Orphan drugs are therapeutic agents designed for the management of rare diseases. Working definitions of rare diseases vary widely across organizations around the world. In the USA, the Orphan Drug Act of 1983 established a definition for use by the US FDA based on a prevalence of not more than 200,000 individuals, which—taking into account the size of the US population—would represent approximately 1 in 1500 individuals . The EU’s definition, which was introduced through legislation in the year 2000, affects joint public health actions and regulatory submissions to the European Medicines Agency (EMA). It is somewhat lower, at not more than 5 per 10,000 (1 per 2000) individuals . In the EU, this legislation implies that the pharmaceutical industry can (1) obtain scientific advice on clinical trial protocols at a reduced charge, (2) gain access to the EMA centralized licensing procedure, (3) get reduced registration costs, and (4) benefit from 10 years of market exclusivity after registration . Japan considers diseases to be rare if they affect not more than 50,000 patients, or less than 1 in 2500 individuals given current population estimates. The 2015 report from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Rare Disease Special Interest Group , which provided an overview of rare disease definitions currently used globally, concluded that there was some global consistency in using the terms ‘rare disease’ and ‘orphan drug’ to describe the technology associated with the rare disease. Based on the results of their systematic literature review, they proposed that the terminology ‘rare disease’, coupled with a prevalence threshold in the range of 40–50 cases per 100,000 (1 in 2000–2500) individuals, could present a realistic starting point for a harmonised definition of rare disease.
Globally, the lack of an explicit definition used by regulatory processes to identify a boundary between rare and ‘ultra-rare’ diseases is noted. Many countries have established separate procedures for consideration of funding treatments for patient populations that are much smaller than the lower bounds of the standard population size eligible for an orphan drug . For example, the health technology assessment (HTA) agency in Italy considers a disease prevalence of 1 per 1,000,000 to represent an ultra-rare disease, whereas the UK National Institute for Health and Care Excellence (NICE) restricts entry into a separate assessment track named the Highly Specialized Technologies (HST) programme to diseases with a prevalence of not more than 1 per 50,000 individuals [5, 6].
Despite the commercial incentives made available to encourage orphan drug development and manufacture, the costs of orphan drugs are high. Factors that reportedly influence their price setting include research and development (R&D), costs, clinical effectiveness, drug quality and disease prevalence [7, 8]. However, the effectiveness of some orphan drugs has not been clearly demonstrated, and the evidence regarding their safety is often sparse at the time of regulatory approval . Furthermore, in the UK, for example, some funders of care under the NHS have refused to fund certain orphan drugs because they are not considered cost effective, thereby denying patients access to potentially useful drug interventions .
In Ireland, all new drugs are considered for HTA prior to a reimbursement decision by the health payer. All HTAs for pharmaceuticals are conducted by the National Centre for Pharmacoeconomics (NCPE). The NCPE evaluation process has been described previously . In short, the relevant applicant pharmaceutical company (‘the applicant’) submits a rapid review dossier to the NCPE. Each rapid review dossier submission pertains to one drug for one indication. The NCPE critically appraises all elements of the dossier. The outcome of the rapid review process (which is a 4-week process) is determined by uncertainty in either the clinical or the economic domains or a combination of both (e.g. lack of robust clinical evidence, no evidence of therapeutic benefit, potentially large budget impact). In doing so, the NCPE determines the requirement for a full HTA submission from the applicant. Where there is a recommendation for a full HTA to be submitted, a prescriptive critical appraisal process (which is a 90-day process) is followed, the outcome of which is an NCPE recommendation to the National Drugs Committee (i.e. the decision maker) on whether or not to reimburse the drug. Likewise, the National Drugs Committee (i.e. decision maker) of the Health Services Executive (HSE), in arriving at their decision, consider all of the criteria set out in the Health (Pricing and Supply of Medical Goods) Act 2013, including the extent of clinical benefit, cost effectiveness, budget impact and available resources. Confidential price negotiations can also take place, which are usually informed by the NCPE appraisal process . In the case of drugs for cancer, the National Cancer Control Programme (NCCP) Technology Review Committee also advises the National Drugs Committee on pertinent criteria, including clinical benefit, disease severity and unmet need.
HTAs, by definition, are tools that help decision making by systematically evaluating properties, effects and/or impacts of health technologies and interventions in order to inform policy, especially on how best to allocate limited funds to health interventions and technologies . In Ireland, the NCPE maintains transparency in the evaluation process and in doing so delivers an independent review of comparative effectiveness and cost effectiveness of the new drug. Summary reviews are available on the NCPE website, with full reviews available to decision makers and payers. Strategies (in the form of managed entry agreements) have been developed in recent years that have helped the decision maker reach a positive decision on financing drugs, for example, patient-access scheme (PAS) agreements. However, the impact of these reimbursement models for products for rare diseases is unknown.
The National Rare Diseases Plan for Ireland 2014–2018 was published in July 2014 . This was a policy framework for the prevention, detection and treatment of rare diseases based on the principles of high-quality care and equity and seeks to be patient focused. A number of recommendations about access to appropriate drugs and technologies were contained in the plan. One key recommendation was that the HSE develop a Rare Diseases Technology Review Committee (RD TRC) that could operate in the drug assessment system in a similar way to that for drugs for cancer established under the NCCP. This RD TRC has now been established.
The number of applicant submissions to the NCPE that pertain to orphan drugs has increased in recent years but has not been explicitly analysed. The aim of this study was to ascertain the number of submissions made to the NCPE that pertained to orphan drugs (from 2012 to 2017 inclusive) and to determine how these drugs proceeded through the NCPE critical evaluation process. In terms of the prevalence, a threshold of 5 cases per 10,000 individuals was used to define ‘orphan drugs’, and 1 case per 50,000 individuals was used to define ‘ultra-orphan drugs’ (informed by the EU definition and NICE, respectively), for the treatment of the indicated rare diseases. Drugs for cancer that also had EMA orphan designation were also included in the analysis. Thus, the aim was to analyse submissions received in three categories: orphan (non-cancer) drugs, orphan (cancer) drugs and ultra-orphan drugs. Specifically, the study was a retrospective analysis to
determine the number of drugs in each category submitted to NCPE from January 2012 to December 2017 inclusive,
determine how these drugs have proceeded through the NCPE evaluation processes and
compare the movement of these orphan drugs with non-orphan drugs in terms of proportions recommended for full HTA after going through the rapid review process.