The 2007 EPPOSI Workshop Tackles the Reality of Orphan Medicines
The eighth European Platform for Patients' Organisations, Science and Industry (EPPOSI) workshop opened at the Danish Parliament in Copenhagen on 18 October with an ambitious agenda for addressing this year's topic, The Reality of Orphan Medicines.
Over 120 rare disease stakeholders attended the two-day event, which included the special presence of HRH Crown Princess Mary of Denmark on the opening day. Alastair Kent (GIG/EGAN) launched the workshop with a pertinent reminder that patients have no choice over their disease. He evoked two major themes in need of examination: Health Technology Assessment (HTA) and Prevalence. EPPOSI offers a unique and vital opportunity to gather together the various rare disease (RD) players with all the special skills, expertise and knowledge they possess. Birthe B. Holm (COMP/EURORDIS/Rare Disorders Denmark) continued the opening remarks by targeting the topic of orphan drugs (ODs) reaching patients within the legal timeframe delineated by EU-level legislation as an issue in urgent need of examination. Torben Gronneb�k (Rare Disorders Denmark/EURORDIS) concluded the workshop opening by listing four criteria necessary to ensure RD patients a decent quality of life: prompt diagnosis; treatment permitting physical independence; socialisation (schooling, respite care); and coping strategies.
The first workshop session, chaired by Alastair Kent and Andrea Rappagliosi (Merck-Serono) addressed a sometimes thorny topic: How to estimate the value of an orphan drug. In his introductory comments, A. Rappagliosi defined HTA as a tool that could help society better appreciate the value of ODs, and referred to European project EunetHTA's definition of HTAA: A multidisciplinary process that summarises information about the medical, social, economic and ethical issues related to the use of a health technology in a systematic, transparent, unbiased, robust manner.
Christine Lavery (MPS Society/EURORDIS) presented The patient's view on health technology assessment for Orphan Medicines, using the powerful example of MPS diseases, a group of lysosomal storage disorders that need early diagnosis. Although treatments became available in recent years for some of these diseases (ERT for Fabry disease in 2001 and for MPS I in 2003), they were not always accessible to patients due to the restrictive use of HTA by some of the local agencies in charge of funding. A combination of lobbying and legal action resulted in the treatments becoming available from April 2005 via national specialised commissioning in England, but not in Scotland or Wales. The model that is used in England to regulate access to ODs includes strict diagnosis criteria, centres of excellence, registries, treatment guidelines and post-marketing follow up, and may be adaptable to other regions or disease areas.
Finn Borlum Kristensen (Natl Board of Health, Danish Center for Evaluation and EUnetHTA, a large EU project on HTA) next presented: Is HTA an appropriate tool to promote access to Orphan Drugs? The aim of HTA is to inform the formulation of safe, effective, health policies that are patient focused and seek to achieve best value. HTA does not mandate policy. The seventh work package of EU project EUnetHTA (European Network for Health Technology Assessment) is dedicated to monitoring the development of emerging/new technologies and is particularly relevant to ODs. EUnetHTA has 59 partners in 22 EU countries and was created to avoid duplication. HTA monitoring is needed during the developmental, experimental, and real-life stages of product development. Trans-national HTA collaboration does not interfere with national competences for healthcare organisation.
The next session explored OD access in a real-life setting by examining three member state (MS) countries:
Francois Meyer, (HAS) described OD access in France. The French system was held up on numerous occasions throughout the workshop as a model. France has a mechanism (Temporary Utilisation Attribution or ATU) that grants temporary medicine authorisation for severe diseases that have no approved alternative. Over 20 of the first 35 market authorised (MA) OD products were granted ATU availability by the French medicines agency before they received MA and 28/28 ODs evaluated were granted reimbursement.
Wim Goettsch (CVZ) described OD access in the Netherlands, a country that has an independent body serving as a sort of "gate keeper" for the health system. The Netherlands operates "intramural funding". There are currently five hospital-administered ODs for very rare diseases that are all fully reimbursed. In determining added-value, an important determinant to consider is the eventual cost-saving that treatment permits via reduced hospitalisations, for example.
Edmund Jessop (NHS) emphasised three conditions necessary for the UK system to function: very rare diseases need a "separate box"; pricing must be fair; and a moral perspective must be included - public acceptance has value. He queried the rationale behind the pricing of a monoclonal antibody (MAB) product in the UK that is ten times greater in price than other MABs. He called for increased transparency regarding price determination for ODs.
Jens Grueger (Novartis) next presented an industry experience via a case study involving orphan drug Glivec (imatinib). It was uncertain whether HTA could be applied. Could it capture all the dimensions of value of OD drugs, some of which are difficult to quantify?
Cees Smit (Dutch Genetic Alliance/VSOP) rounded out the afternoon presentations with a perspective of the patient's view, providing a qualitative example of how to estimate the value of an orphan drug through a 2001 survey of over 1000 haemophilia patients. Quality of life components were compared from 1972 to 2001, including time spent in hospital, absenteeism from school/work, inability to work, and life expectancy. The results were dramatically improved post-treatment. This survey could serve as a model for RDs, but required long term follow-up (~20 years) for which it is difficult to find funding. The average cost of all haemophilia treatments (averaging severe and less-severe cases) comes to about 37 000 euros per year. Evidence-based medicine and QALY (quality life-adjusted years) instruments are becoming more economic-focused but overlook certain aspects, such as long-term loss of professional life for a parent caring for a sick child, resulting in lost tax income for the state. Although EU citizens value healthcare and the EU wants to stimulate OD development, many MS have budget problems. This must be resolved.
The ensuing discussion period brought up whether industry was sufficiently transparent, whether development costs are directly linked to patient population size, and the role of biomarkers. As scientific advances in disease understanding and drug development make the unimaginable become imaginable, patient expectations are growing. But budgets have ceilings. Fair, robust, and transparent decision making is needed.
Participants awoke to crisp autumn Copenhagen sunshine on the second day of the EPPOSI workshop. The morning session was entitled, How many orphan drugs - for how many patients?
The recent successes in OD development have created fear in those holding the purse strings. The spectre of a multitude of ODs, each rare and costly, is worrying to Member States hampered by limited budgets. This session thus sought to find strategies to forecast numbers that could possibly reassure MS.
S�gol�ne Aym� (INSERM/Orphanet) discussed the possibility of a forecast for ODs using epidemiology data. Although prevalence is difficult to determine, figures are essential to present to policy makers. How many RDs depends on what is meant by disease. The World Health Organization defines a disease as a recognisable pattern of signs and symptoms. To date, there are some 5200 distinct phenotypes listed in Orphanet. Five to six new syndromes are described in the literature each month. Using a range of 6000 diseases, how many patients does this mean? A literature survey of 2343 diseases found 1642 stated prevalence. The majority had low prevalence and could be considered ultra-rare. However, most scientists are not epidemiologists and this data source is considered weak. Prevalence is often confused with incidence or life-long incidence. The majority of RDs is due to developmental defects for which there is currently not much pharmacological treatment potential, although other elements to alleviate suffering certainly exist. Registries are a rich source for determining prevalence. An example of this comes from Veneto, Italy, where patients must register to obtain reimbursement. Not all RDs are included in the registry, however, nor do all RD patients register. The prevalence rate of 3.5% that literature yields is overestimated, while the registry rate of 1% is underestimated. The number of treatable patients can be determined by taking the number of designated products (distributed by disease category), and comparing it with the prevalence of patients in corresponding categories. This equation reveals that the patients who would potentially need treatment represent 1.6% of the European population - if all the designated products make it to market. However, these patients are not identified and therefore the number of treated patients would be even lower in reality.
Fabrizia Bignami (EURORDIS) presented a Forecast of Orphan Drugs: perspective from modelisation based on US data (because it has long-term hindsight) of 1711 designations and of 306 potential marketing authorisations. Extending this model to European product development, applying a designation rate of 80 per year, a 16% MA success rate, and a three-year developmental period yields a forecast of 90 medicinal products in five years, including the currently approved 40. This model does not indicate disease group, product type, or other specifics.
Tan Nguyen (FDA) spoke on the Forecast of Orphan Drugs from the FDA perspective. Of 200 designation applications for 2007, approximately 70% are granted; those that are not usually have issues pertaining to prevalence, subsetting or lack of scientific rationale. In the US, an average of 14 ODs are authorised each year. 70% of these are chemical products, versus 30% biologics. There is a higher number of biologics developed in Europe. In the US, the median time from designation to authorisation is 2.8 years for chemicals and 4.1 years for biologics. Infectious/parasitic products have the shortest developmental time-span (1-2 years) and nervous system/perinatal products have the longest (over 5 years). Other US statistics include: the number of RD treated is 186+/-. 30% of these have more than one product; 70% have only one. 16% of authorised products (almost 50 products) are for paediatric diseases and conditions. 88% of authorised ODs have a treatment indication; 9% are preventive - a group that is decreasing significantly; and 3% are diagnostic products. Multinational sponsorship is increasing. The median prevalence is 28 000 patients in the US. Of new molecular entities, 38% are OD. More companies are targeting malignancies. Japan has the shortest median time from designation to market.
Paolo Tomasi (EMEA) next presented a Forecast of Orphan Drugs from the EMEA perspective. He reminded the participants that an orphan designation is competitive, i.e. more than one sponsor can obtain designation for the same product and the same condition. An orphan indication may often be broader than the therapeutic indication. The number of withdrawals from the designation/authorisation process is decreasing. Approximately 30% of applications are coming from SMEs. 46% of OD applications in 2006 were for oncological conditions, followed by muscular/skeletal disorders. Sponsors seem to estimate a longer time to MA than the reality shows, but this may reflect a bias in data collection. One factor linked to successful MA is having previously received a MA for another product. Chemical products are easier for sponsors than biologics. In summation, although the road to MA is difficult, approximately two-thirds of MA applications for orphan drugs receive a positive opinion by the CHMP. According to several mathematical models based on the current trend, an increased number of applications for orphan designation, and an increased number of marketing authorisation applications for orphan-designated products can be expected. The magnitude of the increase is difficult ro predict however, as too many factors are involved. Thus the possibility of a smaller increase or a stabilization of the number of applications and authorisations cannot be excluded.
Geoff McDonough (Genzyme) was the last speaker of the morning with an industry perspective on OD forecast. Genzyme has several RD registries, considered the property of the patients and treating physicians. When contemplating product development, it is important to remember that life-changing therapies carry a global, lifelong responsibility. Determining the number of patients for a disease includes a consideration of theoretical prevalence, actual prevalence, diagnosed patients, and treatment-eligible patients, each time diminishing the number involved. For diseases such as lysosomal storage disorders, which Genzyme treats, prevalence models can only provide "guestimates". Newborn screening is the only way to accurately understand prevalence. Taiwan has completed a pilot screening with some 135 000 subjects, from which 4 cases emerged. It is difficult to leverage prior experience for RDs, due to their complexity.
The ensuing discussion period raised several points:
In the conclusion to the morning session, it was noted that forecasts must include costs. OD costs are not additive and budgets must be calculated to reflect this.
The final workshop session, How to communicate about orphan drugs in the real life setting? was chaired by Terkel Andersen (Haemophilia Denmark/EURORDIS) and Bert Leufkens (Dutch Steering Committee on Orphan Drugs).
Yann Le Cam (EURORDIS) presented Patient Access to Orphan Drugs in the EU: a EURORDIS survey. This survey reviewed the availability of 22 ODs in 28 European countries. Sources included MA holders, COMP, NCAs direct contacts and patient groups. Despite current legislation that requires OD availability within 180 days after MA, several countries surveyed have few or even zero of the ODs accessible. Some general reflections this survey fostered: It is harder for RD patients in smaller countries. In general, the rarer the disease, the higher the price of the product. Lack of transparency is a problem - why are some companies reluctant to divulge information concerning product distribution?
B. Leufkens discussed Orphan Drugs today: what are the communication challenges? Evoking the history of the seven previous EPPOSI workshop topics, he defined three phases of OD development, the current one being tinged with scepticism due to issues of cost and bottlenecks. He referred to a recent news article appearing in the Economist that explored the end of the blockbuster model, a trend that will be helpful to OD development, factoring in better phenotyping, disease characterisation, personalised medicine and political pressure. Communicating the true value of registries is needed so they are not viewed sceptically as marketing gadgets that invade privacy.
Erik Tambuyzer (EBE/Genzyme Europe) presented Industry's communication about orphan drugs. Industry is heterogeneous. It is difficult to offer a unified voice. There are many misconceptions concerning industry: it is too profit-oriented; only positive trial results are communicated; patents are over-protected. These views can be challenged by other perspectives: industry innovates for unmet needs; industry is a major source of healthcare products. Models of success generate interest in the field. Market exclusivity does not equate monopoly. The "spirit" of OD legislation is important to keep in mind. Rare diseases are part of the continuum from common diseases. Complexity of development increases with rarity. Shareholder expectations play a significant role. Financial sustainability is important for industry, but also for patients. Discussion between stakeholders is invaluable. Controversial issues will not just disappear, but need to be addressed head on. It is important to engage personally.
Some important points were raised during the following discussion period:
As the workshop drew to a close, Birthe B. Holm offered the final words. She focused on a few conclusions harvested from each of the three sessions:
HTA is an important tool that must be put into the context of each country. HTA alone is not sufficient for decision making.
Improved data is needed for decision making. The data presented at this workshop need publishing.
Communication is needed to fill gaps. Should a united European HTA be developed?
Finally, a recipe for success was offered. The ingredients include:
While this year's workshop addressed many outstanding questions, it has ironically produced even more. B. Holm left the participants with two: Will society one day believe it can no longer afford Orphan Drugs?
How can the tremendous display of willingness witnessed during the last two days be translated into action?
The Eighth EPPOSI workshop served immediately to fulfil one of the "ingredients" listed in B. Holm's recipe: Due in no small part to the gracious presence of HRH Crown Princess Mary, two newspaper articles concerning rare disease patients appeared Friday in the Danish press.
Thus, an immediate benefit of the EPPOSI workshop: A public already better informed of rare disease issues in at least one European country. The next EPPOSI workshop will take place in Paris in October 2008.