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Rare Disease Clinical Development: Novel Approaches to Overcoming Operational Challenges

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Rare Disease Clinical Development: Novel Approaches to Overcoming Operational Challenges WHITE PAPER Rare Disease Clinical Development: Novel Approaches to Overcoming Operational Challenges Copyright 2020 Medidata Solutions, Inc., a Dassault Systèmes company WHITE PAPER RARE DISEASE CLINICAL DEVELOPMENT: 2 NOVEL APPROACHES TO OVERCOMING OPERATIONAL CHALLENGES Table of Contents Unique Challenges in the Rare Disease Space 4 The Landscape for Clinical Research is Changing, and Patients are at the Center 6 New Methodologies and Technologies Suited to Rare Disease Trials 7 Reducing the Patient Burden 10 Rare Disease Clinical Trials in the Era of COVID-19 12 Summary 13 Endnotes 14 WHITE PAPER RARE DISEASE CLINICAL DEVELOPMENT: 3 NOVEL APPROACHES TO OVERCOMING OPERATIONAL CHALLENGES Rare diseases are serious, chronic, progressive conditions that can be disabling and/or life threatening.1 Most remain perplexing to medical science due to their complexity, diversity, and low prevalence. Somewhere between 7,000 and 8,000 different rare diseases have been identified and collectively, represent a significant burden on humankind as they affect an estimated 400 million people, or one out of every 10 people on the planet.2 Eight out of ten rare diseases are genetic in origin, and half of all rare disease patients diagnosed are children. Today, 95 percent of all rare diseases lack a treatment approved by the US Food and Drug Administration (FDA), leaving most patients and their families with devastating consequences and little hope of a cure.3 Consequently, the pharmaceutical industry is increasing its focus on developing novel therapies for many rare diseases, and approvals in the US and Europe are accelerating. In the US 21 of the 48 new approvals (44 percent)4 in 2019 were for rare disease indications and for Europe 21 out of 42 approvals in 20184. (See Figure 1.) There are new technologies and methodologies capable of changing the game in rare disease clinical development, starting with biomarker discovery all the way through to regulatory submission. Figure 1: Accelerating Rare Disease Approvals5,6 2017 2018 2019 US Food and Drug Administration (FDA) 39% 58% 44% 18 out of 48 NDAs 34 out of 59 NDAs 21 out of 48 NDAs were for rare diseases were for rare diseases were for rare diseases European Medicines Agency (EMA) 59% 50% 23% 19 out of 32 approvals 21 out of 42 approvals 7 out of 30 approvals were for rare diseases were for rare diseases were for rare diseases The complexities of clinical trials in rare diseases present obstacles that slow the path to approval and add considerably to drug development costs. Getting the development plan right from the beginning of the trial is critical. The following paper reviews the challenges that biopharmaceutical sponsors face and presents a variety of solutions capable of streamlining the process to speed delivery of rare disease treatments to the market. WHITE PAPER RARE DISEASE CLINICAL DEVELOPMENT: 4 NOVEL APPROACHES TO OVERCOMING OPERATIONAL CHALLENGES Unique Challenges in the Rare Disease Space The nature of rare diseases poses several difficulties for sponsors in the clinical development process that in many ways are more intense than those faced in studying the safety and efficacy of treatments for more common diseases. The rarity and severity of the disease and the scarcity of patients to participate in clinical trials impact the study design, approach to patient recruitment, retention strategies, and ultimately the trial cost. ā Small Population. By definition, a rare/orphan disease is a condition that affects fewer than 200,000 people in the US and in the EU, fewer than 1 in 2,000 people.7,8 The scarcity of patients eligible for clinical trials is exacerbated by the growing number of therapies in development, causing competition for already hard-to-find patients. With so few patients available to participate in these trials, sponsors cannot afford to lose a single enrolled patient. Due to the very small patient populations, studies in rare disease areas are less likely to have a traditional control population. Often rare disease clinical trials involve complex umbrella, basket, or adaptive designs [see Complex Trial Types definitions below]. As the science associated with the drug development effort evolves and becomes more precise, so does the number of objectives, endpoints, and associated procedures, adding to the overall trial complexity and burden to the patient.9,10 Complex Trial Types11 Rare disease clinical trials often involve complex 1 2 3 umbrella, basket, Umbrella Trial Basket Trial Adaptive Trial or adaptive designs. A type of clinical trial that A type of clinical trial that A type of clinical trial that tests how well new drugs tests how well a new drug evaluates a medical device or other substances work or other substance works in or treatment by observing in patients who have the patients who have different participant outcomes on a same type of cancer but types of cancer that all prescribed schedule and different gene mutations have the same mutation or modifying parameters of (changes) or biomarkers. biomarker. In basket trials, the trial protocol in accord In umbrella trials, patients patients all receive the with those observations. receive treatment based same treatment that on the specific mutation targets the specific or biomarker found in mutation or biomarker their cancer. found in their cancer. WHITE PAPER RARE DISEASE CLINICAL DEVELOPMENT: 5 NOVEL APPROACHES TO OVERCOMING OPERATIONAL CHALLENGES ā Geographic Dispersion. Patients with rare diseases are typically scattered across the world, resulting in the need for sponsors to operate many trial sites, most of which achieve a low patient-to-site ratio. It is common for patients to have to travel to different states in the US and to different countries in the EU to access trial sites. This creates a patient burden that is especially taxing for rare disease patients, who can be significantly ill, and increases costs for sponsors. ā Lack of Disease Knowledge/Difficulty in Diagnosis. In many rare diseases, it is challenging to obtain a deep understanding of the disease process (i.e., etiology, genetics, pathophysiology, and natural history) given the lack of clinical and scientific data collected due to the rarity of cases.12 When a condition is rare, finding healthcare providers who are familiar with a specific disease and have seen other patients with it may be especially difficult. Once connected with the appropriate clinician, patients and their families often have to go through a diagnostic odyssey given the clinical and genetic heterogeneity of rare diseases. Diagnostic criteria may be either unclear or not fully established, especially for non-genetic rare diseases. And in genetic diseases, mutations within the same gene can be associated with different diagnoses.13 Also, there is limited familiarity with rare diseases among both primary care physicians and specialists, with only a small number of experts in each disease. As a result, misdiagnoses are common. It takes an average of 4.8 years for a patient with a rare disease to be correctly diagnosed after consultation with an average of 7.3 doctors. In many cases, patients and caretakers develop deep expertise in their condition.14 Within pharmaceutical companies, knowledge of rare diseases is often dispersed across the clinical, operational, and real-world evidence domains among various stakeholders. Pharma companies are also using specialized global advisory boards of academic and community based specialists to assist them in better understanding the rare disease community, its challenges and needs. ā Pediatric Population. Roughly 50 percent of rare diseases affect children, 30 percent of whom don’t survive past their 5th birthday.15,16 Having a predominately pediatric population leads to more ethical and legal considerations when recruiting and enrolling patients in clinical trials, leading to slower recruitment timelines.17 Enrollment of human subjects, in general, requires informed and voluntary consent of the research participants to understand the risks and benefits of the research. Children are considered a vulnerable research population as they are minors and have a lack of autonomy and decision making capacity to ethically and legally consent to research participation. To apply the general ethical principle of respect for persons, research in children requires both parental permission and child assent.18 Protections for children involved in research are unquestionably critical, but add another layer of consideration when a team is designing a treatment trial. ā Trial Design: For a patient or the parent of a pediatric patient, the chance of being in a control arm of a randomized control trial may be a disincentive, especially when an investigational drug may be able to offer a more efficacious treatment option compared to the standard of care. Additionally, if patients find out they are in a control arm, they may drop out of the trial. These factors complicate the decision process for patients, and they represent risks to a trial’s retention, completion, and valid statistical conclusions. ā High Disease Burden. Rare diseases are often severely debilitating and/or life threatening. The physical and logistical difficulties that patients and their caregivers face can make trial participation onerous and patient retention challenging. WHITE PAPER RARE DISEASE CLINICAL DEVELOPMENT: 6 NOVEL APPROACHES TO OVERCOMING OPERATIONAL CHALLENGES ā Genetic Origins. 80 percent of rare diseases are caused by abnormalities in a person’s genetic makeup.
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