Rising to the Challenge: Developing New Medicines for Rare Disease

The process for researching and developing new medicines is notoriously time-consuming, complicated and costly – and even more so when it comes to therapies for rare diseases.

Shire is now Takeda.

David Whiteman, MD, Global Development Team Lead, Rare Metabolic Diseases, Research & Development, Takeda, has dedicated his career to the development of such therapies – and to helping overcome some of the associated challenges. After completing training in medical genetics and working at Boston Children’s Hospital and the Mayo Clinic, Dr. Whiteman established a specialized medical service for providing diagnosis and medical treatments for rare, genetic diseases. He later joined a small pharmaceutical company to develop a treatment for Hunter syndrome or Mucopolysaccharidosis II (MPS II), a disease he first encountered by chance, as a medical student in the UK. That compound was eventually acquired by Shire.

David Whiteman has devoted his career to researching and pursuing new treatments for patients with rare genetic diseases. For the past 15 years, this has been mostly for Hunter syndrome patients. He has become an expert in this space. His passion and dedication for the science and for this community of rare disease patients and caregivers is commendable. The industry is fortunate for his scientific and medical contributions.

– Joseph Muenzer, MD, PhD, Professor of Pediatric Genetics and Metabolism Genetics

CheckRare: Why is the process for researching and developing drugs for rare diseases so much more complicated than for more common conditions?

David Whiteman, MD: There are a number of factors that contribute to this. One of the first things you need to do when developing a new medicine is demonstrate the unmet medical need. Generally speaking, in common diseases the unmet need for patients is much more obvious – and to learn more about those types of diseases, you can typically pull research papers right off a shelf.

However, with rare diseases there is much more research that needs to be done to set the ground work to understand unmet needs. For example, you may not know the true prevalence of a rare disease. (In my experience, the prevalence is usually higher than I would have thought when I first started working on it.)

CR: How do these challenges impact clinical trials for rare diseases?

DW: Clinical trials for more common diseases typically begin with safety studies in healthy volunteers. However, in rare diseases you can’t give healthy volunteers the therapy that is under investigation, because, in most cases, it is a biologic molecule that is already in their systems; so, giving more of it will not have major effects on function, and will usually not tell you very much about safety. Instead, you are forced almost immediately to treat patients who have the disease you are targeting. This has required a shift in the way that regulatory authorities think. Fifteen years ago, they wanted to see safety data in healthy patients, but that’s simply not an option in the rare disease space. So we’ve had to help facilitate a paradigm shift in that regard.

Another major challenge is related to the small population size of those affected by rare diseases. Recruiting patients can often take 1-2 years for rare disease studies. In one global study I worked on, it took several years to recruit a relatively large number of patients for the trial. We succeeded in enrolling just under 100, which was a record for a rare disease trial at that time.

Trials also typically need to be longer than the average clinical trial. Because of the nature of these diseases, short-term studies that you often see in adult patients (of about 12 weeks) do not work. Instead, it may take 1-2 years of administering a drug to demonstrate an impact in patients.

The underlying challenge is that there may be limited medical understanding of a given rare disease. The lack of this natural history makes designing trials very difficult.

CR: Can you explain natural history studies, and why they are so critical for the development of rare disease therapies?

DW: You cannot underestimate the importance of having natural history data about rare diseases. Data from these studies help researchers to understand the natural course of a disease and to better understand how to best help patients. In a good study, they should be informed by input from the patients and their families themselves.

Part of the challenge is that there is more variability in rare disease patients than in patients with more common diseases. Given the small numbers of patients worldwide with rare diseases, for many diseases there are no natural history studies – or the research may be scattered across medical literature. In contrast, this type of information is readily available for more common diseases like diabetes, asthma, etc.

CR: What are some of the challenges associated with conducting natural history studies?

DW: Not having well-defined natural history data makes it very difficult to design clinical trials to test potential treatments. As a result, a pharmaceutical company that is interested in a particular rare disease may initiate its own global natural history studies to collect information about the normal course of a disease and to learn more about biomarkers.

However, what often happens is that you end up “cannibalizing” your natural history study cohort. These studies require families to enroll their children in a trial without the potential for treatment – a choice that family members would rather not make if given another option. As soon as a potential medicine is discovered, researchers feel a moral obligation to provide that potential therapy to those very sick patients. As a result, patients enrolled in a natural history study may end up having the option to transfer into a clinical trial where they are receiving treatment. We end up trying to learn about the natural course of a disease at the same time we are trying to change it.

CR: It takes an average of 10 years to get a new medicine from laboratory development into the hands of patients. Why is the process for developing new medicines so time-consuming?

DW: The development of new medicines requires extremely rigorous science. Even after decades of working in academic research centers, I was surprised and humbled by the level of research rigor and the high standards I encountered in the pharmaceutical development world.

Companies must be very careful about collecting and ensuring the accuracy of data – confirming that nothing has been plagiarized or falsified – in order to ensure the safety of patients, and not obscuring a therapeutic benefit, or causing one to appear when it is really not there. This includes ensuring that all research and findings that have been conducted in the past can be replicated and scaled up. Medicines don’t always work the same way as you begin to scale up their manufacture.

Regulatory authorities also have very high standards in this regard. Both pharmaceutical companies and regulatory authorities have a responsibility to make sure that medicines can be used, in most rare disease cases, for a patient’s lifetime, so there is no room for error.

Another time-consuming factor is the question of how to best measure results. In the end, we also need to align with regulatory authorities on how we make measurements in rare disease clinical trials, which may require us to provide some education about the rare disease and the available natural history data. This also takes time.

CR: How has the process of drug development changed in recent years with additional collaboration from patients, caregivers and advocates?

DW: When I first began working in clinical trials, the involvement of patient groups and individual patients was very much a one-way street; the companies sought information from the families, while not communicating back very well. More recently, the environment has changed to be a two-way dialogue. We are increasingly involving patients and their caregivers in the design of clinical trials, to ensure that those trials measure things that matter most to them. Takeda and other companies have also committed to reporting out the results of our clinical studies in a transparent manner to study participants, their families, and the scientific community.

I am proud to say that Takeda was an early leader in this push to include input from the community. When we were working on the design of a Phase 3 trial for Hunter syndrome we involved the community at a very early stage and asked them “what is your view of success?” Clinical endpoints related to walking and breathing were included in the trial design based on direct feedback we heard from the community – specifically from Christine Lavery [former Group Chief Executive for the Society for Mucopolysaccharide Diseases, who passed away in December 2017]. Christine was a wonderful collaborator and has left a strong legacy with the community. She had a life well lived as a patient and family advocate.

Takeda meets the challenges of rare disease R&D head on by committing fully to the fight against rare disease.

To learn more, visit www.Takeda.com


Rare Disease Organizations

Rare Diseases Clinical Research Network
An initiative of the Office of Rare Diseases Research (ORDR) and National Center for Advancing Translational Sciences (NCATS). The goal is to advance medical research on rare diseases by providing support for clinical studies and facilitating collaboration, study enrollment and data sharing.

A non-governmental patient-driven alliance of patient organizations representing 724 rare disease patient organizations in 64 countries.

National Organization for Rare Disorders
Provides a unified voice for the 30 million people who wake up every day to fight the battle with a rare disease, including parents and caregivers.

Rare Disease Legislative Advocates
A program of the EveryLife Foundation for Rare Diseases designed to support the advocacy of all rare disease patients and organizations.

Genetic Alliance
A nonprofit health advocacy organization that engages individuals, families, and communities to transform health. They create ways to make it easier to find or build solutions in health services and research.

Global Genes
A rare disease patient advocacy organization that aims to build awareness, educate the global community and provide critical connections and resources that equip advocates to become activists for their disease.

Clinical Trials

An online database of publicly and privately supported clinical studies conducted around the world. ClinicalTrials.gov currently lists thousands of studies with locations in all 50 states and in 191 countries.

Takeda Clinical Trials FAQ
Some common questions about clinical trials.

FDA: What Patients Need to Know About Clinical Trials
The US Food and Drug Administration (FDA) provides this site for patients wanting to learn more about clinical trials. Clinical trials are voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.

Genetic Testing

Genetics Home Reference
An online resource from the National Institutes of Health. The website provides easy-to-understand information about genetic conditions and a range of topics. You’ll find basic explanations of how genes work and how mutations cause disorders. It also includes current information about genetic testing, gene therapy, and the Human Genome Project.

National Society of Genetic Counselors
Provides a helpful, easy-to-use online directory to help connect physicians, patients, and other genetic counselors. Search by state, city, counselor’s name, institution, work setting, type of specialty, or zip code.

Resources for Families and Caregivers

Rare Share
A unique social hub building communities for patients, families, and healthcare professionals affected by rare disorders.

Caregiver Action Network (CAN)
The nation’s leading family caregiver organization working to improve the quality of life for the more than 90 million Americans who care for loved ones with chronic conditions, disabilities, disease, or the frailties of old age. CAN (formerly the National Family Caregivers Association) is a nonprofit organization providing education, peer support, and resources to family caregivers across the United States free of charge.

Center for Parent Information & Resources
A central resource of information and products to the community of Parent Training Information Centers and the Community Parent Resource Centers so they can focus their efforts on serving families of children with disabilities.

Family Caregiver Alliance (FCA)
A community-based nonprofit organization that that aims to illuminate the caregivers’ daily challenges to better the lives of caregivers nationally, provide them the assistance they need, and champion their cause through education, services, research and advocacy. FCA offers programs at national, state, and local levels to support and sustain caregivers.

Family Voices
Family Voices aims to achieve family-centered care for all children and youth with special health care needs and/or disabilities. Throughout their national grassroots network, they provide families resources and support to make informed decisions, advocate for improved public and private policies, build partnerships among families and professionals, and serve as a trusted resource on health care.

An email list of family of parents, caregivers and others who are working with children with physical and/or mental disabilities and delays.

Parent to Parent USA
Programs offering parent-to-parent support as a core resource for families with children who have a special health care need, disability, or mental health issue. Through a one-to-one “match,” experienced support parents provide emotional support to families and assist them in finding information and resources.

Sibling Support Project
A national program dedicated to the lifelong and ever-changing concerns of the millions of brothers and sisters of people with special health, developmental and mental health concerns.

General Health Resources

Center on Technology & Disability
Designed to increase the capacity of families and providers to advocate for, acquire, and implement effective assistive and instructional technology practices, devices, and services for those who suffer from disabilities.

National Library of Medicine
Provides guidance on how to find reliable information online regarding human genetics.

Patient Advocate Foundation
Provides professional case management services to individuals facing barriers to healthcare access for chronic and disabling disease, medical debt crisis, and employment-related issues at no cost.


S44703    02/19

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