Rare Disease Literature Collection 2019

At ORPHA Strategy Consulting, we are joining the global community in observing Rare Disease Day 2019 with a small contribution to knowledge sharing. We've curated a selection of current open source Rare Disease literature, which aims to support the acceleration of research & development, patient engagement, diagnosis, regulatory approval, and - crucially - patient & market access to innovative orphan medicinal products as well as cell & gene therapies. We hope that you will find this literature collection relevant and useful in your daily work to positively impact the lives of persons living with a rare condition.  The blue highlighted external links are current as accessed in February 2019 (note that ORPHA Strategy is not responsible for the content of the external sites). 

Research & Development

  • An evaluation of novel methods to improve drug development in small populations: Marian Mitroiu et al, Applicability and added value of novel methods to improve drug development in rare diseases, Orphanet Journal of Rare Diseases 2018 13:200 https://doi.org/10.1186/s13023-018-0925-0
  • The European ATMP field is still in its early stages, and developers experience multifactorial challenges on many levels: Renske M.T. ten Ham et al, Challenges in Advanced Therapy Medicinal Product Development: A Survey among Companies in Europe, Molecular Therapy: Methods & Clinical Development Vol. 11, December 2018, https://doi.org/10.1016/j.omtm.2018.10.003
  • Orphan Drug Designation is an important value inflection point, particularly for small- and mid-sized biotech, however, it is generally just the start of the clinical development process. Early promise must be substantiated. This analysis shows that failures occurred in 27.8% of all designations granted in Europe, the main reasons being safety and efficacy issues: Viviana Giannuzzi et al, Failures to further developing orphan medicinal products after designation granted in Europe: an analysis of marketing authorisation failures and abandoned drugs. BMJ Open 2017;7:e017358, http://dx.doi.org/10.1136/bmjopen-2017-017358
  • When focusing on new molecular entities only, this study finds that the capitalised clinical development cost per approved orphan drug is half that of a non-orphan drug: Kavisha Jayasundara et al, Estimating the clinical cost of drug development for orphan versus non-orphan drugs, Orphanet Journal of Rare Diseases (2019) 14:12, https://doi.org/10.1186/s13023-018-0990-4
  • Real-world evidence is not unique to Rare Diseases, but increasingly essential to the entire evidence generation lifecycle of orphan medicinal products; therefore, the recent FDA paper cannot be missing from this collection: Framework for FDA's Real-World Evidence Program, December 2018
  • Traditional randomised clinical study designs are often considered infeasible or even unethical in life-threatening rare conditions without adequate treatments. Therefore, single-arm open label studies are an important methodology for orphan drug development. This recent review finds there has been a large increase in submissions to the EMA and FDA using non-randomised study designs involving comparisons with external controls in recent years. This study demonstrated that regulators may be willing to approve such submissions, although approvals are often conditional on further confirmatory evidence from post-approval studies: Goring S, et al, Characteristics of non-randomised studies using comparisons with external controls submitted for regulatory approval in the USA and Europe: a systematic review; BMJ Open 2018; 0:e024895, https://doi:10.1136/bmjopen-2018-024895 (link will be active soon)
  • Review - Future of Rare Diseases Research 2017–2027: An IRDiRC Perspective: the scale of the “rare disease problem” — thousands of rare diseases, the vast preponderance of them with no approved treatment, and decades-long diagnostic odysseys for many patients — led to the realisation that the time had arrived for global cooperation and collaboration: The International Rare Diseases Research Consortium (IRDiRC) was founded in 2011, Clin Transl Sci (2018), https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1111/cts.12500
  • Low prevalence, lack of knowledge about the disease course, and phenotype heterogeneity hamper the development of drugs for rare diseases. Rare disease registries (RDRs) can be helpful by playing a role in understanding the course of the disease, and providing information necessary for clinical trial design, if designed and maintained properly. This paper describes the potential applications of a RDR and what type of information should be incorporated to support the design of clinical trials in the process of drug development: Marijke Jansen-van der Weide et al, Rare disease registries: potential applications towards impact on development of new drug treatments, Orphanet Journal of Rare Diseases (2018) 13:154, https://doi.org/10.1186/s13023-018-0836-0
  • This review makes the observation that registries with biobanks had the function of both stand-alone registries (the capacity to collect comprehensive clinical and epidemiological data) and stand-alone rare disease biobanks (the ability to contribute to Omics research). It finds registries with biobanks offer a unique, practical, cost-effective, and impactful solution for rare disease research. Monique Garcia et al, Impact of biobanks on research outcomes in rare diseases: a systematic review, Orphanet Journal of Rare Diseases (2018) 13:202 https://doi.org/10.1186/s13023-018-0942-z
  • Collaboration and data sharing is the future and particularly crucial in Rare Diseases. This work represents a case study in how data collected during routine patient care can inform precision medicine efforts for the population at large. It suggests that health policies can promote innovation by defining appropriate uses of real-world evidence, establishing data standards, and incentivizing data sharing: Vineeta Agarwala et al,  Real-World Evidence In Support Of Precision Medicine: Clinico-Genomic Cancer Data As A Case Study, HEALTH AFFAIRS 37, NO. 5 (2018): 765–772, https://doi.org/10.1377/hlthaff.2017.1579 
  • This paper concludes that the use of Real-World Evidence (RWE) resulted in a reduced sample size of pivotal phase III studies, which led to substantial time savings compared to the approach of sample size calculations without RWE: Reynaldo Martina et al, The inclusion of real world evidence in clinical development planning, Trials (2018) 19:468, https://doi.org/10.1186/s13063-018-2769-2
  • Italy has considerable and longstanding expertise in registries; this article is a case study for rare disease registry governance and organisation with a particular focus on patient empowerment: Anna Ambrosini et al, The Italian neuromuscular registry: a coordinated platform where patient organisations and clinicians collaborate for data collection and multiple usage, Orphanet Journal of Rare Diseases (2018) 13:176, https://doi.org/10.1186/s13023-018-0918-z

Patient Engagement

  • EURORDIS - Today, the 30 million Europeans living with a rare disease and their family members (often the main carers) remain a marginalised and largely invisible population, with little information about their diseases and their rights, few treatments, and a high level of psychological, social and economic vulnerability. This paper presents evidence on the unmet everyday needs of people living with a rare disease and their family members (often the main carers), while also offering a synthesis on policy and recommendations to achieve holistic care for rare diseases. Achieving Holistic Person-Centred Care to Leave No One Behind - A contribution to improve the everyday lives of people living with a rare disease and their families - Executive Summary and Full Report, May 2019, eurordis.org/carepaper
  • Rare diseases can lead to a significant reduction in quality of life for patients and their families. Ensuring the patients voice is central to clinical decision making is key to delivering, evaluating and understanding the efficacy of therapeutic interventions. Patient reported outcome measures (PROMs) are used to capture the patient’s views about their health status, the impact of rare diseases and their treatments on patient’s quality of life and symptoms:  Anita Slade et al, Patient reported outcome measures in rare diseases: a narrative review, Orphanet Journal of Rare Diseases (2018) 13:61, https://doi.org/10.1186/s13023-018-0810-x
  • Patient involvement in clinical research & development is not unique to, but absolutely crucial in Rare Diseases. This article shows that engagement activities with the potential to avoid protocol amendments and/or improve enrolment, adherence, and retention may add considerable financial value: Bennett Levitan et al, Assessing the Financial Value of Patient Engagement: A Quantitative Approach from CTTI’s Patient Groups and Clinical Trials Project, Therapeutic Innovation & Regulatory Science 2018, Vol. 52(2) 220-229, https://doi.org/10.1177/2168479017716715 
  • The European Conference on Rare Diseases & Orphan Products is the unique forum across all rare diseases, across all European countries, bringing together all stakeholders - patients’ representatives, academics, healthcare professionals, industry, payers, regulators and policy makers: 9th European Conference on Rare Diseases and Orphan Products, 10-12 May 2018, Vienna, Executive Summary
  • Rare childhood conditions are associated with substantial estimated losses in quality of life, including evidence of disutility among parents. Continued research is needed to assess and measure the effects of childhood disease from a family perspective: Norma-Jean Simon et al, Health utilities and parental quality of life effects for three rare conditions tested in newborns, Journal of Patient-Reported Outcomes (2019) 3:4, https://doi.org/10.1186/s41687-019-0093-6
  • This paper argues that existing value frameworks, registries, and outcomes-based contracts largely fall short of consistently measuring the full range of outcomes that matter to patients; and that greater use of Patient-Centered Outcomes Measures (PCOMs) in rare diseases would enable a fast track to Patient-Centered Care: Thomas Morel et al, Measuring what matters to rare disease patients – reflections on the work by the IRDiRC task force on patient-centered outcome measures, Orphanet Journal of Rare Diseases (2017) 12:17, https://doi.org/10.1186/s13023-017-0718-x
  • PRO assessments in rare disease clinical trials have been particularly successful through partnerships between investigators, PRO methodologists, and patient organizations. The overall goal of PRO measurement is to understand the patient experience and it provides an essential part of evaluating the impact of disease and treatment. Ethan Basch et al (2014), Patient-Reported Outcomes in Clinical Trials of Rare Diseases, J Gen Intern Med 29(Suppl 3):S801–3, https://link.springer.com/article/10.1007/s11606-014-2892-z 
  • Family caregiving is a growing phenomenon with the increased prevalence of chronic illness and shorter hospitalizations. Rare diseases pose significant challenges not only to patients living with these kinds of pathologies but also to those who care for these patients. The present work aims to increase knowledge of the challenges that are common or specific to fathers and mothers of children diagnosed with a rare disease. Paola Cardinali et al (2019), The Caregiving Experiences of Fathers and Mothers of Children With Rare Diseases in Italy:  Challenges and Social Support Perceptions. Front. Psychol. 10:1780. doi: 10.3389/fpsyg.2019.01780
  • There is a limited literature on the spillover disutility of illness on family members and caregivers. Caring for an ill or disabled family member imposes a well-documented burden on the caregiver. The benefits of a health intervention may be underestimated if “spillover” effects on family members are not captured, resulting in inaccurate conclusions of economic evaluations. Eve Wittenberg et al, Disutility of illness for caregivers and families: a systematic review of the literature, Pharmacoeconomics. 2013 June ; 31(6): 489–500. doi:10.1007/s40273-013-0040-y

Rare Disease Diagnosis 

  • When it comes to a child with a rare disease, the search for an answer can turn into a diagnostic odyssey. Today, it can take an average of five years to get an accurate diagnosis. Too many families around the world bounce between physicians and specialists only to receive multiple misdiagnoses. The consequences can be devastating. Global Commission to End the Diagnostic Odyssey for Children with a Rare Disease, Year One Report (Takeda, Microsoft, and EURORDIS, January 2019) - the key recommendations include: 1) Empowering Patients and Families; 2) Equipping Frontline Providers with Tools for Diagnosis and Referral; 3) Reimagining the Genetic Consultation
  • The quality of the relationship between individual patients and physicians, and between the patient community and the scientific community, is critically important for optimising the use of available data and enabling international collaboration in order to provide a diagnosis, and the attached support, to unsolved cases: Sabina Gainotti et al, Review - Meeting Patients’ Right to the Correct Diagnosis: Ongoing International Initiatives on Undiagnosed Rare Diseases and Ethical and Social Issues, Int. J. Environ. Res. Public Health 2018, 15, 2072; https://doi.org/10.3390/ijerph15102072

Patient & Market Access

  • The objective of this Environmental Scan is to identify, describe, and compare how HTA agencies internationally make reimbursement recommendations on orphan drugs. The Environmental Scan will also present information on how public payers evaluate and make funding decisions on orphan medicinal products: Drugs for rare diseases - a review of national and international health technology assessment agencies and public payers’ decision-making processes. Ottawa: CADTH, 2018. (Environmental scan; no. 77), https://cadth.ca/drugs-rare-diseases-review-national-and-international-health-technology-assessment-agencies-and
  • This article reviews the theory of economic evaluation and argues that its focus upon individual utility and efficiency omits potentially important social values, which is particularly relevant in Rare Conditions: Jeff Richardson et al, Health technology assessment (HTA) and economic evaluation: efficiency or fairness first, JOURNAL OF MARKET ACCESS & HEALTH POLICY, 2018, VOL. 7, 1557981, https://doi.org/10.1080/20016689.2018.1557981
  • Access to rare disease therapies is challenging in many countries because the legal and policy frameworks may be absent, funding may be insufficient and/or payers do not see the justification with the prices for these therapies. The industry has, however, a real opportunity to partner with healthcare systems to address these issues, for example, through education towards payers, responsible and evidence-based pricing, and innovative contracting: François Lucas, Improving market access to rare disease therapies: A worldwide perspective with recommendations to the industry, Medicine Access @ Point of Care 1–7, 2018, https://doi.org/10.1177/2399202618810121
  • Conditionally approved drugs only rarely receive positive HTA recommendations (12%), making market access highly challenging. This is particularly relevant to orphan drugs, which often come to market with substantial scientific uncertainties: Rick A. Vreman et al, Weighing of Evidence by Health Technology Assessment Bodies: Retrospective Study of Reimbursement Recommendations for Conditionally Approved Drugs, Clinical Pharmacology & Therapeutics, 2018, https://doi.org/10.1002/cpt.1251
  • This paper identifies the different methods for public funding of OMPs in order to map the availability for rare disease patients, as well as to compare the public expenditures on OMPs in 8 EU member states: Márta Szegedi et al, The European challenges of funding orphan medicinal products, Orphanet Journal of Rare Diseases (2018) 13:184, https://doi.org/10.1186/s13023-018-0927-y
  • "Affordability is distinct from the value of a product or service. Thus, an essential medicine might offer a large health benefit or high value,  but still might not be affordable (because of limited resources, high prices, or both)’’. Given the technical challenges of using health technology assessment, focussing solely on value-based pricing also has the potential to undermine existing and effective systems of competitive tendering and price-volume agreements. Sarah Garner et al, Value-Based Pricing: L’Enfant Terrible?, PharmacoEconomics (2018) 36:5–6, https://doi.org/10.1007/s40273-017-0567-4

Further Rare Disease Resources, Expedited Programs (FDA), Support for Early Access (EMA)

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