static-content.springer.com10.1007... · Web viewTable 3. Summary of papers describing real-world examples of patient involvement in the life-cycles of orphan or ultra-orphan drugs;

Table 3. Summary of papers describing real-world examples of patient involvement in the life-cycles of orphan or ultra-orphan drugs

Author/year Purpose of the paperPatient/carer population Methods/approaches used Findings Comments

Research - generalMavris & Le Cam (2012)[70]

Europe

To describe the results of a survey conducted by the European Organization for Rare Diseases (EURODIS) on the financial and non-financial support provided by patients’ organizations

772 rare disease patient organizations were contacted, of which 309 provided responses

Self-administered survey Respondents reported their involvement in supporting research at the European level• Within the Framework Programme 7 (FP7) there is emphasis on the inclusion of rare disease patients as contributors, evaluators and advisors, in advisory groups and also as participants/beneficiaries by the European Commission• Patient organizations have participated as observers in E-RARE, a European Research Area – NET funded project aimed at coordinating rare disease research and developing joint activities to implement transnational funding actions• Patient organizations are included in the Executive Committee and in the Therapies, Diagnostic, and Interdisciplinary scientific committees of the International Rare Disease Research Consortium

Polich (2012)[71]

Multi-country

To present a framework describing the process through which patient organizations transform experiential information into biomedical research

Rare disease patients • Performed review of published literature• Conducted interviews with rare disease patient organization founders

Based on experiences of patient organizations, the following steps in patient-driven research were identified:1) Pursue possible treatment “leads”: gather anecdotal evidence of patient experiences with various treatments2) Share information and expand access: prior to disseminating “leads”, patient groups work to balance timely information release and patient safety3) Pursue different strategies for validating and integrating their findings into professional biomedical literature (e.g., publish data themselves, collaborate on follow-up studies with professionals, or having professionals publish the findings as a case history)

Presented other contributions of patient organizations to research:1) Assisted with patient recruitment through the formation of cohorts on online networks2) Provided information on patients’ perceptions of effectiveness and adverse reactions3) Tracked treatment effectiveness over longer durations and explored a broader range of therapeutic modalities



Boon et al (2009) [72]

Netherlands

To investigate a patient organization’s roles in influencing R&D and policy making

Neuromuscular disease patients

Case study Provided historical account of organization’s role in co-founding scientific collaborations

Wastefelt et al (2006) [73]

Europe and the United States

To provide examples of the role of patient-parent advocacy groups in promoting research on rare diseases

Rare disease patients N/A Presented two examples• Indicated that organizations such as the National Organization for Rare Disorders (NORD), the Genetic Alliance, and the European Organization for Rare Diseases (EURODIS) have been integral in supporting clinical research, empowering patients, increasing rare disease awareness, and driving patient-centered research

• The Histiocytosis Association of America (HAA), founded by parents of an afflicted child, promotes education on childhood histiocytoses to encourage research for a cure; has supported the Histiocyte Society in facilitating international studies

Rabeharisoa (2003) [74]

France

To describe the model of the French Muscular Dystrophy Organization’s (AFM) engagement in research and the implications of this model in establishing relations between patients and professionals, steering research, and its consequences for the dynamics of patient organizations movements

AFM • Analyzed minutes from meetings of the AFM’s scientific council & specialized commission, as well as those of the board of governors, from 1981 to 1995; focused on questions around research policies adopted, how they were implemented, and how they differed from traditional policies• Conducted 30 interviews with various patients and professionals

Described the development and implementation of AFM’s model for engagement in research:• AFM unable to use auxiliary model of engagement in research (i.e. an organization working to support professionals) since knowledge of neuromuscular diseases was scattered or non-existent• Developed a model (“partnership model”) with two main characteristics: 1) Patient organization is master of its research policy 2) Patients are specialists’ partners in their own right in knowledge production and care and treatment of their disease

Rabeharisoa & Callon (2002) [75]

France

To describe how patient organizations have contributed to research in France

Patient associations contributing to research in France

• Conducted an internet search• Conducted postal survey of164 organizations that could be expected to support research

Described two different types of patient organizations involved in research in France:• Auxiliary associations: use one of two approaches: 1) Leave scientists and specialists to choose research priorities and handle the production and distribution of knowledge OR 2) Acquire the knowledge required to enter into discussions with specialists• Partner associations: revolve around the importance of patients’ experience in describing their diseases and deciding on solutions needed, pooling and comparing the



experiences of its members in order to build up a collective expertise

Presented findings of the survey:• 34% of patient organizations reported funding research• These organizations generally supported research in proportion to their budgets

Proretina SND[76][Website]

Germany

To describe the activities of a patient organization for rare retinal degenerative conditions

Patients with rare retinal degenerative conditions

N/A Described activities of PRO RETINA Germany eV, a self-help organization established by patients and their caregivers, which includepromoting research through funding awards and support for national and international seminars and conferences

Research – priority-settingDavila-Seijo et al (2013) [78]

Spain

To identify and prioritize treatment uncertainties relevant to Dystrophic Epidermolysis Bullosa (BED) patients to guide research priorities

BED patients Used The Priority Setting Partnership (PSP) approach of the James Lind Alliance:1) Identified all potential partners, including patients and carers, physicians and other health care professionals involved in treating the disease, patient organizations and experts on the disease (initiation phase)2) Conducted an on-line survey of patients, carers and health professionals to collect up to 20 treatment uncertainties; reviewed literature to identify additional uncertainties (consultation phase)3) Collated responses: excluded non-treatment uncertainties, removed duplicates, and combined similar uncertainties (collation phase)4) Conducted second on-line survey to elicit each respondent’s 5 top uncertainties from the total list (77) (ranking phase)5) Held half-day workshop with 3 patients, 2 carers, 6 health professionals, and a patient organization representative to identify the top 10 uncertainties (prioritization phase)

Number of surveys administered: 154Number of responses received: 62Treatment uncertainties:• 73 identified through survey• 50 identified through literature review• 77 remained after collation

Number of responses received to second survey: 46Treatment uncertainties:• 24 remained

Top 10 uncertainties identified to guide research priorities:1) Wound care methods2) Treatments to control itch3) Pain control strategies4) Value of management in reference centres5) Effectiveness of a "tumour early diagnosis protocol"6) Long-term results of syndactyly surgery7) Effective methods to avoid or delay syndatyly8) Role of tissue engineering9) Role of stem cell therapy and bone marrow transplantation10) Role of growth hormone in decreasing the delay of growing and puberty

Nierse et al To describe how research Neuromuscular disease • Conducted interviews with patients to 4 research domains were identified:



(2013) [77]

Netherlands

priorities of neuromuscular disease patients were identified

patients obtain information on illness experiences and impact on patients’ lives and identify research areas• Held 3 focus groups with patients to further explore research areas• Validated findings using an “expert” group of 11 members of the patient association• Developed and administered questionnaire for prioritizing research topics to 246 patients

1) Health2) Quality of life3) Quality of care4) Basic issues

Linertova et al (2012) [79]

Europe

To describe how a set of 10 rare diseases were selected in Europe for future studies of socio-economic burden and QOL (BURQOL-RD)

Rare disease patients • Sought input from patient organizations involved in BURQOL-RD (also comprises health economics research institutions and national bodies in health policy and research in rare diseases)• Patient organizations helped to establish a set of criteria to select an initial set of rare diseases• Used a two-round Delphi process to obtain a prioritized list of 10 rare diseases from each participant• Used majority voting to finally rank the diseases• Identified 6 attributes of diseases: prevalence, age at onset, genetic disease vs. other origin, physical and/or mental impairment, existence of valid diagnostic test, and availability of effective disease-modifying treatment• Established final list based on combinations of attributes and the final Delphi-based rankings

The 10 rare diseases selected Cystic Fibrosis, Prader-Willi syndrome, Hemophilia, Duchenne muscular dystrophy, Epidermolysis bullosa, Fragile X syndrome, Sclerodermia, Mucopolysacharidosis (MPS), Juvenile idiopathic arthritis and Histiosytosis

Also reported that professional networks providing integrated care and reference centres for all 10 diseases have been established; there are also patient organizations in most of the participating countries

It is unclear how “need for carer” was chosen as an attribute when it was not in the list of 6 determinants reported in the paper

Research – drug discoveryWood et al (2013) [80]

United States

To describe the growing roles of ultra-rare and rare diseases patients/parents in drug discovery using three patient organizations

Jonah’s Just Begun – Foundation to cure Sanfilippo (MPS III); Hannah’s Hope Fund for giant axonal neuropathy; and The Hereditary Neuropathy Foundation and CMT1A

Not specified – reported experiences of patient organizations involved in activities aimed at finding treatments

Presented a flow diagram of steps undertaken by these organizations in their efforts raise funds for research aimed at finding a treatment following diagnosis:1. Read research papers2. Connected with scientists and clinicians3. Formed a not-for-profit foundation4. Raised funds for research and a natural history study5. Advocated for support from government groups (FDA, NIH, etc.)6. Started a company to develop treatment,

Concluded thatresearch can be driven by patients and parents, facilitated through collaboration between rare disease foundations



7. Sought company funding through research grants8. Encouraged and educated others in the disease community

Described activities of specific organizations:(1) Jonah’s Just Begun – Foundation to cure Sanfilippo• Alongside other MPSIII organizations, brings researchers together globally for meetings and formed the Helping Advance Neurodegenerative Disease Science (HANDS) consortium of scientists, advisors, and parents• Initiates preclinical research projects• Provides small grants to academic researchers• The founder also started the company Phoenix Nest to commercialize potential treatments

(2) Hannah’s Hope Fund for giant axonal neuropathy (GAN):• Funds research on GAN at the University of North Carolina• Raised US$5million to fund preclinical gene delivery studies and GMP vector manufacture for Phase I and Phase II gene delivery trials• Also funds basic research into the identification of molecular targets for GAN treatments• One founder also started BioGan Therapeutics to pursue small business innovation research grants to fund small molecule therapeutic discovery

(3) The Hereditary Neuropathy Foundation and CMT1A:• The foundation increases awareness through campaigns, a cooperative agreement from the Centers for Disease Control and Prevention, and established the National CMT Resource Center (online portal providing support, education, and dissemination materials).• Developed the Therapeutic Research in Accelerated Discovery (TRIAD) model which creates partnership with academia, government, pharmaceutical companies, and



the biotech industry• Has funded research leading to assay development to screen for the CMT1A phenotype

Mavris & Le Cam (2012) [70]

Europe



Self-administered survey Respondents reported funding the following:• Research (37% in the past 5 years)• Initiation and financing of a specific project (77%)• Co-funding the operating budget of a specific project (75%)• Acquisition of new equipment (54%)• Research fellowships (47%)Respondents identified the following research priorities:• Basic research (81%)• Diagnosis (56%)• Natural history (54%)• Therapeutics (57%)

Parkinson (2012) [81][Abstract]

United Kingdom

To describe outcomes of initiatives led by the charity Alstrom Syndrome (AS) UK

AS UK N/A Described how AS UK gained Big Lottery Medical and Scientific Funding to fund research

RegistriesBacon et al (2013) [82][Abstract]

United States

To describe the use of the RDCRN Contact Registry for the Inherited Neuropathies Consortium (INC)

Inherited neuropathy patients, with a focus on Charcot-Marie-Tooth (CMT) patients

N/A Presented characteristics of registry participants:• Contains 1, 042 individuals, as of March 11, 2013 (39% males; 9% < 16 years of age)• 53% CMT1A, 4% CMT1B, 10% CMT2A, 2% CMT4, and 5% CMTX; 27% have multiple diseases, another type of peripheral neuropathy, or do not know• Registry participants have contributed to INC protocols designed to develop instruments to measure quality of life of children & adults


United Kingdom


AS UK N/A Described how AS UK partnered in an EU wide project aiming to create a registry to increase knowledge, improve treatment management, and develop clinical research for 3 rare diseases

Boon et al (2009) [72]

Netherlands



Case study Provided historical account of organization’s role in stimulating the set-up of patient registries



Pattacini et al (2009) [83]

Italy

To describe a web-based clinical record into which patients can record treatment-related data

Hemophilia patients N/A Described new outpatient clinical record (registry) for hemophilia patients:• In several centres• Has specific ‘pathways’ through which patients can enter data• Collects data on bleeding or traumatic events and treatments (including home infusions)• Patients underwent a 6 hour training course

Presented findings to date:• 50 patients trained to use the system• 825 log-ins made• 105 bleeding events or traumatic events (site, cause, days lost from work/school) and 2505 treatments (drug, dose, batch and adverse reactions) registered

Frost et al (2008) [84]

Multi-country

To describe the role of an online community (PatientsLikeMe) in the development of a registry/database for collecting information on treatment effectiveness (lithium treatment for Amyotrophic Lateral Sclerosis (ALS))

ALS patients A mixed methods qualitative and quantitative study of forum posts and treatments adopted by the ALS community following first release of trial results demonstrating the potential benefit of Lithium:• Used individual patient data available in personal health profiles on PatientsLikeMe• Collected all forum posts containing the word “Lithium”• Plotted the frequency distribution of posts and overlaid it on known significant events

Reported 10,600 posts to the forum, of which 687 contained the word “lithium”• First post regarding lithium treatment (11/14/2007) referenced online Italian newspaper article describing findings from recent conference claiming ALS patients treated with lithium did not experience symptom progression over the 15 month trial• Patient and family member of posted intentions to begin a patient-driven observational study on lithium treatment - set up website including rationale for lithium treatment and database for patients to record: functional status pre- & post-initiation of lithium therapy, lithium dosage, lithium blood levels, side-effects, benefits, and other treatments• PatientsLikeMe also began collecting observational data on lithium use• PatientsLikeMe posted link to published Italian study, leading to numerous discussions persuading doctors to prescribe lithium, how much lithium to take, how to monitor lithium blood levels, when to adjust dosages, possible side effects or benefits, and patient experiences• PatientsLikeMe announced adaptations to site, which included functionality to record blood levels of lithium, graph multiple people’s functional levels, and filter views by various characteristics

Note: since submission of the manuscript on 3/14/2008, the number of PatientsLikeMe users has increased to 2,200 with 250 reporting lithium use. Side-effect surveys have been completed by 125 patients. The dedicated study page now includes additional filters, individual summaries of data completeness, and a lithium side-effects report



Mallbris et al (2007) [85]

Sweden

To describe the establishment and utility of Sweha-Reg, a Swedish population-based registry created to capture baseline epidemiological data and provide a framework to study the quality of life of hereditary angioedema patients

Hereditary angioedema patients

Case study Described how recruitment, participation, and confidentiality are managed:(1) Recruitment:• Through multiple recruitment sources (HAE specialized physicians and clinics, hospital discharge databases, correspondence with medical directors and immunologic HAE-laboratories, and website and magazine campaigns)• Informed consent to approach potential cases obtained from treating physician; Self-referral also possible

(2) Participation:• An initial questionnaire collects demographic data, social, educational, economical, and health status, quality of life, family history of HAE, co-morbidities, potentially predisposing trigger factors, previous and ongoing medication, attack characterization, and symptom severity• A subsequent telephone interview captures the natural course of HAE and the efficacy, safety and outcome of different treatments in patients and the usage of health and social services• Blood sample also collected• Participants followed over time

(3) Confidentiality:• Participants receive a study-identification code to anonymize records• Access to data will eventually be open to any HAE-treating physician upon request

TREAT-NMD [86][Website]

Multi-country

To describe the role of patient organizations in an EU-funded ‘network of excellence’


N/A Described how patient organizations have been involved in creating registries• Registries governed by a charter and an oversight committee, which includes patient representatives

BiorepositoriesTerry et al (2007) [87]

Multi-country

To describe the establishment of biorepositories by patient organizations using Pseudoxanthoma Elasticum (PXE) International as an example

PXE International Case study Presented historical account of activities ofPXE International• Founders met with other members of the advocacy community• Utilized community engagement to incentivize research through establishment of the PXE International Blood and Tissue Bank



• Brought together various researchers, eventually forming the PXE International Research Consortium• Initiated various research projects, including study leading to identification of gene mutation causing PXE (is co-inventor on the gene patent)• Collaborated with industry, helping to coordinate the development of a PXE diagnostic test• Helped establish Genetic Alliance BioBank (centralized repository of biological samples and data to enable translational genomic research on rare genetic diseases; includes training for advocacy organizations and access to own institutional review board

TREAT-NMD [86][Website]

Multi-country



N/A Described how patient organizations (through EURODIS are involved in leading EuroBioBank, the only biobank network dedicated to rare disease research in Europe.

Disease-specific outcome measuresDe Blieck et al (2013) [88]

United States

To develop a disease-specific clinical outcome measure

Batten disease (juvenile neuronal ceroid lipofuscinosis (NCL)) patients

• Identified patients through a limited-content registry of NCL-affected children developed by academic clinicians and researchers• Elicited input from patients in the development of a rating scale, based on similar scales in adult movement disorders• Pilot-tested, refined, and validated scale through iterative process involving patients (included remote testing via telemedicine)

Registry contained 198 families with 237 children (enrolled between 2001 and 2012)

Presented Unified Batten Rating Scale

Reported that the scale has now been used in clinical trials, including an FDA-approved 8-week Phase II RCT of oral mycophenolate

Clinical trialsMavris & Le Cam (2012) [70]

Europe



Self-administered survey Respondents reported several ways in which their organizations are involved in clinical trials, including:• Helping to Creating links between patients, researchers, and physicians (76%)• Identifying patients to participate in clinical trials (57%)• Providing information & counselling for trial participants (49%)• Assisting in protocol design (48%) • Identifying patients’ needs and expectations in clinical trials (45%)



• Promoting collection of biological samples (28%)

Organizations also reported their involvement in the European Clinical Research Infrastructures Network (ECRIN), which supports clinical trials, through:• Representation in ethics committees• Design of outcome measures• Scientific evaluation• Membership on scientific and ECRIN advisory boards• Involvement in global discussions on acceptability of the risk• Clinical trial training

Boon et al 2009 [72]

Netherlands


Neuromuscular disease Case study Provided historical account of organization’s role in recruiting patients to participate in clinical trials

Regulatory processesKomlos (2013) [136]

United States

To describe the Patient-Focused Drug Development initiative, created under the fifth authorization of the Prescription Drug User Fee Act (PDUFA V), which aims to obtain a better understanding of patients’ perspectives on disease severity and their feedback on available treatments

Patients from disease areas involved in the Patient-Focused Drug Development Initiative

N/A Described the PDUFA V:• Signed into law in 2012 as Title I of the FDA Safety and Innovation Act (FDASIA)• Specifies that the FDA must obtain patient perspectives on at least 20 disease areas over the next 5 years through publicly held meetings involving patients, caregivers, and other relevant stakeholders (discussions to focus on the diseases and their impacts on patients’ daily lives, the types of treatment benefit that matter most to patients, and patients’ perspectives on the adequacy of available therapies)• Meetings begin with an overview of the disease area and current treatment options; questions are posed to an invited panel of patients and/or caregivers; audience attendees and webcast participants also participate• FDA consulted with patient organizations on how questions should be posed• The FDASIA has also helped to expand role of patients and caregivers in regulatory processes through the Patient Representative Program, which gives patients and caregiver the opportunity to speak to disease-specific issues relating to medical products in various stages of development, review, and approval



Mavris & Le Cam (2012) [70]

Europe



Self-administered survey Respondents reported involvement in regulatory processes through the EMA:• Patient representatives sit on the Committee for Orphan Medicinal Products (COMP), the Patients’ and Consumers’’ Working Party (PCWP), the Paediatric Committee (PDCO), the Committee for Advance Therapies (CAT) and the Pharmacovigilance Risk Assessment Committee (PRAC)• Patients roles include dossier evaluation for orphan designation (COMP), approval of a Paediatric Investigation Plan (PDCO), classification of advanced therapy medicinal products (CAT), promoting drug development, ensuring clear information to patients, and attempting to achieve equal access to treatments at the European and national levels

Bignami et al (2011) [137]

Europe

To describe the role of patients in the development of advanced therapy medicinal products

Patients, including those with rare diseases

N/A Presented examples of the role of patient organizations in regulatory processes• European Genetic Alliance and EURODIS) worked with the European Commission (EC), the European Parliament, and others to establish the Orphan Medicinal Products Regulation in 2000; also worked with the EC and European Parliament to bring regulations to the statute book• In 2005, the EMA Management Board endorsed a framework of interaction between the EMA and patient and consumer organizations, which lead to the creation of the Patients and Consumers Working Party (PCWP) in 2006• Patient representatives serve on EMA Management Board, Paediatric Committee (PDCO), Committee for Advanced Therapies (CAT),and Pharmacovigilance Working Party (PhVWP)

Ayme et al (2008) [90]

Europe and United States

To describe progress made in patient empowerment with rare diseases

Rare disease patients and patient organizations

N/A Presented examples of the various activities in which patient organizations have been involved, one of which was:• Legislation: 3 patient representatives serve on the Committee for Orphan Medicinal Products (COMP)

Clinical practice guidelines



TREAT-NMD[86][Website]Multi-country



N/A Described how patient organizations collaborate with specialists on the development of international consensus documents outlining best practice in diagnosis and patient care

Peer support and knowledge exchangeMavris & Le Cam (2012) [70]

Europe



Self-administered survey Respondents reported their involvement in on-line patient support communities• EURODIS and the National Organization for Rare Disorders (NORD) initiated the RareConnect project, which are disease-specific patients’ communities created by patient organizations

Respondents also reported establishing training initiatives (Thalassaemia International Foundation, and ECRIN)


United Kingdom


AS UK N/A Described an Asian mentoring scheme developed by AS UK in response to the high number of Asian patients in families whose cultural practice involves consanguinity

Pierri (2012) [89][Abstract]

United Kingdom

To describe the creation of The Route Map for Adrenoleukodystrophy (ALD) and Adrenomyeloneuropathy (AMN)

ALD and AMN patients N/A Described the development of on-line patient guide (Route Map) for improving the quality of care for ALD and AMN patients, empowering patients and their families to contribute to the NHS system, improving relationships between patients and specialists, and improving awareness of the conditions• Patients involved throughout its development, along with NHS professionals• Patients participated in questionnaire development, focus groups to discuss general and specific issues, and in discussions on the patient experience and care they have received

Ayme et al (2008) [90]




N/A Presented examples of the various activities in which patient organizations have been involved, two of which were:• Education: organizations frequently provide education through the publication of guides, brochures, newsletters, etc. and by hosting workshops and conferences; majority of US support groups have established websites providing access to educational materials and in Europe, Orphanet lists thousands of resources for over a thousand rare diseases



• Financial support to patients: UK Children Living with Inherited Metabolic Disorders (CLIMB) provides grants to families in need


Multi-country



N/A Described how patient organization is involved in procuring aids (e.g., guide dogs), assisting with social and economic problems (e.g., pensions), and providing contacts for psychological counselling

The organization works at the federal, state, and local levels with the Commissioner for the Disabled and advisory boards to provide accessible information and mobility, improved guidelines for the visually impaired and blinded in public space, improved visual contrasts, and corresponding legal guidelines

Patient and public awarenessAyme et al (2008) [90]




N/A Presented examples of the various activities in which patient organizations have been involved, one of which was:• Awareness: Patient organizations have hosted conferences and published magazines (In France, rare disease awareness has been longstanding through the French Muscular Dystrophy Association telethon)

AdvocacyMavris & Le Cam (2012) [70]

Europe



Self-administered survey Respondents reported involvement in developing national plans for rare diseases• As part of the EUROPLAN project, national conferences were held in 15 European countries with multiple stakeholders discussing the transferability of the EU policy documents in 6 areas, including rare diseases


United Kingdom


AS UK N/A Described AS UK’s role in raising awareness of the importance of clinics for AS patients, which led to the funding of two clinics by the NHS National Specialized Commissioning Group

Ayme et al (2008) [90]




N/A Presented examples of the various activities in which patient organizations have been involved, one of which was:• Advocacy and lobbying: Lobbying by the rare diseases community resulted in the adoption of the Regulation on Orphan Medicinal Products by the European Parliament



Terry et al (2007) [87]

Multi-country

To describe the role of a patient organization in developing guidance for advocacy organizations using Pseudoxanthoma Elasticum (PXE) International as an example

PXE International Case study Described how PXE worked with the Genetic Alliance to publish an Interactive Guide to Building Advocacy Organizations


Multi-country



N/A Described how organization works at the federal, state, and local level with the Commissioner for the Disabled and advisory boards to work towards providing accessible information and mobility, improved guidelines for the visually impaired and blinded in public space, and improved visual contrasts and corresponding legal guidelines

TREAT-NMD[86][Website]

Multi-country



N/A Described the role of patient organizations in advocating for funding (the French Muscular Dystrophy Association, AFM, in particular, with the support of EURODIS) to support the establishment of the network• Network is governed by an Executive Committee made up of 9 academic representatives and 4 patient representatives

Documents

static-content.springer.com10.1007... · Web viewTable 3. Summary of papers describing real-world examples of patient involvement in the life-cycles of orphan or ultra-orphan drugs;