including taxes (PPIT)) | 1. 100% coverage for positively reimbursed orphan drugs. Also includes a special reimbursement regime. Regulated by Health Insurance and a Medical Professional 2. Cost effectiveness |
| Denmark [10, 24] | Yes (EU) | No | Yes (EU) | Yes (EU) | EU- 10 Years | No | Scientific advice, free protocol assistance, pre-licensing access | Free | 1. 100% of approved orphan drugs at hospitals, needs based co-payments for pharmacy prescription 2. Cost- effectiveness |
| Estonia [10, 25] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU– 10 Years | No | No | Free (No policy) | 1. 50–100% reimbursement by the Estonia Health Insurance Fund 2. Therapeutic Advantage |
| Finland [10, 25] | Yes (EU) | No | Yes (EU) | Yes (EU) | EU– 10 Years | No | Free administrative/ scientific (protocol) advice | Free–With justification | 1. Basic reimbursement of 35%, with 65%–100% for certain diseases or conditions. 2. Cost-effectiveness |
| France [3, 4, 16] | Yes (EU) | Yes | Yes (EU) | Yes (Intra-national and EU) | EU– 10 Years | Tax exemptions | Pre-licensing access, scientific advice, free protocol assistance | Price negotiations | 1. 65% to 100% for reimbursed orphan drugs–Complementary health insurance often completes reimbursement 2. Therapeutic advantage, unmet need, socio-economic benefits |
| Germany [3, 4, 26] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU– 10 Years | No | Pre-licensing access | Free–Under criteria | 1. Automatically reimbursed, based upon a cost benefit analysis by IQWiG (if successful) if no therapeutic alternative–Co-payment of €10 per drug, limited to an annual threshold of 2% of individual yearly net income. 2. Cost-effectiveness |
| Greece [20, 27] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU– 10 Years | No | Pre-licensing access (compassionate use) | Reference pricing | 1. Reimbursement by the public insurance system for orphan drugs on the reimbursement list–Patient must pay 50% of cost in excess of the reference price. 2. Cost effectiveness |
| Hungary [3, 10, 21] | Yes (EU) | No | Yes (EU) | Yes (EU) | EU– 10 Years | No | Pre-licensing access | Free (No policy) | 1. Reimbursement under legal special equity procedure 2. Specialised HTA for orphan drugs |
| India [28] | No | No | No | No | No | No | No | Fixed | 1. Predominately self-funded (for orphan medicines)–Patient foundations, NGO’s utilised for funding assistance 2. Cost-effectiveness, clinical efficacy |
| Ireland [10] | Yes | No | Yes (EU) | Yes (EU) | EU– 10 Years | No | No | Fixed–Decisions made by the corporate pharmaceutical unit in the Health Service Executive | 1. Differential—Community and national high tech drug schemes 2. Cost-effectiveness |
| Israel [13] | No (Orphan drug Government offices established) | No | No | No | No | No | Pre-licensing access (compassionate, off-label use) | Free (No policy) | 1. Reimbursement for drugs in the Israeli ‘basket of services’ 2. Cost-effectiveness, Social, Ethical, Legal Implications |
| Italy [1, 4, 10, 16, 26, 29, 30] | Yes (EU) | Yes (draft) | Yes (EU) | Yes (EU) | EU -10 Years | No | Pre-licensing access, scientific advice, free protocol assistance | Price negotiations (Reference Pricing) | 1. Reimbursement (licensed orphan drugs), through a standard pricing/reimbursement process, Law 658 and 5% AIFA special fund) 2. Cost-effectiveness, budget impact, need, existing therapies |
| Japan [1, 12, 23, 29, 31, 32] | Yes | No | Yes | Yes | 10 Years | YesFinancial subsides, tax credits, corporate tax reductions, user fee waivers | Priority review, fast track approval, free protocol assistance | Fixed–Cost plus 10% | 1. 100% (30% from insurance companies, 70% from national/ regional governments) for approved orphan drugs 2. Cost effectiveness |
| Latvia [10, 33, 34] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU- 10 years | No | Scientific advice, free protocol assistance) | Free (No policy) | 1. 100% for orphan drugs on the reimbursement list or individual reimbursement for up to €14,229. 2. Cost effectiveness, Therapeutic advantage |
| Macedonia [27] | No | Yes | No | No | No | Fee reduction | Shorter registration period | Reference Pricing | 1. Reimbursement by public funds based on HTA (Macedonian or reference based) 2. Cost-effectiveness |
| Poland [3, 21, 26] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU– 10 Years | No | Pre-licensing access | Reference Pricing–With review by the Minister of Health | 1. Reimbursement of 100% if successful, conducted with HTA and comprehensive data, price data in other EU countries, also reimbursed through therapeutic programmes. 2. Cost-effectiveness, Therapeutic advantage |
| Portugal [24] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU- 10 Years | No | No | Free (No Policy) | 1. NHS reimbursement scheme–All citizens covered for positive drug decisions (on national reimbursement list) 2. Cost-effectiveness |
| Romania [20, 21, 27] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU- 10 Years | No | No | Free (no policy) | 1. National Programme for Rare Diseases provides reimbursement for orphan drugs on application. 2. Cost-effectiveness |
| Serbia [22] | No | Yes | No | No (Accelerated Review/Access is Possible) | No | No | No | Reference Pricing | 1. Positive reimbursement list dictates drug payments–by the patient or public funds. 2. Cost effectiveness, Therapeutic advantage |
| Singapore [1, 35] | Yes | No | Yes, but, Doctor or Dentist designates orphan diseases | Yes (Legislation enables the importation of orphan drugs for a specific rare disease, top registration priority) | 10 Years | No | No | Free–Orphan drug legislation has yet to be ‘activated’ | 1. Reimbursement decisions made by the Centre for Drug Administration (CDA)–Aims to simplify and streamline evaluation of pharmaceuticals in Singapore 2. Cost-effectiveness |
| Slovakia [3, 10, 21] | Yes (EU) | No | Yes (EU) | Yes (EU) | EU– 10 Years | No | Pre-licensing access | Free (No policy) | 1. All authorized orphan drugs reimbursed with a €0.16 co-payment per package 2. Cost effectiveness, Therapeutic advantage |
| Spain [4, 26] | Yes(EU) | Yes | Yes(EU) | Yes (EU) | EU- 10 years | Reduced rebates | Pre-licensing access | Fixed (Cost plus system) | 1. 100% if reimbursement status is approved 2. Therapeutic advantage |
| Sweden [4, 10, 16, 36] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU -10 Years | No | No | Free | 1. Reimbursement conducted by public social insurance. If the total cost exceeds 4300 SEK the patient will receive the medicines free of charge 2. Cost-effectiveness, Human value, Solidarity |
| Switzerland [3] | No | No | Yes | No | No | Tax exemptions | Pre-licensing access (off-label, compassionate use) | Free (No policy) | 1. Public reimbursement after a deductible and 10% co-payment (annual co-payment threshold of $646 USD). 2. Cost-effectiveness, Human value, Solidarity |
| The Netherlands [3, 4, 15, 16, 18, 37] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU– 10 years | Registration fee waivers | Pre-licensing access | Price negotiations | 1.100% reimbursement for approved orphan drugs. The Dutch Policy Rule for Expensive Hospital and Orphan Drugs supports hospitals financially for prescribing orphan drugs. 2. Cost effectiveness–Dispensation from submitting evidence regarding orphan drugs (lack of evidence) |
| Taiwan [1, 35] | Yes | No | Yes | Yes | 10 Years + 2 Years | Grants, Fee Reductions + Others determined by the central competent authority | Regulatory Assistance | Price Negotiations | 1. 70% to 100% (for low income families) reimbursement for orphan drugs for rare diseases classified under the Rare Disease Prevention and Medicine Law by the Department of Health/ Bureau of National Health Insurance 2. Cost-effectiveness, clinical efficacy. If approved by US FDA, no clinical trials are required |
| Turkey [38] | No | No | No | No | No | No | Pre-licensing access | Reference pricing | 1. Reimbursement for all orphan drugs successful in entering the market, regardless of licensing. 2. Clinical Efficacy–Orphan Drugs exempt from pharma-economic analysis |
| United Kingdom [4, 10, 16, 30, 39] | Yes (EU) | Yes | Yes (EU) | Yes (EU) | EU- 10 Years | No | Ongoing debate on pre-licensing access | Fixed–With approval by the Department of Health and rate of return limits imposed by the Pharmaceutical Price Regulation Scheme (PPRS) | 1. Reimbursement for approved orphan drugs if incremental cost-effectiveness (ICER) criterion is met. The National Cancer Drug Fund from the National Health Services funds some orphan drugs in the United Kingdom. 2. Incremental cost-effectiveness ratio (ICER) (based on a threshold varying between £20,000 and £30,000 per quality adjusted life year (QALY)–Can be higher for orphan drugs. |
| United States [1, 3, 23, 31, 40, 41] | Yes | No | Yes | Yes–Fast Track / Priority Review, Accelerated Approval, ‘Breakthrough’ | 7 Years | Yes (50% tax credits, FDA fee waivers, grants programme) | Scientific advice, protocol assistance, pre-licensing access | Free | 1. 95% under Medicare–approved health plans, subject to prior authorization for reimbursement and after total “out of pocket” costs have exceeded $4350 USD. 2. Cost effectiveness–No systematic HTA conducted by US payers for Orphan Drugs |
HTA, Health Technology Assessment; MOH, Ministry of Health; NHIF, National Health Insurance Fund; FDA, Federal Drug Administration; IQWiG, Institute for Quality and Efficiency in Health Care
N.B. Countries included within the EU have access to an overall range of incentives offered in over-arching EU legislation for medicines that have been granted an orphan designation by the European Commission including: fees reduction for protocol assistance, marketing authorization application (and the potential for accelerated applications), inspections, annual fees and products utilising the centralised procedure as well as access to free scientific advice regarding marketing authorization and clinical trials.
Cost-effectiveness HTA criteria in decision making includes the importance of clinical efficacy.