Orphan devices: yesterday is history; tomorrow is mystery: towards a European orphan device directive?
© Dooms. 2016
Received: 1 November 2015
Accepted: 19 January 2016
Published: 3 March 2016
Regulatory and economic frameworks stimulated the research and development of orphan drugs, but very little has been done for devices necessary for the in-vivo diagnosis, prevention and treatment of life-threatening conditions with a low prevalence/incidence.
A general public consultation in Europe has shown a positive attitude towards an “orphan device” directive. The United States of America have a Humanitarian Use Device exemption, but Europe is still waiting for such a stimulating framework. Post-marketing surveillance (“materio-vigilance”) will be necessary for follow-up, patient-reported outcome measures (quality of life versus survival) needed and off-label use data available for patient-safety reasons.
The marketing period for devices is shorter than for medicinal products. Incentives are necessary to stimulate research and development of such “orphan devices” especially when surgical intervention is the only option.
Orphan devices are medical devices intended for the in-vivo diagnosis, prevention or treatment of a very rare life-threatening or chronically debilitating condition. Several institutions (for example, the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Australian Therapeutic Goods Administration (TGA)) have put in place regulatory and economic frameworks to facilitate the development of orphan drugs (118 authorized by EMA to date), but much needs to be done for similar medical devices, especially in Europe. Do we need an EU-directive for orphan devices?
During the twentieth century, several breakthroughs in surgery were achieved . For example, Alfred Blalock (1899–1964) developed a surgical procedure in 1944 to relieve the cyanosis in the Blue Baby Syndrome, a kidney was transplanted between identical twins in 1954, and a liver transplantation was performed in 1963 by Thomas Starzl (°1926). Numerous new techniques were developed such as direct blood transfusion by George Washington Crile (1864–1943) in 1905, amniocentesis in 1952 by Douglas Bevis (1919–1994), and diagnostic ultrasound by Ian Donald (1910–1987) in 1958.
The negative pressure ventilator (“Iron Lung”)
Stereotactic brain surgery
Orthopedic traction table
Operating theaters now have a large collection of sterile medical material to be implanted during surgical interventions such as neuro-stimulators, prostheses, heart valves, stents, osteosynthesis material and pacemakers. All this material is evaluated by “notified bodies” in every EU-Member State (Regulation 93/42/EEC from 14 JUNE 1993 concerning medical devices and Regulation 90/385/EEC concerning implantable active medical devices) and assigned a CE (Conformité Européenne) marking when approved. Different systems have also been used to evaluate post-marketing the efficacy and safety (“materio-vigilance”, Eudamed) of such devices. The use of a medical device outside the population or purpose for which the safety and effectiveness profile has been evaluated (off-label use) is quite common with low-prevalence diseases (mainly in children). To encourage the research into, and development of, medical material (“orphan devices”) for the in-vivo diagnosis, prevention and treatment of rare diseases we do need incentives such as a centralized European procedure and protocol assistance. This is of particular urgency because the marketing period for devices is shorter than for medicinal products: the risk on obtaining no return on investment for R & D on devices is real. The absence of incentives will become more important as we continue to enter the era of personalized medicine with the capabilities of bio-sensors, micro-fluidic tissue/organs on a micro-chip, artificial organs and diagnostic imaging instruments.
Actual opinions within EU member states
*The Association Internationale de la Mutualité thought there is neither enough information nor evidence to justify it.
*The European Social Insurance Platform mentioned that medical devices already on the market were not specific to “rare disease”.
*The UK National Health Service stated that they did not believe that there were sufficient problems in the development and commercial marketing of devices to justify the administrative effort and special privileges for orphan regulations.
*The Ministry of Health, The Elderly and Community Care in Malta felt that such a regulation would neither be necessary nor beneficial and that the current legal framework already provided stimulation for rare diseases.
*The Dutch Ministry of Public Health, Welfare and Sports, Drugs and Medical Technology considered a EU regulation in this matter not the right way forward as there are different reimbursement systems within the different EU Member States.
*Baxter Healthcare did not see any justification to introduce such legislation.
*The Finnish rare-disease patient organization replied to this question of the consultation that developing equipment and determining norms in the EU would help those countries who still have challenges to improve their national standards. The ability to improve the national standard was considered insufficient in many EU countries and the markets too small.
*The Swedish government agreed that there was a need to investigate the conditions required for developing incentive measures and legislation for orphan devices similar to orphan drugs, but they suggested a thorough analysis of the financial impact and possible rules should first take place.
*The UK Genetic Interest Group (patients) suggested that the burden of regulation should be kept to a minimum with a single European application.
Nevertheless, “orphan-device” legislation has yet to be introduced in Europe today  as we have for orphan medicinal products since 2000. Only some EU Member States have national rules (for Belgium: Royal Decrees 15 July 1997 and 18 March 1999) for medical devices (“dispositif à usage unique”).
In the United States of America a Humanitarian Use Device (HUD) [8, 9] is a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects or is manifested in fewer than 4000 individuals in the United States per year. The application (since 1990) must contain sufficient information for the FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury and that the probable benefit to health outweighs the risk of injury or illness from its use taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. Up to the present, 65 HUD’s have been approved by FDA, mostly implantable (programmable) therapeutic devices in pediatrics (pediatric devices) , cardiology (ventricular assist devices in congestive heart failure) , neurology (microelectrodes for neurostimulation), hematology (cryofilter for cryofiltration apheresis) , otorhinolaryngology (auditory brain stem implants) and orthopedics (craniosynostosis).
Custom made (active implantable) medical devices are devices that are made by special request (eventually 3D-printed) of a health professional intended to be used for a particular patient . Several agencies (UK, TGA, FDA)  have regulations in place to allow the use of these unique one-time devices foremost in unmet medical need situations. Technological changes, improvements and refinements provide a much shorter marketing period to obtain revenue to develop newer versions of the device.
Position: policy recommendation
A regulatory European framework with economic incentives needs to be installed to stimulate the research and development of orphan devices similar to the legislation around orphan drugs. Incentives are needed (as for orphan drugs) to enable useful medical devices to reach the patients and clinicians in a timely fashion. Collection and analysis of publicly accessible safety/efficacy data (EUDAMED: European Databank on Medical Devices) needs to be centralized between all EU Member States to reach a sufficient number of patients to perform comparative-(cost)effectiveness and –safety studies.
All pictures are taken from the archives of HistArUz, the Museum of the History of Medicine and Pharmacy at the University Hospitals Leuven, Belgium: http://www.uzleuven.be/histaruz.
I would like to thank the reviewers for their most stimulating comments.
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