This article is based on an issue panel given at the ISPOR 19th Annual European Congress (2016). To view the authors’ presentations, go to

The patient’s voice in the evaluation of orphan drugs

by Benoit Arnould, PhD1; Sheela Upadhyaya, HDN2; Charlotte Roberts, BA3; Samantha Parker MBA4

1Patient Centered Outcomes Senior Director, Mapi, Lyon, France; 2Associate Director, Highly Specialised Technologies, NICE, London UK; 3Business Development Manager, MPS Commercial, Amersham, UK; 4Chiel Patient Affairs/Health Policies Offcier, Lysogene, Neuilly sur Seine, France


Patient testimony offers an additional perspective on rare diseases and their treatment, and can provide information that is not captured by clinical trial assessments.

Mixed methods research, combining qualitative and quantitative research within the same program, can be used to integrate the patient perspective into clinical research programs.

The NICE Highly Specialised Technology appraisal program provides an example of how patients’ submissions can be incorporated into the decision-making process of health technology assessment bodies.


This article considers ways that health technology assessment bodies can take into account the voice of patients with rare diseases when granting access to orphan drugs.

Benoit Arnould - Challenges for patient-centered outcomes research in rare diseases

The difficulties of working with rare diseases mean that researchers, payers and health technology assessment (HTA) bodies may have to make decisions about orphan drugs based on limited information, particularly with respect to patient-reported outcomes (PROs). This is important given the profound effect that rare diseases can have on patients’ lives.

There are a number of challenges for PRO research in rare diseases. The number of patients is limited, generic measures may not be valid or responsive enough for rare conditions, self-reporting may be difficult due to the patient’s age or cognitive impairment, and disease-specific measures can be costly and time-consuming to implement. Moreover, the range of possible evaluations can be complex (e.g., symptoms, functioning, quality of life, caregiver and family burden, and valuation across different age groups or disease stages). Consequently, HTA bodies often receive dossiers that lack essential information concerning PROs. Greater efforts are needed to systematically include the patient’s perspective in the evaluation of orphan drugs.

Table 1. Mixed Methods Research

One approach is to use mixed methods research [1], whereby qualitative research is combined with quantitative research within the same program (see Table 1).

This framework can be used to integrate the patient perspective into clinical research programs, with relatively small increases in costs and the burden for researchers and patients.

At present, the patient’s voice is largely transmitted in the form of testimonies. Key issues include the extent to which testimonies affect HTA decisions, whether this is sufficient to ensure reliable decision making and, if not, whether qualitative research (combined with quantitative research) would fill the gap.



Sheela Upadhyaya - The HTA perspective

How do testimonies from patients or their representatives impact on HTA decisions? Is this reliable enough to support decisions from a public health perspective?

The Highly Specialised Technology (HST) appraisal program at the National Institute for Health and Care Excellence (NICE) evaluates ultra-orphan conditions, and is unique in the way it includes patients within the process. Decision-making centers on an assessment of value, and takes into account the nature of the condition, the impact of the new technology, costs to the National Health Services (NHS) and social services, value for money of the product, indirect and non-health benefits, and delivery of any specialized services. The appraisal process involves three stages: scoping, evaluation and guidance development. Patients are involved in all stages, and participate in associated meetings.

During scoping, patients and patient groups can provide clarity on patient numbers, current treatment regimens and best supportive care, and details of the condition and outcomes that should be considered. During the evaluation stage, patient testimonies are sought, together with further clarification of patient numbers and patient experiences of the condition and the new drug. Patients and patient groups are then invited to comment on the draft guidance, to ensure that their submitted information has been represented accurately.

Patients and patient groups are provided with a template and guidance on how to submit information. A lay member of the HST Committee then summarizes submitted testimonies into slides for presentation at Committee meetings, during which the patients and patient groups check whether the information has been presented accurately, and whether the Committee have understood it correctly.

Patient experts are individuals with experience of the broader patient population relevant to the evaluation and/or relevant personal experience. Their role is to provide statements which will help the Committee consider key criteria such as the nature of the condition and burden of disease. They also attend Committee meetings as individuals.

From the HST’s perspective, patients are able to bring the condition to life for the Committee. Their input is of value for defining and clarifying the patient population, patient numbers, the burden of disease, what is important to patients, which patients will benefit most, the impact of treatment, the likely uptake of treatment, and whether there might be adherence issues.

Although the HST values patient input and considers it interesting and important, challenges remain. There is frequent discussion about whether patient submissions are evidence or testimony. Is there actually a need to quantify the information? And what quality assurance mechanisms should be deployed around the delivery of the information?

Charlotte Roberts - The patient’s perspective

How do patient representatives communicate toward HTA bodies? To what extent do HTA bodies listen to the voice of the patients, their families and their representatives?

In the UK, patient organizations contribute to HST evaluations in several ways. They attend scoping meetings, identify patient experts to write submissions and attend HST Committee meetings, support and counsel patient experts, and encourage the wider patient community to respond. They also provide information on patient numbers, and can identify patients across the spectrum of the disease to participate in the process.

Whereas patient organizations have a broad knowledge about the disease and the impact of the drug, patient experts have first-hand experience. Patients involved in the HST process need to be supported, because of the demands it places on them in terms of emotions, time commitment, sense of responsibility, and exposure to confidential information. Despite their inevitable emotional involvement, the voice of patients should carry weight.

It is difficult to quantify the extent to which HTA bodies listen to this voice, but patients do give an additional perspective and may be able to provide information not captured by clinical trial assessments. In particular, quality-of-life data can be difficult to capture but often has the greatest impact on patients. Patients can also refute incorrect perspectives. For example, patients involved in the HST evaluation of a treatment for mucopolysaccharidosis (MPS) IVA (Morquio syndrome) were able to provide examples of how treatment had increased their energy levels, something that was not necessarily captured by clinical trials’ data. In addition, although increased wheelchair use was considered a negative outcome, one patient explained that she had started using a wheelchair because she now felt well enough to go out socializing, which she had not done previously.

The MPS Society, a patient organization for mucopolysaccharide disease, was involved in the development of the first Managed Access Agreement. This novel scheme was set up to enable treatment to be provided to patients with MPS IVA who derived benefit from it, while discontinuing it in those who did not, and to gather long-term data on treated patients. The Managed Access Agreement was written in collaboration with NHS England, NICE, a pharmaceutical company, an expert clinician, and the patient organization. Patients with MPS IVA who met the eligibility criteria agreed to attend four assessment visits within the initial 14 months and to complete quality-of-life questionnaires every 4 months for 5 years. Treatment will be withdrawn after 1 year for patients who are not compliant or do not meet four out of five predetermined clinical criteria. While the program is underway, the MPS Society has been communicating separately with patients receiving the treatment, and has identified some benefits that are important for patients but have not been captured by the quality-of-life tools used for the Managed Access Agreement. Examples include increased energy, strength and mobility, as well as improved sleep, less pain, and increased independence.

This illustrates that despite their emotional involvement, patients provide insight into the benefits of treatments beyond clinical trial measurements, and play a key role in the decision-making process.

Samantha Parker - The industry perspective

How do pharmaceutical companies capture the patient perspective when developing therapeutic innovations? How do they align their endpoint strategy to patient needs and priorities?

It can be difficult to evaluate some clinical endpoints in rare diseases using standardized assessment tools. In particular, in the field of pediatric neurodegenerative diseases the target alters depending on the age of the child. For example, children with MPS IIIA show normal development until the age of 1–4 years, after which they regress in terms of behavior and cognition, and develop major hyperactivity and sleep disorders. This has a substantial adverse effect on the quality of life of patients and their families. To make things more complex, there is, currently, no biomarker for the disease to use as a surrogate marker of clinical outcome. This means that researchers have to assess somewhat intangible effects of drugs.

In a Phase I–II gene therapy trial, the clinical assessment tools used to evaluate disease progression were exploratory and not optimal in terms of comprehensiveness, specificity, and meaning for patients and their families. However, the patient community for this disorder is small, and the researchers became aware of indirect testimonies that the treatment was having an effect on sleep and hyperactivity. This illustrates how important it is to capture the patient’s perspective.

Companies developing treatments for rare diseases need to make their activities patient-centric, and gain a broader understanding of the impact of the disease and treatments on patients and their families. This can be done in several ways. Patient organizations can be involved in the design of the protocol, study inclusion criteria, and recruitment strategy. Researchers working on rare diseases can attend patient group discussions, where they might hear useful anecdotal information about small issues that are not covered in publications. Facebook and Twitter can also be useful in this respect. Testimonies from clinical trial participants provide additional information that can be helpful.

Semi-structured interviewing is a technique that may be able to help clarify the patient’s perspective. It is currently being used as part of a natural history study in MPS IIIA, to look at specific aspects of the disease that were identified as being troublesome based on the testimonies of participants of an earlier clinical trial. Sleep and behavior were identified as particular problems. Although sleep can be quantified as part of a trial, this does not address the wider effect that disordered sleep might have.

The objectives of the semi-structured interview are: to capture meaningful aspects of the disease and how it affects the patient and family life from the parents’ perspective; to cover specific areas related to the MPS IIIA clinical phenotype and how these change over time; to explore thoughts and feelings not picked up by the standardized assessment tools used in the study; and to collect data that could be used as a control in future clinical trials.

Rigorous methodology is needed, in order to ensure data quality. A specific interview guide was developed and included in the study protocol. The interviews are conducted face-to-face, last 60 minutes, and are performed by external psychologists or researchers who have undergone training on the disease and the aspects of interest. They are audio-recorded, which allows the interviewer to pay full attention to the parent, and enables auditing to be performed. The interview is designed to be exploratory and capture the parents’ own words and spontaneous expressions; it involves open discussion, with no direct questions. Transcripts are analyzed using software specifically designed for qualitative analyses. This allows traditional qualitative analysis, and facilitates the break-down of qualitative data into groups.

The results are not available yet, but it is hoped that this approach will provide a way of bridging the gap between testimony and quantitative measurements.


  1. Tashakkori A, Creswell JW. The New Era of Mixed Methods. J Mix Meth Res 2007;1(1):3-7.Enregistrer