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This is just one anecdote, but it epitomizes two key challenges confronting the biopharmaceutical industry and regulators in the rare disease field: Understanding an illness from the perspective of patients and caregivers and choosing patient-relevant endpoints. It has been more than a decade since the concept of “patient centricity” emerged. In the intervening years, some developers have sought to put its tenets into practice, engaging in sustained, substantive dialogue with patients throughout the drug development process. But, at some companies, patient centricity simply means a 30-minute meeting with patients whose feedback is then overlooked. When I broach the topic with patient advocacy group (PAG) representatives at industry conferences, they routinely roll their eyes. Patient centricity has become a broken promise. Why? And how can we mend it?
In this report, we provide a detailed examination of what developers can do to maintain a sharp and consistent focus on the needs of rare disease patients. We explain:
How to run adaptive trials that streamline development and reduce patients’ chances of receiving a placebo or an inactive dose. Ways to partner with PAGs to design trials that work better for patients while complying with scientific and regulatory requirements. How to select optimal endpoints for a condition and validate novel endpoints with correlation analyses. How to utilize expedited regulatory programs to gain access to advice and guidance, rendering every aspect of development—from nonclinical, preclinical, CMC, and clinical—more efficient. How to dispel the regulatory myths around cell and gene therapies to make better decisions. How to do the preparatory work to ensure market access so that patients can benefit.
Despite the obstacles, focusing on patients makes pragmatic sense. Companies that do so from the earliest stages of development can, finally, fulfill the promise of patient-focused drug development and keep this evolving term both authentic and relevant to healthcare’s highest aim. In other words, that little boy.
Rachel Smith, MD
Jennifer Schranz, MD Senior Vice President, Global Head, Rare Diseases, Ipsen
Jennifer has over 24 years of experience in clinical development and medical affairs across small (Vicuron, Viropharma, Nabriva), mid-sized (Ipsen) and large pharmaceutical companies (Wyeth, Merck, GSK). Prior to this, Jennifer trained as a physician in internal medicine and infectious diseases, with a focus on HIV/AIDs, at the University of Toronto, Canada and SUNY Stonybrook, New York. During her career she has utilized traditional approaches to clinical development, as well as specialist approaches in rare and orphan diseases, working with small molecules, biologics and vaccines. Jennifer is Senior Vice President and Global Head of Rare Diseases at Ipsen and leads their strategy to advance rare disease therapeutics and transform the treatment of these often-neglected conditions. Ipsen’s rare disease portfolio currently focuses on bone and growth disorders (Fibrodysplasia Ossificans Progressiva, Severe insulin-like growth factor-1 deficiency) and rare liver diseases (Primary Biliary Cholangitis), with an additional interest in rare neuromuscular disorders. Jennifer is passionate about advancing research in rare disease to support underserved communities, whilst building high-performing teams to bring these medicines to patients in need.
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Patients are the Customers
Patients—not companies, not regulators, not healthcare providers, payers, or investors—are the ultimate consumers of medicines and treatments. Yet the healthcare industry lags far behind other sectors in focusing product development on the people it is supposed to serve. One problem is the structure of our healthcare system, built around players with conflicting priorities. Developers, whether large, small or midsized, desire a return on investment and market success; regulators seek to uphold sound scientific, safety, and efficacy standards; and health technology assessment agencies compare treatments, cost-effectiveness, and the systemic economic impact of new therapies. Payers in universal healthcare systems must deliver care to large populations in budget-conscious ways. Private payers want to run profitable businesses. In this complex and contentious environment, it is easy to understand how all these players can lose sight of patients. There are many reasons companies fail to engage effectively with patients before designing their trials and selecting endpoints. For one thing, it takes time and money to fully understand a rare disease and how it progresses, including its impact on the daily lives of patients and caregivers. And companies have very little time to spare—they may face investors or shareholders who demand swift progress, incentivizing them to launch trials, meet development milestones, and raise the next round of funding. At the same time, while regulatory agencies often reasonably insist on established endpoints, they have been slow to set up a framework for novel rare disease endpoints. Meanwhile, many companies find it daunting to communicate with patients and fear that direct collaboration could raise legal or ethical issues. Finally, the field lacks clear metrics to measure or reward success in the arena of patient engagement. Any one of the parties listed above would recognize that this little boy’s rare smiles, his ability to feed himself and express emotion—and his family’s relief—represent a better quality of life. But collectively, they don’t know how to quantify that. Of course, patients cannot be at the center of all aspects of drug development—for example, CMC, GMP, GLP, and preclinical models. And companies cannot make a drug commercially viable if it is not compliant with technical standards. That is why the term patient-centric is, in some cases, a misnomer. But CMC, GMP, and all the rest don’t matter if a product does not address what patients care about.
Patient centricity is a broken promise. How can we fix it?
How to keep the promise
The Patient's Perspective
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8 min read
Ipsen takes a data- and patient-driven approach to rare disease research.
6 min read
Regulatory strategies for EU orphan drug development: Roundtable
Parexel experts and former senior EU regulators share the regulatory challenges sponsors must understand to navigate the EU’s orphan drug designation process and gain authorization.
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Meet the panelists
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Jennifer Schranz, MD
Rachel Smith, MD Executive Director, Rare Disease Center of Excellence, Parexel International
Rachel brings more than a decade of experience in every development phase of rare disease and cell and gene therapy (CGT) clinical trials to her work with Parexel’s rare disease clients. Previously, she served as Vice President of Clinical Operations, Portfolio Director of Rare Disease, and Global Head of the Cell & Gene Center of Excellence at Veristat LLC. She led programs in ADA-SCID, Canavan disease, congenital adrenal hyperplasia, Fabry disease, Gaucher disease, metachromatic leukodystrophy, and Wiskott-Aldrich Syndrome. Rachel has expertise in clinical development strategy, novel and adaptive trial design, decentralized trials, and other creative solutions for rare disease products with a non-classical route to market.
Fixing a Broken Promise
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Patients—not companies, not regulators, not healthcare providers, payers, or investors—are the ultimate consumers of medicines and treatments. In this section, a Parexel expert and rare disease patient herself, along with a valued sponsor, share insights from the perspective of patients and caregivers, and navigating the challenging, fast-changing rare disease space.
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A Patient-First Approach To Rare Disease Clinical Development
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Fixing A Broken Promise
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I recently worked with a family whose little boy suffered from a rare neurodegenerative disorder. His parents enrolled him in a clinical trial testing a drug designed to halt or slow the disease’s progression. Later, the company announced plans to scrap the program after the study failed to show a benefit on all its endpoints. But the boy’s quality of life had, in fact, improved with the medication. He started to feed himself instead of being fed. He smiled more often, and he vocalized for the first time. These small victories were powerful. The boy’s parents sought out other families in the trial and learned their children, too, had gained similar, meaningful ground. The parents joined together and appealed to the company and to regulators, arguing that the drug had real impacts not captured by the trial’s endpoints. Ultimately, convinced by these families’ testimonies and evidence, the firm decided to continue working on the drug.
Rachel Smith Executive Director, Rare Disease Center of Excellence, Parexel International
A Patient-Driven Approach
I recently worked with a family whose little boy suffered from a rare neurodegenerative disorder. His parents enrolled him in a clinical trial testing a drug designed to halt or slow the disease’s progression. Later, the company announced plans to scrap the program after the study failed to show a benefit on all its endpoints. But the boy’s quality of life had, in fact, improved with the medication. He started to feed himself instead of being fed. He smiled more often. And he vocalized for the first time. These small victories were powerful. The boy’s parents sought out other families in the trial and learned their children, too, had gained similar, meaningful ground. The parents joined together and appealed to the company and to regulators, arguing that the drug had real impacts not captured by the trial’s endpoints. Ultimately, convinced by these families’ testimony and evidence, the firm decided to continue working on the drug.
Patients are the customer
A Patient Driven Approach
Patient's Perspective
Ipsen takes a data- and patient-driven approach to rare disease research
Regulatory Strategies
Ipsen is a global, mid-sized biopharmaceutical company focused on building and expanding a high-value, sustainable pipeline in oncology, rare disease (RD), and neuroscience. For example, in March 2023, the company completed the acquisition of Albireo (NASDAQ: ALBO), a biotech focused on bile-acid modulators to treat pediatric and adult cholestatic liver disease with an approved RD product, Bylvay. Ipsen has executed an internal and external innovation strategy that prioritizes best-in-class technology platforms and products that can differentiate from existing treatment options or fill unmet patient needs. We spoke with Ipsen’s Senior Vice President and Global Head of Rare Diseases, Dr. Jennifer Schranz, about what she considers best practices in navigating the challenging and fast-changing rare disease space.
At Ipsen, we undertake a strategy refresh every two years, which includes a rigorous examination of the rare disease regulatory and policy environment and our evolving portfolio. We set the bar high for internal programs and the acquisition of external assets. Programs we invest in—or sustain investment in—must be potential game changers based on transformational or disruptive technologies. First-in-class or best-in-class products make the biggest impact for patients and fare best in the current market. We define unmet need with a cross-functional group that includes scientists, clinicians, regulatory, market access, patient affairs, and other experts. We focus on conditions with no or few approved therapies available where there is a well-defined mechanism of action and preclinical data. We hone in on epidemiology to determine the possibility of developing and delivering an innovative treatment in this area. Is it rare or ultra-rare? Is the natural history of the disease well understood? Are there patient registries? Are there established patient advocacy groups that will provide a patient journey and advise on clinical endpoints? Will we need to conduct a natural history (NH) study or rely on disease registries to inform clinical development? For example, first-in-class products often require an NH study to ensure we have captured endpoints that are both clinically meaningful and relevant to patients, and acceptable to regulatory authorities. We also examine the current standard of care, the landscape of existing and future competitor treatments, and whether there are well-established regulatory and reimbursement pathways. Finally, we prioritize disease-modifying treatments over symptomatic ones to truly impact the course of the disease. It’s an exhaustive process; it takes discipline and passion to do regularly. But we take it seriously because making wise advancement decisions is critical to the patients whose lives we hope to improve and our sustainability as a company. At Ipsen, our focus and areas of strength in rare diseases include; musculoskeletal (bone), metabolic, endocrine, gastrointestinal (liver) and neuromuscular disorders. Still, any company can apply these concepts to a strategy refresh in their area of focus.
Every few years, we refresh our rare disease strategy
We consult patients to design efficient and relevant trials
We’ve found that involving patients in our protocol design process, especially in the procedures and assessments schedule, and identifying which quality of life data matters to them is valuable. Patients get fatigued if we put too many procedures or tests into the protocol. But we must balance practicality and pragmatism for patients with what regulators will allow. In general, secondary endpoints—such as the number of debilitating disease-related events per day or week—may be more important to patients than biomarkers, such as blood values or an imaging procedure. In contrast, regulators focus on primary endpoints that can be objectively measured. To gather patient insights, we invite patients to review a trial’s consent forms, schedule of assessments, and other study materials. We also conduct Patient Advisory Boards to understand the patient journey and to ensure endpoints are clinically meaningful and feasible in a clinical trial setting. And Ipsen recently conducted a patient-led symposium at a scientific congress. A clinician moderated the session, and primary biliary cholangitis (PBC) patient advocates spoke directly to the scientific audience. The seminar was called “The Person Behind the Chart.” We wanted to give a voice to PBC patients on what it’s like to live with that disease. The patient voice is increasingly persuasive for regulators, health technology assessment (HTA) agencies, and clinicians. We see this, especially at the FDA, where their series of Patient-Focused Drug Development public meetings and their policy of allowing patients to speak at Advisory Committee meetings have given an open forum to patients. The testimony and data presented at these gatherings have reshaped the agency’s thinking in some cases.
We see long-term benefits from investing in site education and training
One challenge in rare disease drug development is the ratio of sites to patients needed for a study. You may have to educate and train many sites to find one patient and ensure ample consideration for that patient’s and family’s circumstances to allow travel to the study site for procedures. It is critical to understand that patients may have mobility issues and live in remote areas. Sites are not clinical trial factories, and preparing each one to run compliant clinical research studies takes a lot of effort. Nurses, study coordinators, logistics support staff, and clinicians need to be up to speed on good clinical practice guidelines and regulatory requirements, including some practices that may run counter to how they currently care for patients. But we’ve found a tremendous benefit for the common good because the training and education invested in a site elevate that locality scientifically and increase patient access. In addition, it prepares sites to administer new products in expanded access programs even if they don’t ultimately participate in the trial.
For us, randomized controlled trials remain the gold standard
Although NH studies can inform endpoint selection—including patient-reported outcomes—we've learned that there is nothing as convincing as data from a placebo-controlled trial. Of course, enrolling a placebo control arm is sometimes hard or impossible. Crossover studies are not always possible. Although the FDA has issued a guidance document on using an NH study as an external control for open-label single arm trials, we’ve found many unresolved methodological and statistical issues. There will always be questions on whether the patients are truly matched, even when patients serve as their own control. And if you have an ultra-rare population of patients that you first enroll in an NH study and then enroll in a pivotal clinical trial, the disease may have progressed over that time period to the point where you are not studying the same condition. Also, retrospective NH studies necessitate a lot of theoretical matching and modeling. RCTs remain the gold standard.
We communicate with integrity, even for tough decisions
Sometimes we must make difficult decisions about assets in our pipeline, even terminating programs. If safety signals emerge during development or the risk-benefit profile of a product changes due to the potential for adverse events versus efficacy gains, we explain those tough decisions to patients and investigators. But we always put the safety of patients first, and we treat them with the respect and honesty they deserve. High integrity sometimes means communicating disappointing news with transparency, even when you know that patient organizations are waiting for this news with bated breath. This is not a conversation we want to have, which is why we take our due diligence so seriously, are thorough in our asset selection, and always listen to and act on the needs of the patients.
“First-in-class or best-in-class products make the biggest impact for patients and fare best in the current market.”
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“We’ve found that involving patients in our protocol design process, especially in the procedures and assessments schedule, and identifying which quality of life data matters to them is valuable.”
