Orphan drug development and the impact on non-medical support groups.

The Orphan Drug legislation in the United States and later in the EU has had a significant impact on patients worldwide who suffer from an orphan condition. Apart from providing statutory encouragement and incentives to pharmaceutical companies to develop therapeutic products it has resulted in the encouragement of patients to come together to form patient bodies to advocate on behalf of patients. Starting in a modest way patient groups have gained experience in working with clinicians and scientists and representing their members to companies and to healthcare providers in national European and global environments. This article describes the history and evolution of the patient body and the coming together of national patient groups through umbrella organisations which have proven to be a powerful advocate for pan European and global collaboration and humanitarian aid. It also will review of some unintended consequences of the legislation.

Force majeure: therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease.

Gaucher disease is the first lysosomal disorder for which clinically effective enzyme replacement therapy has been introduced. Lifelong treatment with imiglucerase, the recombinant glucocerebrosidase manufactured by the Genzyme Corporation (MA, USA), is administered intravenously - usually at biweekly intervals. An acute shortage of imiglucerase (to 20% of prior global supply) has occurred as a result of viral contamination of the production facility; production was halted, and a full supply of imiglucerase is not anticipated until January 2010. An urgent meeting of physicians, researchers, and patients was convened through the agency of the European Working Group for Gaucher Disease; this was instigated by patients internationally represented by the European Gaucher Alliance. Here we present a position statement based on the findings of the group, with key recommendations about identification and monitoring of at-risk patients threatened by the abrupt withdrawal of treatment, the equitable distribution of residual imiglucerase - and access to alternative treatments including those that have completed phase III clinical trials but have not yet been licensed.

Compassionate use of orphan drugs.

BACKGROUND: EU regulation 726/2004 authorises manufacturers to provide drugs to patients on a temporary basis when marketing authorisation sought centrally for the entire EU is still pending. Individual Member States retain the right to approve and implement such 'compassionate use' programmes which companies will usually provide for free. Nevertheless some companies have opted not to partake in such programmes, in effect restricting access to drugs for patients in need. Here we survey the state of compassionate use programmes in the EU with particular reference to the rare disease field, and provide legal and ethical arguments to encourage their increased compassionate use in the EU and beyond. We contend that if enacted, these recommendations will be mutually beneficial to companies as well as patients. METHODS: Requests for information from the European Medicines Agency were made under the UK Freedom of Information Act 2000. Legal, ethical and economic/pragmatic analysis identified means by which provision of therapy in compassionate use programmes might be increased. RESULTS: More than 50 notifications of compassionate use programmes have been submitted to the EMA by Member States since 2006. About 40 % relate to orphan drugs. As there is a compulsory register of programmes but not of outcomes, their success is difficult to evaluate but, for example, the French programme expedited treatment for more than 20,000 (orphan and non-orphan) patients over a period of three years. CONCLUSION: Compelling self-interested, legal and ethical arguments can be mounted to encourage manufacturers to offer therapies on a compassionate use basis and these are often equally applicable to provision on a humanitarian aid basis. The EU's compassionate use programmes are instrumental in ensuring continuity of access to drugs until approval and reimbursement decisions are finalised. We propose the creation of a registry of drugs offered on a compassionate use basis; further transparency would allow such programmes to be evaluated and direct patients to sources of treatment.

The European Gaucher Alliance: a survey of member patient organisations' activities, healthcare environments and concerns.

BACKGROUND: The European Gaucher Alliance (EGA) was established in 1994 and constituted in 2008 as an umbrella group supporting patient organisations for Gaucher disease. Every two years, the EGA conducts a questionnaire survey of member associations to help develop its priorities and annual work programme. Results of the latest survey are presented. METHODS: Between June 2012 and April 2013, the 36 members and associate members of the EGA were asked to complete a questionnaire detailing membership numbers, disease specific treatments used by patients, means of access to treatment, availability of treatment centres and home infusions, sources of support for patients with Gaucher disease, patient organisations' activities, collaborations, funding sources and any issues of concern. Questionnaires completed in 2012 were revised in January 2013 and responses analysed between July and September 2013. RESULTS: Thirty three members returned data on one or more questions. Findings identified inequalities in access to treatment both within and between members' countries. Three of 27 countries, for which data were available, relied totally on humanitarian aid for treatment and 6% of untreated patients in 20 countries were untreated because of funding issues, a situation many feared would worsen with deteriorating economic climates. Access to treatment and reimbursement represented 45% of members' concerns, while 35% related to access to specialist treatment centres, home infusions and doctors with expertise in Gaucher disease. Member associations' main activities centred on patient support (59% of responses) and raising awareness of Gaucher disease and patients' needs amongst the medical community, government and healthcare decision makers and the general public (34% of responses). Twenty one (78% of respondents) indicated they were the only source of help for Gaucher disease patients in their country. For many, activities were constrained by funds; two members had no external funding source. Activities were maximised through collaboration with other patient organisations and umbrella organisations for rare diseases. CONCLUSION: The survey provided a 'snapshot' of the situation for patients and families affected by Gaucher disease, helping the EGA direct its activities into areas of greatest need.

The legal imperative for treating rare disorders.

BACKGROUND: Life-saving orphan drugs are some of the most expensive medicines. European Union governments aim to accommodate their provision within stretched healthcare budgets but face pressure to reduce funding of such treatments. Patients struggle to retain or gain access to them as their special status is questioned, causing distress and in some cases, fears of premature death. In the UK and EU reimbursement and pricing model of drugs, and orphan drugs in particular, is being re-evaluated. METHODS: Using the United Kingdom as a case study we present, for the first time, legal arguments which compel governments to provide orphan medicinal products. These include (i) disability legislation, (ii) national and organisational constitutions, (iii) judicial review, (iv) tort law and (v) human rights legislation. We then address directly potential objections to our analysis and counter arguments which aim to limit provision of orphan drugs to the intended patient recipients. RESULTS: We demonstrate that a compelling case can be made that the law demands the treatment of orphan diseases. CONCLUSIONS: Our legal framework will assist doctors and patients in ensuring the continued provision of treatments despite significant economic pressure to reduce funding. These legal avenues will empower stakeholders in drafting funding guidelines throughout the EU. The legal right to treatment extends beyond rare diseases and our analysis may therefore affect allocation of healthcare budgets throughout the EU.

Limitations of drug registries to evaluate orphan medicinal products for the treatment of lysosomal storage disorders.

Orphan drugs are often approved under exceptional circumstances, requiring submission of additional data on safety and effectiveness through registries. These registries are mainly focused on one drug only and data is frequently incomplete. Some registries also address phenotypic heterogeneity and natural history data and publications on these aspects have contributed to the knowledge and awareness of these rare diseases. However, for the assessment of long-term outcomes and for cost-effectiveness, the incompleteness and variable quality of the data raises concerns on the usefulness of these registries. The existing registries for orphan drug treatments for lysosomal storage disorders (LSD's) illustrate these limitations. LSD's are inherited disorders of lysosomal metabolism with a wide variety in clinical symptoms, ranging from severe life-threatening neurological disease to mild or even asymptomatic cases. Their prevalence is extremely low and thus data is scarce and scattered all over Europe. In the past few years, several enzyme replacement therapies and an oral substrate inhibitor have been developed which provide lifelong treatment of LSD's. For Fabry disease, two enzymes were authorized at the same time resulting in two different drug registries being required by the European Medicines Agency (EMA) to monitor effectiveness and safety. This has lead to patient data being divided between two separate registries which may have contributed to delays in the assessment of important outcomes. Three treatments (including a recently approved new enzyme) have now been authorized for Gaucher Disease and two other potential therapies are in the pipeline. Dividing up the data on Gaucher disease patients in to five separate registries benefits nobody. We argue that disease specific (rather than drug specific) registries, supervised by independent clinicians are urgently needed for the best long-term evaluation of treatments of these rare diseases.