The survey characterizes who the inquirers were, why they were contacting the helplines, about which diseases, and which responses they received; a total of 13 data were collected for each call, email, or other. Interoperability was ensured by using the ORPHA codes to share information on the diseases for which inquirers contact the helplines [16]. ORPHA codes refer to the Orphanet classification of diseases.

For the survey, all helplines were supplied with the same standardized form to fill in with their data. All fields had been agreed and tested. All helplines filled in the survey based on the totality of inquiries received in November 2012. Data from the whole survey are presented here. Details on the types of data collected ar found in Multimedia Appendix 1.

Demonstration of compliance with national legislation on data privacy protection was mandatory to become a full network member. Helplines applying to the network documented their registration to the national regulatory authority in writing.

As this survey was a descriptive and anonymized analysis of the inquiries received, it was not necessary to seek prior authorization from an ethics committee. Data identifying the participating individuals were not shared. Demographic data used in this analysis only included age range (and not the exact date of birth), gender, category, and region of residence. None of the demographic data collected could lead to an inquirer’s identification.

Each helpline was responsible for its own funding; some benefited from public grants or donations but their funding was often fragile and their sustainability was challenged.

Various operating modes could be observed among these helplines according to their specific characteristics (information for the Danish helpline VISO [National Organization for Knowledge and Specialist Consultancy] was excluded as its administrative status was changing): nature, composition, mode of operation, cost structure, and scope.

Nature was defined as being governed by a patient-driven organization (seven helplines) or by health care professionals/government organization. Helplines governed by health care professionals or by the government were grouped together as they represented four helplines (governed means the administration of the service from the legal point of view; not known for the Danish helpline). Composition referred to the type of respondents who could be either paid staff only (7/12, 58%), by volunteers only, or by a mix of volunteers and paid staff (4/12, 33%; not known for the Danish helpline). Regarding the mode of operation, there was no mutually exclusive mode of operation, as all helplines except one received inquiries both by telephone and by emails. However, some were contacted by phone for one-half or more of their inquiries (6/12, 50%), others were more often contacted by email (6/12, 50%), depending on how helplines advertise their telephone number or email address, and on the inquirers’ choice. The cost structure showed that nine helplines charged a local call or full call to phone inquirers, two were offering free of charge call service (not shown; not known for the Danish helpline). The scope pointed out that nine helplines were providing information on all rare diseases, three focused on one rare disease, or a group of rare diseases (congenital anemia, neuromuscular disorders, and myasthenia gravis). Other characteristics were not considered for this analysis (hours of operation, resources for service awareness campaigns, date of creation, etc).

Possible responses were agreed upon by helplines prior to the survey. These responses are outlined in Textbox 1.

A total of 1676 inquiries were received during November 2012, ranging from 3 to 389 per helpline (average 139.7; 95% CI 66.0-213.3). During this period, 51 respondents (paid staff or volunteers) answered the inquiries, for an average of 33.9 inquiries per respondent, ranging from 1.5 to 97.3 (95% CI 13.5-52.2). This represented a large diversity between helplines and can be explained partially by the age of the helpline, by their respective advertisement resources to make the service known to their respective publics. Information on the existence of the helpline was found on the Internet (317/1169, 27.12%; 95% CI 24.6-29.7), through health care professionals (284/1169, 24.29%; 95% CI 21.8-26.8), media (182/1169, 15.57%; 95% CI 13.5-17.7), or other means (including patients’ organizations 127/1169, 10.86%; 95% CI 9.1-12.7; Table 1). Telephone and emails represented 95.29% (1597/1676; 95% CI 94.3-96.3) of methods used to contact a helpline, and the telephone was the most frequent (988/1676, 58.95%, 95% CI 56.6-61.3; Table 2).

There were a total of 1426 inquiries on the various diseases from all helplines. From these inquiries, 37.66% (537/1426) discussed distinct diseases or groups of diseases. When the disease was identified and coded, the largest class of rare diseases inquired for was cognitive/neurological disorders (535/1426, 37.52%), followed by musculoskeletal disorders (148/1426, 10.39%), reflecting the presence of two helplines specialized in neuromuscular diseases (Association Française contre les Myopathies-Téléthon [AFM-Telethon] and Myasthenia Gravis Romania), as shown in Table 1.

Among these 537 diseases, 95 (17.7%) were very rare diseases with less than 4500 patients in the European Union and the prevalence was unknown for 37.1% (199/537) of them, indicating very little information available. The threshold of 4500 patients corresponds to a disease prevalence of 1 in 100,000 inhabitants in the European Union. A significant number of diseases (49/537, 9.1%) were not rare diseases (prevalence >5/10,000 inhabitants in the European Union or >250,000 cases in the European Union; Table 3). In such a case, most of the helplines could still respond to the inquirer.

Globally, the number of enquiries by respondent was manageable (average 32.9, ranging from 1.5 to 97.3; 95% CI 13.5-52.2). No helpline was saturated (however, not all respondents were working full time to respond to inquiries). The duration of inquiries was on average 23 minutes (median 15; 95% CI 9.3-36.4) and the distribution is shown in Table 4. Inquiries needing more than 20 minutes represented 41.54% (604/1454) of all inquiries. There were 537 different rare diseases discussed, a majority of which are very rare and with very little information available.

Table 9 shows that the number of male inquirers who used telephone were slightly higher than those who used email, although this difference was not statistically significant. There were 28.3% (280/988, [95% CI 23.1-33.6]) males who preferred the telephone compared with 25.2% (153/607, [95% CI 18.3-32.1]) who would have rather used email.

For inquiries about information on a disease, specialists or experts, contact with other patients, and for social care, we analyzed the exact match between the request and the response given calculated as the proportion between the purpose of the inquiry and the relevant response given. For 1574 inquiries about information, specialists, contact with other patients, social care, or exemption, a response could be given to 1173 for a satisfaction rate of 74.52% (1173/1574; Table 10).

When the purpose of the inquiry was to obtain information on the disease, 68.1% (464/681) of responses contained information on the disease. For the remaining requests for information, 28.3% (193/681) the respondents could redirect the inquirer to a more specific information source (Table 10).

When the purpose of the inquiry was to identify a specialist/expert, 62.1% (251/404) of inquiries were satisfied, and when the purpose was to establish contact with another patient, 44% (34/77) were satisfied. When the purpose was to obtain information on social care, 45.4% (109/240) of the inquiries were satisfied. Lastly, when the purpose was to obtain information on exemption for full coverage of care expenses, 55.2% (95/172) of inquiries were satisfied (Table 10). Of note, when the response given did not exactly match the question, helplines could redirect the inquirer to another service or source of information in most cases.

The issue of information is crucial, especially when dealing with rare diseases. In this field, the need for reliable and validated information is equally strongly perceived by patients, their relatives, and health professionals. To the best of our knowledge, this is the first study focusing on the activity measurement of a network of helplines active in rare diseases. Even if individual helplines conduct their own activity and satisfaction surveys, these surveys are rarely published.

The 12 participating helplines diverge in their nature, composition, operation mode, and scope. Some are managed by patients’ organizations, others by health care professionals or governmental organizations; some employ paid staff only, others volunteers only, and others a mix of paid staff and volunteers; some operate mostly by telephone, others mostly by email; some are addressing all rare diseases, and others a single or a group of rare diseases. One question was to explore whether this was reflected in the category of inquirers, in the type of questions helplines receive, in the type of answers they provide, in the duration of calls/emails, or in the diseases inquired. In other words, whether the service differed given the type of helpline. Overall, despite some differences, these factors do not influence significantly the service provided by the helplines. They may differ greatly in terms of structure, governance, composition, or specificity, but the service provided to the inquirers is of same quality.

By providing quantitative information across a range of important variables, our survey showed that these helplines, although different in language and location, can work together and collaborate. They can exchange data that document on their overall activity, and focus where the needs are. A priority is to provide information on very rare diseases, to help patients identify a specialist or a specialized center, or to address social issues. These findings are consistent with the results of the EurordisCare3 survey conducted in 16 European countries, which documented difficulties in accessing specialized centers for rare diseases, and the need for more information on social services [17].

For the collection of information on the diseases inquired, it was important to implement the use of Orpha Codes by all helplines. An Orpha code is unique identifying number assigned by Orphanet to a given disease or a group of diseases. Orphanet is the reference portal for information on rare diseases and orphan drugs, for all audiences [16]. Compared with the Call Profile Analysis conducted in 2009 and 2011, 10 of 12 helplines used the Orpha codes in 2012, compared with 7 of 11 helplines in 2011 and to 3 of 8 in 2009, ensuring more complete information on the diseases. A large part of the inquiries related to rare neurological/cognitive disorders (536/1445, 37.09%). The need for information on these disorders has been reported [18] and reflects their considerable burden on patients and families.

The telephone was the most frequent method used to contact a helpline (988/1676, 58.95%). This was also the case in previous Caller Profile Analysis performed in 2011 and 2009 (not shown), and this figure is stable. We showed the comparison between telephone and emails, and both methods will continue to co-exist; despite the increasing use of the new technologies as sources of health-related information [19,20], people still value and consult more traditional information sources [21,22]. This seems to be the case also for rare diseases. The method for contacting the helpline service (telephone vs email) did not differ by inquirers’ category, except for patients who tended to use the telephone more and for students who tended to use the email more. A confounding factor could be the age, with a trend for the youngest inquirers to use email more often, but there were too few inquirers of 19 years of age or below to do this analysis.

As no major difference exists among helplines according to their nature, scope, or composition, we cannot recommend one type of helpline compared with another. The respective roles of helplines run by patients or by health care professionals appear complementary, for example, the former providing more often psychological support or contact with another patient or an association, and the latter providing more often information to obtain full coverage of care by health insurance or information on treatments and regulatory affairs.

Recommendations for funding is based on the average duration of inquiries, on the complexity of finding accurate medical information, and range of possible purposes. Also, it seems a 1.5 full-time staff is needed to start operating the service, for an annual budget of €150,000 to €300,000, according to average European salaries, including training costs both for staff and volunteers and service quality assurance.

The helplines that are member of the European Network of Rare Diseases Helplines are very heterogeneous. In particular, their monthly activity varies greatly (in our survey conducted in November 2012 it ranged from 3 inquiries to 389). Helplines with highest numbers of respondents were organized in a national or regional way: national ones are Maladies Rares Info Services in France and the Coordinating Centre for Rare Diseases of the Veneto Region, and regional ones with AFM-Téléthon with respondents at the headquarters and in each of their 25 regions services, and with SIO-Feder with 6 respondents in 5 regions.

Although an 11-month survey is questionable in terms of duration and outcome measures, November might be considered as a representative month. There was no special rare disease-related event in any of the participating countries that could affect the number of inquiries. For example, the annual fund raising event “Téléthon” in France and Italy takes place at the beginning of December, and for 36 hours the public number of Maladies Rares Info Services is displayed on several television channels and broadcasted on radios. Other national events take place in other periods, except in November.

Nevertheless, in this attempt to compare the activity and the service provided by helplines that differ greatly in their nature, composition, scope, and cost structure, a main limitation was the absence of real choice for the inquirers (eg, in no country was there the choice between a patients-driven or a health care professionals/governmental authority-driven helpline). Even if the inquirer could always contact the helpline by telephone or by email, this was in fact determined by the respective publicity of the telephone number or email address.

One outcome measure would have consisted in analyzing the inquirers’ satisfaction. For the time being, this information is not collected by the helplines, but some are attempting, based on printed or Web-based questionnaires, they evaluate the quality of oral or written responses given, of their Internet website or online forums/social media.

To measure the inquirer’s satisfaction is certainly an essential need. The feasibility is debated, as no satisfying method arose: a simple question could be asked to the inquirer at the end of a call; however, this way of assessing the call would certainly lack neutrality. As in most cases no contact details are collected, it is not possible to envision a third person contacting the inquirer back by telephone to measure his/her perception of the conversation. This could be done more easily for the emails. One key strategic question is the added value of the helplines for the patients/inquirers throughout the course of the disease. Also, the inquirers’ category needs further thinking: some groups are largely under-represented (ie, media, psychologists).

For the inquirers’ or patients’ gender we used only three categories: male, female, or unknown. However sexual identity issues exist in rare diseases, with people harboring XXY, XYY, and androgen-insensitivity syndrome. Altogether, sexual abnormalities represented 3.27% (50/1530) of the inquiries concerning rare diseases. We did not integer this characteristic in our survey.

The grouping of rare diseases in 11 categories was an arbitrary process: most of the rare diseases do not belong to one class only as they often are multisystem diseases. In our subgroup of 537 diseases discussed during the inquiries, each rare disease could be classified in three categories on average. For example, Ataxia-telangiectasia (ORPHA code 100, ICD-10 G11.3) belongs to 11 categories in the Orphanet classification.

Our data suggest helplines, although heterogeneous, are complementary to each other, not competitive. The co-existence of general helplines dealing with all rare diseases and more specific ones benefits the inquirers who can choose which helpline to contact according to the question they have. Inquirers looking for a specialist are often undiagnosed, and will naturally turn to general helplines rather than contacting a specific one, as they do not have a diagnosis yet.

The telephone is still the method of choice to contact a helpline. The impact of the cost for the phone calls was difficult to determine, as only two helplines offered free phone calls to inquirers. The non-free calls were charged as a local call in the vast majority of cases, representing a small expense.

A minimum of 75% of inquiries could be satisfied, within an average of 22.8 minutes, for a number of different rare diseases (536 distinct diseases, including 95 very rare ones). Given the complexity of rare diseases and the scarcity of the information, we consider this outcome as an indicator of a high quality service, to the benefits of the public, and the patients in particular.

Therefore, the service responds to a real demand by the public, however it is not saturated. This leaves the possibility to expand the scope of the helplines, for example, by providing assistance to patients when they are reporting suspected adverse drug reactions as provided for by Directive 2010/84/EU or by providing information on patients’ right to cross-border care, as provided for by Directive 20110/24/EU. The European Network of Rare Diseases Helplines proposes advice and information to guide the creation of helplines where they do not exist yet, as in to estimate the work load, staff, and budget needed.

To make the helplines better known to the public and to increase the European added value of the service, the network asked the European Commission DG Connect to reserve a 116 number for services of social interest. A 116 number is a six digit number, free of charge that can be used by all citizens of the European Union and beyond. In parallel, Member States are developing national plans or strategies for rare diseases and one coordinated objective is to improve information to the public on these diseases. This study demonstrates the helplines’ utility and provides useful information for the planning and budgeting of equivalent services where they do not exist or need to be professionalized.