7
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Accelerating evidence gathering and approval of precision medicine therapies: the FDA takes aim at rare mutations

      brief-report
      , PhD, MPH 1 , 2 , 3 , , , JD 3 , , JD, PhD 3 , , JD, PhD 3
      Genetics in Medicine
      Nature Publishing Group US

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Patient heterogeneity in drug response has led to alternative models to the randomized clinical trial (RCT) for drug development, and enabled the evolution of newer regulatory frameworks in recent years. In 2012, the US Food and Drug Administration (FDA) published a popularly used Guidance for Industry on Enrichment Strategies for Clinical Trials to Support Approval Of Human Drugs And Biological Products. 1 Enrichment strategies refer to the a priori identification and selection of subpopulations of patients, often on the basis of molecular profiling, to increase the likelihood of efficacy of a particular treatment or intervention. 1 More recently, the FDA released a Draft Guidance for Industry: Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease, 2 which provides flexibility to evidence standards to show that a drug works for low-frequency mutations (i.e., “molecular alterations”; strictly for simplicity, we use the short-hand “mutations” in this paper although the Guidance applies to a broad set of molecular alterations). With this new guidance, the FDA proposes to provide sponsors with a strategy for identifying and determining clinical trial eligibility of different patients who have variable molecular modifications. Notably, this new guidance provides broad recommendations for going beyond traditional enrichment strategies, to allow for the grouping of patients having different molecular subtypes of low frequency. The guidance forms part of the FDA’s efforts to advance the development and availability of safe and effective targeted treatments for rare diseases, as well as common diseases due to rare mutations. 3 By focusing on molecular subtypes of low frequency and allowing for the grouping for trial eligibility, the FDA is signaling a change in evidentiary standards. This change has implications not only for pharmaceutical industry sponsors, but also for multiple actors in the drug development process. In this paper, we examine the impact of these changing evidentiary standards on the conduct of clinical trials, drug approvals and prescriber duties, and patients, as well as the need for data sharing. Possible impact on clinical trials The FDA Guidance states, “clinical trial assays should be designed to detect all possible molecular alterations that comprise the group that is expected to respond.” 3 Typically, in an enrichment design, a strong biomarker that can identify a subgroup of patients for whom the treatment is expected to be particularly effective allows for the enrollment of a small sample size that is adequately powered to detect an appropriate treatment effect (e.g., in phase III studies 0.025 for a one-sided statistical significance). An accepted concept in precision medicine (including by FDA authors) is agreement that within a clinical study, a predictive biomarker should be able to distinguish between a subgroup of patients who will benefit (biomarker positive) from those who will not benefit (biomarker negative) from treatment. 4, 5 The new FDA draft guidance explicitly cautions sponsors to use analytically valid assays; however, no discussion is provided about clinical validity concerns that might arise in the course of using biomarkers to identify molecular alterations of low frequency. The FDA acknowledges, “low numbers…would in most settings preclude meaningful empirical inferences about treatment benefits or risks….” 3 Nevertheless, the new Guidance presumes that “extrapolation across multiple subsets may be possible despite the low frequency or absence of patients in some subsets.” 3 The new evidence standards thus appear to favor internal validity over external validity, but do not address explicitly how sponsors are to interpret this departure from the accepted standards of evidence and rigorous RCT design and conduct. This presents challenges given that many stakeholders rely on RCTs for evidence of clinical validity and utility. The need for data sharing The creation and integration of more data to support low-frequency molecular drug indications will require new collaborative approaches to data generation by researchers, clinical laboratories, and genetic databases. The need for data sharing is evident both upstream (to support clinical trial inclusion criteria) and downstream (enhanced pharmacosurveilllance) of approval. Upstream, it is unlikely that sponsors will be able to generate data on rare mutations on their own. For example, the approach pioneered for the cystic fibrosis transmembrane conductance regulator (CFTR) gene depended, in part, on evidence from a genetic database, which was progressively populated by researchers and clinical laboratories. 6 Higher standards for genetic databases will need to be developed and perhaps even regulated, to ensure the quality of data. More reliance on external databases by sponsors can raise concerns about database transparent aggregation, curation and interpretation of variants, data quality, and possible conflicts of interest. Indeed, previous FDA draft guidance initiated discussions on establishing standards, or even certification, for variant databases. With drugs approved with lower evidentiary standards, the FDA Guidance also calls for enhanced postapproval patient surveillance. While clinical data sharing is an emerging norm for clinicians and laboratories, 7 both the FDA and sponsors will need to take a greater leadership role in promoting and funding data sharing. Including rare mutations on drug labels will support more rigorous patient monitoring and data sharing than the current use of off-label prescribing. Drug labeling and prescribers’ duties to patients To offset the lower evidentiary standard, the FDA draft guidance calls for detailed labeling information to accompany drugs, including information about the level of evidence supporting rare molecular indications. Stakeholders, such as prescribers and payers, traditionally work on the assumption that indications, including molecular indications, are based on clinical trial data. The FDA guidance calls for labels to include a transparent description of the (limited) evidentiary basis for rare molecular indications. While commendable, this shift will demand greater scientific literacy and accountability on the part of health professionals prescribing the drug. Because so few medicines have been approved specifically to treat rare diseases, 8 there is a significant amount of off-label use in rare diseases. This status quo puts significant responsibility on clinicians. Off-label use might be the standard of care for many patients who are in dire need of new drugs to manage their rare condition. However, off-label prescribing may expose physicians to legal claims of medical malpractice if informed consent is insufficient or if sound medical judgment, based on the available evidence, 9 was not properly exercised. Furthermore, it is possible that the new Guidance would require that patients be tested for the relevant biomarkers, a practice that is not routinely carried out with off-label prescribing. The Guidance could help to ensure that some (as opposed to no) evidence is generated in clinical trials for rare mutations. In addition, this approach could help inform prescriber and patient shared decision-making in selecting a therapy. One caveat, however, is that prescribers will need to explain complex labels, that drugs are “indicated,” but that this indication is supported only by limited evidence. Impact on patients The new Guidance may change clinical practice and impact patient care in addition to the effects of changing drug labels and prescriber duties. Particularly salient is the question of how likely it is that a new treatment, if approved under these new evidentiary standards, would be used in clinical practice, given that clinicians typically use RCTs for evidence of clinical validity and utility. Accepting groupings of patients with particular molecular variations into a given clinical study may be a windfall for industry sponsors looking to identify the right patient for the drug. However, within the real world context of clinical practice, this may be less useful in identifying the right drug for the patient, which is ultimately the desired health outcome. Nevertheless, the new Guidance provides opportunities to further clinical research on low-frequency mutations for both rare and more common diseases, and this may ultimately be beneficial for patients, who have hitherto been underserved with respect to targeted treatments. Conclusion The FDA is leading international efforts to encourage the adoption of precision medicine, and to improve accessibility of drugs for individuals with rare disease. What does this change ultimately mean for patients with rare diseases? The Draft Guidance may improve incentives for sponsors to run small trials, ultimately improving the evidence base and therapeutic options for these patients. It might encourage sponsors and regulators to determine molecular indications according to standard albeit lowered evidentiary standards, rather than putting the onus on clinicians to rely on “off-label” use. Indeed, what was once an off-label use might, with the new Guidance, become an on-label use, with any adverse outcomes reported through postmarket surveillance mechanisms. Success will depend on innovation by, and collaboration between, multiple stakeholders, including prescribers, regulators, payers, and patients.

          Related collections

          Most cited references3

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          Future of Rare Diseases Research 2017–2027: An IRDiRC Perspective

          The International Rare Diseases Research Consortium (IRDiRC) was founded in 2011 with the conviction that rare diseases research had reached a critical juncture. Proof of principle existed that rare diseases could be diagnosed, new treatments successfully developed and approved, and improvements in quality and quantity of life achieved. Government research funders, companies, scientists, and patient advocacy groups had all demonstrated their commitment and effectiveness in contributing to progress in rare diseases research. However, the work was largely atomized, with each organization, each country, and the champions of each disease pursuing independent, often duplicative solutions. 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 realization that the time had arrived for global cooperation and collaboration among the many stakeholders active in rare diseases research, to capitalize on these proofs of principle, and maximize the output of rare diseases research efforts around the world. IRDiRC's initial aims were to aid in the achievement of two overarching objectives: to contribute to the development of 200 new therapies and the means to diagnose most rare diseases by the year 2020.1 For more detailed information on the history, governance, and nascent stages of the Consortium, please refer to the accompanying piece on the first 6 years of IRDiRC.2 Due to the remarkable global surge in activity in rare diseases research over the last 6 years, including contributions by IRDiRC, the Consortium's 2020 goal for 200 new therapies was achieved in early 2017—3 years ahead of schedule—and the goal for diagnostics—the ability to diagnose most rare diseases by 2020—is within reach; these accomplishments were celebrated at the 3rd IRDiRC Conference in Paris in February 2017.3 The 6 years preceding this 2017 conference have been truly extraordinary for the rare diseases research community and for rare disease patients. Major public‐sector research initiatives focused in this area have emerged or expanded in many countries, most notably from the US National Institutes of Health (NIH), the European Commission (EC), and the newly formed Japan Agency for Medical Research and Development (AMED). Engagement and partnering among public funders, scientists, industry, and people living with rare diseases have gone from being the exception to commonplace. IRDiRC has been a major positive factor in raising public awareness about rare diseases, the need for more research to address them, and for collaborative tools which allow ethical data sharing for and with patients. It has also clearly led to increased investment of public‐ and private‐sector research funds for rare diseases, in addition to the research funding raised by patients and patient organizations. IRDiRC has helped to catalyze several important initiatives that are improving collaboration among researchers and enhancing the ability of patients to engage as constructive partners in research.2, 4 As gratifying as these developments are, those who lead much of the global rare diseases research community are well aware of the enormous challenges that lie ahead for all patients living with rare diseases to receive an accurate and timely diagnosis, to have approved treatments available, to get access to those treatments, and to realize improvements in their quality and quantity of life; in short, to be able to live the best life possible. Although the means to diagnose most rare diseases that are caused by mutations in the coding genome is on track to be achieved either via genotype–phenotype correlation or novel gene discovery, in practice most patients with rare diseases spend years in the healthcare system before an accurate diagnosis is made. For rare diseases that have yet to be defined, next‐generation genomics and improved data sharing have resulted in faster discovery of disease gene and consequent development of new diagnostics, although there are signs that the rate of disease gene discovery is now slowing, as the remaining unsolved diseases are likely more complex.5 To respond to this subsequent level of complexity, novel approaches, particularly ones that better address the nonprotein coding regions of the genome, will need to be developed. There is some cause for confidence with regard to new therapies as the rate of rare disease therapeutic development has been increasing. However, it remains the case that 94% of rare diseases lack an approved treatment,6, 7 that the number of currently untreatable rare diseases that have a first treatment approved each year remains low, and that serious inequities remain with regard to patient access to effective treatments even when they are available. Additionally, the present model for recovering drug development costs from market sales has not been proven in its application to rare diseases with worldwide populations of hundreds or less. To address these therapeutic discovery issues, new approaches including data‐mining and repurposing, in addition to new models for funding drug discovery and covering treatment costs, will be necessary for the comprehensive treatment of rare diseases worldwide. With this paradox in mind—the desire to celebrate unprecedented progress but recognizing the immense need and opportunities that remain—IRDiRC set about devising new global rare disease goals for the coming decade. Through this year‐long collaborative process, IRDiRC aimed to set goals that would achieve all that is scientifically possible in the short term, and aggressively push the limits of what is currently impossible in the longer term, all with the knowledge that patients are waiting, and “Time Equals Lives.”8 IRDiRC: 2017–2027 Process To assure input from all stakeholders and arrive at a short list of ambitious but achievable IRDiRC goals for the next decade, a multistep, year‐long, objectives‐setting process was implemented. Initially, ideas on critical problems in the rare diseases field and solutions to them were solicited broadly from IRDiRC member organizations and nonmembers represented on the IRDiRC Scientific Committees from academia, patient organizations, the biopharmaceutical industry, and regulatory bodies, in each of the three scientific focus areas: diagnostics, foundational/interdisciplinary, and therapies. The hundreds of ideas submitted were grouped and consolidated, debated online and in‐person, and then voted on to determine which were of highest priority and need. Based on this process, a series of potential goals were generated, along with activities to advance the goals, and metrics to measure progress. During the internal IRDiRC Meeting in Paris, France in February 2017, the candidate goals, activities, and metrics were further refined by the IRDiRC members. At the open IRDiRC Conference that followed, the goals were presented to the greater rare disease community for feedback, discussion, and questions to further shape the IRDiRC vision and objectives for the next decade. This vigorous, animated, and informed session added broad public input to the goal‐setting process and in addition spurred excitement and engagement about IRDiRC's plans to deliver on the promise of science for people living with rare diseases over the next decade. Following the Meeting and Conference, the final IRDiRC Vision and 2017–2027 Goals were formally adopted by vote of the IRDiRC Consortium Assembly. Framework Given the unusually broad scope of IRDiRC—in science, constituencies, and geography—the IRDiRC goal‐setting process incorporated an unusually broad series of criteria. First, the process utilized the “SMART” criteria—that is, candidate goals needed to be Specific, Measureable, Achievable, Realistic, and Timely. They also needed to be within the scope of IRDiRC's research mission. Lastly, they needed to be easily understood by a wide variety of stakeholders and audiences, while also being bold and transformational. Therefore, it was determined to organize the process on four levels—Vision, Goals, Activities, and Metrics. The Vision is IRDiRC's overarching statement of the end state toward which all its activities drive; the Vision is aspirational and not time‐delimited. The Goals state bold but distinct achievements that IRDiRC commits to accomplish over the next 10 years that will advance the realization of the Vision. The Activities are discrete, shorter‐term projects IRDiRC will perform to advance each of the Goals; the list of Activities will continually change, depending on successes and failures of previous Activities and evolution of the field. The Metrics will assess and track progress of Activities over time, ensuring accountability and progress toward the Goals. The new IRDiRC Vision, the IRDiRC Goals for 2017–2027, and exemplar Activities and Metrics, follow. The IRDiRC Vision Enable all people living with a rare disease to receive an accurate diagnosis, care, and available therapy within 1 year of coming to medical attention IRDiRC is well aware of the aspirational nature of this Vision; IRDiRC is also cognizant that some aspects of the Vision are outside its research mission. However, IRDiRC also believes that the Vision is achievable with all stakeholders’ commitment, cooperation, and collaboration. Thus, the challenge inherent in the Vision is intentional, aimed at galvanizing the broad rare disease community, within IRDiRC and outside it, to not only enable universal diagnosis and treatment, but also ensure that these interventions reach people with rare diseases, and have the intended positive impact on their health and well‐being. The IRDiRC Goals for 2017–2027 The three Goals that IRDiRC members have committed to achieving in the next decade to advance the realization of the IRDiRC Vision follow, along with the rationale, challenges, and opportunities of each. Goal 1: All patients coming to medical attention with a suspected rare disease will be diagnosed within 1 year if their disorder is known in the medical literature; all currently undiagnosable individuals will enter a globally coordinated diagnostic and research pipeline Recent data indicate that approximately half of the individuals with a suspected rare disease are undiagnosed, while those who have received a diagnosis wait on average 5–6 years,9, 10 and diagnostic delays of several decades have been observed. The clinical introduction of new diagnostic methods such as next‐generation sequencing has allowed the laboratory turnaround time to be as short as several weeks to diagnose some of the rare diseases with a known molecular basis. Each undiagnosed rare disease represents an opportunity to open up a new area of biological insight, and it follows that, as the number of novel genes and pathogenic variants identified increases, so does the diagnostic yield. The time has come for researchers, clinicians, and patients worldwide to collectively understand the etiology of the vast number of rare diseases, make the final push to enable the diagnosis of all rare diseases, and facilitate access to an efficient diagnosis for patients. Within the next decade, IRDiRC will work together to implement a system whereby patients with a suspected rare disease of known molecular basis will be diagnosed within 1 year of initial presentation to a medical professional instead of confronting a years‐long diagnostic odyssey. The challenges in achieving this part of Goal 1 are principally operational, involving public and physician awareness, efficient referral within the medical system, and the requirement for radically more efficient sharing of diagnostic expertise and data among practitioners and researchers worldwide. Rare disease mechanism discovery The number of unsolved patients following whole exomes sequencing argues that more disease genes and variants await discovery, thus the discovery effort must be expedited. So far, most of the known disease variants fall in coding regions of the genome, but much less is known, for example, about the role of noncoding region variants and structural variants in disease.5 This calls for approaches that are complementary to whole exome sequencing (WES) such as whole genome sequencing (WGS), long read technologies, and transcriptome sequencing that can more effectively target noncoding regions and/or structural variants. Moreover, variant interpretation still needs improvement through developments in bioinformatics, analysis algorithms, and data sharing. Wide acceptance of data standards and ontologies (e.g., Human Phenotype Ontology (HPO)11 and Orphanet Rare Disease Ontology (ORDO)),12 and automated exchange of phenotypic and genomic information via shared platforms and tools (e.g., Matchmaker Exchange13 and RD‐Connect14) should be required to transform sequence information into diagnostic knowledge. Functional analyses at scale will need to be developed to facilitate variant interpretation in conjunction with data sharing. Patient access to diagnosis After initial presentation to a medical professional, patients with a rare disease often spend a long time trying to find a specialist with appropriate expertise to recognize the syndrome or perform the correct diagnostic test. Comprehensive and easily accessible information about subspecialty medical professionals and diagnostic laboratories can help shorten this time. In conjunction, sequencing and analysis costs will need to continue to drop to improve affordability. Finally, robust data should be collected and analyzed on diagnostic utility, clinical utility, and cost‐effectiveness to facilitate reimbursement of sequencing‐based diagnosis by more health insurance companies. International network for undiagnosed patients It has been shown that undiagnosed patients have an increased chance for their diagnostic challenge to be “solved” in a research setting where more comprehensive sequencing, analysis, and data sharing can be performed. It is time to establish global networks of clinical and research laboratories to collectively tackle undiagnosed diseases. Ideally, appropriate consents including the provision for research and data sharing should be obtained from the outset of the clinical testing process. Samples for further research using sequencing and other genomic methods should be collected and stored in appropriate biorepositories. However, there is only so much that can be done without cooperation and coordination on a larger scale. If a diagnosis is not made after initial sequencing, then the data should be immediately transferred to a global network of appropriate expertise that can accept it for further study and immediate feedback of the result. The Undiagnosed Diseases Network International (UDNI)15—modeled after the US NIH's Undiagnosed Diseases Program (UDP)—is an example of a program established to aid in this effort. Collaboration with the UDNI as well as UDP will bring crucial attention to complex cases, where collective expertise will lead to a higher chance of providing a much‐needed diagnosis in order to identify the best course of treatment for each patient. IRDiRC also encourages collaboration with national programs, such as the Japanese Initiative on Rare and Undiagnosed Diseases (IRUD),16 to capitalize on additional knowledge and data sharing with the aim of bringing diagnoses to rare diseases patients. Education of physicians and engagement of patients To take advantage of fast‐evolving technologies, established networks, and available tools, it is necessary to educate physicians and engage patients and families. For example, education can be provided via courses on rare diseases and new diagnostic methods and targeted to various end‐users, including physicians and patients, with different levels of knowledge at the outset. Patient engagement in research and clinical networks should continue to be facilitated. Metrics Online Mendelian Inheritance in Man (OMIM)17 and Orphanet18 will continue to be reliable resources for monitoring newly reported diseases and disease genes. The time it takes for a patient to be diagnosed could come from surveys of specialty physicians, clinical labs, and patient organizations, or more targeted sampling via rare disease networks. Goal 2: 1000 new therapies for rare diseases will be approved, the majority of which will focus on diseases without approved options Although the rate of therapy development for rare diseases has been increasing, the fact remains that most rare diseases—well over 90%—lack an approved treatment and the number of currently untreatable rare diseases to receive a first treatment each year remains low. The introduction of regulations, policies, and incentives dedicated to orphan drug development has spurred significant investment in therapeutic development to the benefit of rare disease patients.19 Since 2010, IRDiRC has tracked the number of orphan medicinal products (OMPs) receiving first approval for a new indication in the European Union and/or the United States, and has found an increase from 15 in 2010 to more than 40 in 2014 and 2015, with a current average of ∼35 approvals per year. Between 2010 and 2016, over 220 OMPs have received first approval for a new indication in the European Union and/or the United States. While significant, this achievement does not negate the fact that patients with one of the thousands of other rare diseases are still waiting for a therapy to be approved for their conditions. Innovative approaches, including clinical trial design, data and specimen collection, clinical end points, repurposing, natural history studies, and engaging the many players involved are necessary for exponentially improving therapy development on a global scale. Therapeutic development pipeline Assuming a constant delivery of OMPs from the pipelines of biopharmaceutical industries, in the next 10 years treatments would become available for only ∼600 of the 7,000 known rare diseases. Thus, new approaches will be needed, particularly since the current pace may not be sustained. In 2016, only 34 new indications were approved, suggesting a slowing of the development and approval pace. Moreover, developed drugs have often clustered around similar technologies or therapeutic approaches that will soon have maximized their capacity to generate new therapeutic advances. For instance, the systemic manifestations of several lysosomal storage disorders (LSDs) have been quite successfully addressed by treatments based on enzymatic replacement through recombinant proteins containing mannose‐6‐phospate residues or small molecules through substrate inhibition, but the list of remaining LSDs to be targeted is significantly shrinking and all these drugs leave unaddressed the same manifestations (e.g., the central nervous system involvement). The “lower‐hanging fruits” of easily developable indications, addressable by traditional approaches, will likely decrease over time, leaving more complex therapeutic targets and yet unproven technologies. In addition to challenges specific to rare diseases, the risk‐adjusted development costs in the pharmaceutical industry have witnessed an overall increase, and postregulatory approval access challenges have become larger due to budgetary constraints of payers.20, 21 In order to achieve the IRDiRC goal of 1,000 new therapies in the next decade, a significant increase in R&D productivity is needed, with a compounded annual growth rate at or above 10%, thus tripling the current rate. Moreover, the IRDiRC goal is for new orphan drug approvals to be predominantly for diseases currently without approved drugs. Although IRDiRC anticipates that many of the 1,000 new approvals will be new indications for existing agents rather than new molecular entities, scalability and sustainability will be significant challenges, both to the regulatory system, and to healthcare budgets. IRDiRC includes representatives from the world's major pharmaceutical regulatory agencies and is deliberately increasing representation from health technology assessment agencies, in order to anticipate and mitigate these challenges. Potential advancements in therapeutic development This important goal can be achieved only through a dramatically more efficient development process driven by a radically new approach utilizing common standards across distinct research fields, sharing of best practices, creating sustainable business models, and redefining the regulatory environment. New methodologies are needed to streamline drug development. These include early stage improvements such as increasing the efficiency of data collection and sharing, improving the understanding of disease progression and phenotypes, improved methods for preclinical assessment of safety and efficacy, and methodologies for small size clinical trials. In addition, later stage advancements including defining end points more universally suitable for measuring patient's benefit, providing medical relevance, generating regulatory benefit/risk evidence, and quantifying a product's economic value for payers, companies, and society at large are essential. The emerging European Reference Networks22 and the potential collaborations with the US Rare Diseases Clinical Research Network23 provide an unprecedented opportunity for coordinating global rare diseases research to: improve care standards, increase access to diagnosis and treatment, increase the understanding of phenotypes and natural history, increase enrollment of patients into clinical trials, and more effectively create and manage disease registries. Engaging patients and regulators Placing patients at the center of clinical research, drug development, and evaluation is increasingly recognized as paramount to fully understanding a disease and to identifying meaningful end points. Their knowledge, contribution, empowerment, and participation are crucial to increasing the efficiency of such efforts. Close cooperative actions with regulators will also be indispensable, particularly via early dialog with regulators and product development with protocol assistance to ensure regulations are adhered to at every step, thus maximizing the potential outcome of a marketing authorization. To cope with an increased volume of applications and requests of protocol assistance, a number of changes will be necessary: streamlining the approval process, creating collaborative review processes between regulators from different jurisdictions, increasing human resource and training programs, and potentially updating regulations to assist in accelerating therapy development. Efforts are already under way to streamline and align regulatory processes across jurisdictions24; IRDiRC aims to aid and foster such efforts, as they will ultimately contribute to the development of new rare disease therapies. In addition to coordinating research efforts, data sharing, and patient engagement, it is also vital to promote changes to the drug development landscape such as new models of risk and incentive sharing between public and private partners, systematic repurposing of existing agents, and developing a more flexible regulatory framework. IRDiRC is committed to work as a key enabler of this quantum change as reflected in the vision. IRDiRC promotes the development and sharing of new tools, best practices, and recommendations to inform research policies and strategies worldwide. IRDiRC also will foster new methods to enable dialog between private and public research funders and regulators with the goal of bringing about this quantum change needed to reach the ambitious goal of developing 1,000 new therapies within the next decade. Metrics The number of new indications treated with medicinal products for rare diseases receiving marketing authorization in the European Union, the United States, and Japan will be the main indicator of progress toward the 1,000 therapies goal, based on information from the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). A number of secondary metrics will also be developed to monitor the quality of evolution of the field, e.g., the number of medicinal products for rare diseases with marketing authorization but without orphan designation, and the number of RDs that are addressed by these medicinal products. Goal 3: Methodologies will be developed to assess the impact of diagnoses and therapies on rare disease patients While faster diagnosis and increased development of new therapies are essential, their impact on people living with rare diseases cannot be assumed; for example, patients can benefit only to the degree that they have access to the interventions, and access may or may not lead to the intended improvement in quantity and/or quality of life. Although IRDiRC members, representing funders, companies, patient advocacy groups, scientists, and other stakeholders agreed on this truism, they varied in their view of IRDiRC's role, as a research organization, in addressing the impact issue. While patient advocacy group members tended to support inclusion of impact assessment as critical IRDiRC research, many scientific and funder members felt that this was more the mandate of health technology assessment authorities. A rich and important debate, including with numerous stakeholders participating in the IRDiRC Conference in February 2017, concluded with the realization that no matter what organization is charged with impact assessment, the methods to do that assessment are currently woefully inadequate, and that IRDiRC therefore could and should focus on the development of improved methodologies and tools for performing such impact assessments. Appropriate access to diagnosis and treatment depends on a multitude of factors, including clinical guidelines and recommendations; regulatory policies; pricing; insurance, coverage, formulary, and reimbursement; and even the awareness of healthcare providers. The efficiency and extent of translation of diagnostic and treatment developments into tangible outcomes and practice are currently hampered by limited assessment of their impact on patients. Development of robust methods to measure access, effectiveness in real‐world settings, and impact on patient outcomes will therefore be a focus of the IRDiRC over the next decade. Such research needs to particularly involve underdeveloped areas worldwide, which starts by expanding our global footprint into more underrepresented regions and the inclusion of such members in all activities. Equally important, as a global health issue, IRDiRC members are committed to implement these advances equitably to reduce existing and potential health disparities. Such disparities include those between Indigenous and non‐Indigenous peoples, which, at its core, requires indigenous‐specific reference genetic data sets to improve clinical diagnosis and optimize therapies.25, 26, 27, 28 We anticipate that this research will not only benefit rare disease patients worldwide, but also have impacts in the wider context of personalized medicine. Measurement of impact Assessing the impact of diagnosis remains a complex issue. Counting the number of diagnostic tests might be relatively simple given the various worldwide, country‐specific, and company‐specific listings but is nonspecific and indirect, speaking only to availability and not access. Quantifying the number of people who have received a diagnosis, the length of the diagnostic odyssey, and the impediments to diagnosis is, however, not straightforward. This quest goes beyond the mandate of a single clinical or research team. Aggregating this information requires a multidisciplinary and multistakeholder approach that must navigate the continuum from clinical research to healthcare services in multiple systems and cultures. Thus, measuring the impact of diagnosis may include such items as quantitative and statistical analysis, assessment of quality of life, and/or economic dissection of repercussions on medical care. Assessing the impact of treatment is also largely limited to regulated therapies, since these are easier to count. It has been suggested that other types of treatments or interventions, such as nonpharmaceutical approaches, physical and behavioral therapies, and/or devices may be as valuable to patients as “drugs,” but these are generally neglected when considering impact. Similarly, research into healthcare system optimization and the implementation of recommendations to improve its functions may have an important impact on patients’ outcomes and health. The use of existing tools and platforms, e.g., the NIH Genetic Testing Registry,29 and RARE‐Bestpractices,30 that help develop rigorous process and qualitative markers for the evaluation of the diagnostic and modes of care should be factored into any methodology development. The funders should engage in identification and financial support of research projects that will tackle the complexities around the measurement of health outcomes. Research in health systems, economics, and ethical frameworks should also be promoted. Furthermore, IRDiRC may consider how to engage appropriate stakeholders in healthcare systems to ensure that any methods developed could be recognized rapidly, and applied at both the national and international levels. CONCLUSION The members of IRDiRC and, more important, their organizations, have committed themselves to an ambitious set of 10‐year goals that will advance the realization of the IRDiRC vision of prompt and accurate diagnosis, effective treatment, and amelioration of illness for all people living with rare diseases. In an ambitious and multifaceted project like IRDiRC's, coordination and monitoring of progress will be essential; these will be performed by the IRDiRC Committees and Scientific Secretariat. The Committees and their Task Forces will promote activities to advance the goals, and metrics will be applied to monitor progress toward the goals. Some may question whether the costs of IRDiRC's vision can be justified, given the low prevalence of these disorders. We, the leadership of IRDiRC, believe that, to the contrary, the global community cannot afford not to achieve these goals, and the resources the member organizations are committing to rare diseases research to realize the IRDiRC vision testify to this conviction. On a purely financial level, the cost to health systems of caring for people whose rare diseases are undiagnosed or untreatable are disproportionate and growing. On a human level, we believe that every person with an illness, whether rare or common, has the same right to a diagnosis and treatment, and that the contributions to humanity of rare disease patients are well beyond our imagining. We are all familiar with how people living with HIV/AIDS, once an undiagnosable, untreatable rare disease, are continuing to enrich the human family in innumerable ways, and how much the work to diagnose and treat HIV/AIDS taught us about human biology and other diseases. This is our vision for the millions of people living with the thousands of other rare diseases. As leaders of the global rare diseases community in the public and private sectors, we are under no illusions about the challenges to achieving our new goals by 2027. However, we are equally aware of the epochal advances in rare diseases science and medicine over the last decades, the evolution of a culture of collaboration, teamwork, and common cause that now unites the rare disease community, and the reality that the pace of progress is positioned to accelerate. These are goals that can only be achieved with fundamental changes in the conduct and sharing of science, and application of that science as rapidly as possible to advance the care of rare disease patients—changes IRDiRC members have committed to catalyze. We believe that these goals are eminently achievable over the next decade—but only with continued commitment to scientific excellence, rapid and ubiquitous sharing of approaches and data and resources, and continued monitoring of progress and constant reevaluation of direction based on new data. IRDiRC's is a rigorous, noble—and achievable—vision, which we believe will bring out the best in science, in medicine, and in ourselves. We welcome new members, who share our vision and commitment to action, to join us. And we look forward to updating the community on our progress. Conflict of Interest The authors declared no conflicts of interest. Supporting information Supporting Information Click here for additional data file.
            Bookmark
            • Record: found
            • Abstract: not found
            • Article: not found

            Laboratory and clinical genomic data sharing is crucial to improving genetic health care: a position statement of the American College of Medical Genetics and Genomics

              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Precision medicine needs randomized clinical trials

              Clinical trial design has dramatically evolved with the advent of precision medicine. As a result, expedited drug-approval decisions have been made on the basis of evidence obtained in uncontrolled clinical trials. Herein, Saad et al. discuss the need to conduct randomized controlled trials at all phases of drug development in oncology, and present strategies to facilitate a seamless transition between phases of drug and/or biomarker development.
                Bookmark

                Author and article information

                Contributors
                amalia.issa2@mcgill.ca
                Journal
                Genet Med
                Genet. Med
                Genetics in Medicine
                Nature Publishing Group US (New York )
                1098-3600
                1530-0366
                10 July 2018
                10 July 2018
                2019
                : 21
                : 3
                : 542-544
                Affiliations
                [1 ]ISNI 0000 0000 8794 7643, GRID grid.267627.0, Personalized Medicine & Targeted Therapeutics, , University of the Sciences in Philadelphia, ; Philadelphia, Pennsylvania USA
                [2 ]ISNI 0000 0000 8794 7643, GRID grid.267627.0, Pharmaceutical Sciences; Health Policy & Public Health, , University of the Sciences in Philadelphia, ; Philadelphia, Pennsylvania USA
                [3 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Centre of Genomics and Policy, , McGill University, ; Montreal, Quebec Canada
                Article
                99
                10.1038/s41436-018-0099-0
                6752286
                29988078
                99bff29d-33cb-4dbc-8251-aa5ddf5dc3b8
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

                History
                : 9 February 2018
                : 7 June 2018
                Categories
                Comment
                Custom metadata
                © American College of Medical Genetics and Genomics 2019

                Genetics
                Genetics

                Comments

                Comment on this article