Introduction
A disease is defined as rare when the prevalence is lower than one in 2000 individuals in the European Union [
1]. However, the total number of people suffering from a rare disease is large. It is estimated that between 5000 and 7000 rare diseases exist. Thus, the proportion of individuals with a rare disease is estimated at 6 to 8% of the population in the EU, according to the European Organization for Rare Diseases [
2]. Most rare diseases are associated with unmet needs due to a lack of available treatments and the relative lack of research to discover and develop such treatments, and consequently a high socio-economic burden [
3].
Because of this high burden, health authorities decided upon regulatory incentives for Orphan Medical Products, which led to an increase in the number of applications for market authorization of orphan drugs. However, trials in rare diseases are more challenging than clinical trials in more frequent diseases. The classical randomized controlled trial (RCT) cannot always be conducted, because of small numbers of eligible patients and the heterogeneity of the patient groups. Patients may be in various stages of a disease and disease courses may be far from uniform. When an RCT is conducted, it may be subject to imperfections in practical conduct, inclusion criteria, and trial design [
4]. In recent years, new clinical trial methods have been developed that promise to be more efficient than classical RCTs [
5‐
8].
When it comes to maximizing the chance of a successful trial, the patients or parents of a child with a rare or ultra-rare disease can play a pivotal role when they are involved in an early stage. Although there is no structural evidence that patient involvement improves the efficacy of trials [
9], there are some examples where patient involvement has made a difference [
10,
11]. If the burden of participation is considered to be out of proportion, recruitment may fail or participants may drop out before trial completion. Early involvement of patient representatives can help identify design aspects that may render a trial acceptable for potential participants. By removing or adapting undesired design aspects the chance of success of a trial may be enhanced. Patients can also assist with the choice of informative and relevant outcome measures [
12]. The role of the patient organizations has consequently become more important in terms of funding research and setting the research agenda [
13‐
15].
One example where the activity of the patient community has had considerable influence on the research field is Hemophilia. This collaboration resulted in the implementation of quality initiatives that directly improved hemophilia patient care [
16]. Patients have changed the field and have become equal partners in the discussion on treatment policy. They are active in setting the research agenda, and in the debate on which outcome measures should be included in studies [
17].
In order to investigate the patients’ views on clinical trial design, we conducted a qualitative study in a selected group of 10 educated rare disease patient representatives. Our main question was: Which aspects of trial design are relevant to you, and what is your opinion on these topics?
Methods
For this research, we have followed the Standards for Reporting Qualitative Research (SRQR) and the Consolidated criteria for reporting qualitative research (COREQ) guidelines [
18,
19] For the analysis a thematic analysis was used [
20].
Participants and recruitment process
Ten patient representatives were interviewed, who were all members of the Patient Think Tank (PTT) of a European research consortium for methodology of rare disease trials called ASTERIX [
21]. The PTT-members have been chosen to represent a wide range of rare disease categories, varying from acute to chronic diseases. They had all been trained extensively in clinical trial design and regulatory issues, either by the EURORDIS summer school, EUPATI courses or through at least ten years of experience. Some of the PTT-members have a rare disease themselves, whereas others are parent of a child with a rare disease. One of the PTT-members is a professional representative of patients with a particular rare disease. Three of the ten PTT-members are male. The PTT-members live in various countries in the EU: the Netherlands, Poland, Germany, the UK and Ireland. The selection of participants was a convenience sample: it was an opportunity to be able to speak to this variety of persons involved in rare diseases as they were all part of the ASTERIX project. In this capacity, the participants, being PTT-members, knew the reason and objectives of the study.
Data collection
The PTT-members were approached by the patient contact person of ASTERIX and were asked if they would be interested in participating in an interview about their experience with rare disease research, and what aspects of trial design they would perceive as important. All ten PTT-members agreed to participate and gave their oral consent. The interviews were held between May 18th and July 17th 2015, by videoconference. Each participant was interviewed once by two (out of three) interviewers (CG, MJW, and MdP). All interviewers followed a two day course on qualitative interviewing prior to the research, and had some previous experience in conducting qualitative interviews. Of the ten interviews, six were conducted in English, and four in Dutch. For the interviews the program GoToMeeting was used, which provides the possibility for video-conference. All interviews were recorded, for which the participants also gave their oral consent. Each interview was conducted according to a pre-set Interview Guide (see Additional file
1). The median interview duration was 53 min, with a range of 41 to 69 min.
Data analysis
The verbatim transcript of every interview was sent to the respective participant to give the participants the opportunity to remove quotes that they did not want to appear in the final manuscript. For the analysis, the program MaxQda was used. A code tree was developed, based on the interview questions and the main topics that emerged, to structure the interview coding process. As a means to achieve reliable coding, transcripts were coded by the first author (CG) and checked by the second author (MJW). Several times, the researchers met to discuss the coding. Any discrepancies were resolved by discussing the codes, until consensus was reached. The codes were then grouped into conceptual categories, and a summary of all quotes within each conceptual category was made. The interrelationships between the categories were discussed between the coders, and a clear structure for the manuscript was made. The resulting manuscript was sent to all participants to check whether the topics that were most relevant to the participants were presented appropriately.
Discussion
In this study we tried to identify what are the most relevant topics for patients regarding trial design in rare diseases. We have found some general, and some more specific topics within four themes.
In general, it can be concluded from this study that for many rare disease patients, taking part in a trial is not an univocal decision. In the literature, for non-rare diseases most often altruism is mentioned as the main reason for participation in a clinical trial [
22]. However, for many rare diseases a treatment is still beyond reach, and beside altruism, a chance to receive an experimental treatment may be a driving factor in rare disease patients. When there are no treatments available, a trial is often the only hope. This means that sometimes, patients are willing to risk anything to participate, even when the chance of getting any personal benefit from the trial is relatively small.
Because for many rare disease patients a trial is a source of hope, many want to decrease the chance of being allocated to the placebo arm of a trial as much as possible. This statement, although understandable from a patient, or patient parent’s perspective, is at odds with the principles of randomized clinical trial design. One of the suggestions made by our PTT-members, to diminish the need for placebo comparison, without decreasing the comparison with a placebo, was to start with collecting patient data in a registry, when no drug trial is in the pipeline yet. Such a registry could provide information on the patients not under treatment, that might be helpful in reducing the placebo group at a later stage. However, such a design does not include randomization. Additionally, the cross-over study design was mentioned as an option. Although such a design is a good way to divide the possible negatives of both trial arms equally over all patients involved, a cross-over design is only possible in very specific circumstances [
23].
There are several other topics that are important to patients. One of the topics that patients are specifically interested in, is the choice of outcome measures. No one can assess the clinical relevance of an outcome measure better than those who live with the consequences of a disease on a day to day basis. Therefore, patient involvement in the choice of outcome measures should be the default. This is also in accordance with the work done by the IRDiRC taskforce on Patient-Centered Outcome Measures [
24]. This task force identifies the needs to develop outcomes that are relevant to patients, to improve the quality and feasibility of rare disease trials. Also, we recommend that patients are involved in the decision on study length, the target population and the type of information that is provided to potential participants. The input of patients can be useful in for example editing informed consent forms or information leaflets to make them more comprehensible and concrete for patients.
In the collaboration between patients and researchers (pharmaceutical or academic), one of the most important factors is communication. Patients want to be kept informed, and want to know what the pros and cons are of participating in a trial. When patients and researchers work together from the first stages of trial design on, they level more equally with researchers. More experienced patient representatives have an insight in what aspects of a trial are relevant, based on previous trials or experience. They should also be involved in the design phase when decisions are made about (possibly invasive) measurement procedures because they have an idea of which procedures may not be accepted by potential participants. Such a collaboration may also help researchers to recruit and retain enough participants in a later stage. Collaboration between patients and researchers has already shown its value in many research areas [
25‐
28].
The main strength of this study is the qualitative nature of the study design. All topics that are covered in this paper were raised by the participants, who all have some personal or professional experience with trials in the setting of rare diseases. Since the group of patient representatives that we asked to participate in this study is the Patient Think Tank of a European research project (the ASTERIX project), the participants and the interviewers had a good understanding and could rely on an already existing relationship. Each interview was conducted by two interviewers and recorded, which was helpful in making the interviews smooth, efficient and comprehensive. All participants reviewed and approved the transcript of their interview, as well as a draft version of this manuscript.
There are also some limitations to this study that should be considered. Firstly, the group of participants is a convenience sample, and cannot guarantee knowledge saturation. On the other hand, the participants were selected to be part of the Patient Think Tank based on their experience but also taking into account the variety of rare diseases that they represent. Therefore, the group was a balanced mix between acute and chronic diseases, and rare and ultra-rare diseases, and both patients and parents of rare disease patients were present. Also, they represented ten different patient organizations in several countries in Europe. Nonetheless, a group of ten is probably too small to reach data saturation, and cannot guarantee that all opinions are documented. Secondly, for some participants it was not possible to take part in the interview in their native language. However, the level of English of the participants was very high, as can be expected of a group that takes part in a Patient Think Tank in a European project. For practical reasons the interviews were conducted during video-conferencing, which might have been a drawback if the interviewers and PTT-members had not known each other beforehand.
Acknowledgements
We would like to thank Gavin ten Tusscher, MD, PhD, for his help with the translation of the Dutch quotes.