Rare Disease Drug Development: Clinical, Scientific, Patient, and Caregiver Perspectives

By Raymond A. Huml

This book provides a broad overview of rare disease drug development. It offers unique insights from various perspectives, including third-party capital providers, caregivers, patient advocacy groups, drug development professionals, marketing and commercial experts, and patients. 

A unique reference, the book begins with narratives on the many challenges faced by rare disease patient and their caregivers. Subsequent chapters underscore the critical, multidimensional role of patient advocacy groups and the novel approaches to related clinical trials, investment decisions, and the optimization of rare disease registries. The book addresses various rare disease drug development processes by disciplines such as oncology, hematology, pediatrics, and gene therapy. Chapters then address the operational aspects of drug development, including approval processes, development accelerations, and market access strategies. The book concludes with reflections on the authors' case forreal-world data and evidence generation in orphan medicinal drug development. 

Rare Disease Drug Development is an expertly written text optimized for biopharmaceutical R&D experts, commercial experts, third-party capital providers, patient advocacy groups, patients, and caregivers.

• Language: English
• Publisher: Springer
• Release date: Nov 8, 2021
• ISBN: 9783030786052

Book preview

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021

R. A. Huml (ed.)Rare Disease Drug Developmenthttps://doi.org/10.1007/978-3-030-78605-2_1

1. Introduction to Rare Diseases and Market Overview

Raymond A. Huml¹  

(1)

Syneos Health Clinical Solutions, Morrisville, NC, USA

Raymond A. Huml

Email: [e-mail]

Keywords

Rare diseaseOrphan drugDrug developmentMarket overviewClinical trialPatientPatient advocacyCommercialization

Illustration 1

Artist’s rendition of the editor and his daughter, Meredith L. Huml, coauthor of Chap. 3, from the 2019 Facioscapulohumeral Muscular Dystrophy (FSHD) Society-sponsored Walk and Roll fundraising event – which occurred on the campus of North Carolina State University and raised over $29,000 for FSHD clinical research.

Artwork courtesy of the artist.

Introduction to Rare Diseases

Rare diseases were once a neglected aspect of pharmaceutical research relegated to nonprofits and philanthropic projects. However, in today’s research environment, blockbuster drugs are few and far between, and regulators are incentivizing developers to pursue unmet needs. As a result, drug targets are increasingly being discovered and pharmaceutical companies are investing billions in rare disease research – with some impressive results [1].

This is great news for people who suffer from rare diseases that often have few if any treatments. However, it creates significant challenges for the biopharma companies conducting this research, particularly if they are accustomed to running trials for common conditions that affect millions of people worldwide.

Patient recruitment and retention are arguably the greatest challenges to the timely execution of clinical trials [2]. For rare diseases, recruitment success depends not only on finding enough patients but also on retaining them for the duration of the trial. Rare diseases have small and often widely scattered populations, so recruiting patients to trials can be extremely challenging.

Historical success with patient recruitment – in addition to site qualifications – needs to be considered in parallel with current market competition and results in an ever-changing patient recruitment environment. Multiple companies supporting the biopharmaceutical industry, such as contract research organizations (CRO), have begun to leverage sophisticated data modeling tools and techniques to find additional patients for biosimilar and rare disease trials and/or to find patients more quickly. In addition, these companies seek to better understand the population of interest and refine their statistical assumptions when conducting clinical trials or real-world analyses. The largest and most well-established companies that support the biopharmaceutical industry now have unparalleled access to big data from clinical trials, electronic health records, medical claims, laboratory tests, and prescriptions.

For rare diseases, there is typically a lack of natural history data, suitable animal models of disease, regulatory guidance, and agreement on primary and secondary endpoints, as well as genotypic and phenotypic variability within the same disease. These factors make it very difficult to define common treatment patterns, assess how those treatments are working, and identify gaps – all of which are vital to the clinical research process. There are no silver bullet solutions to these challenges, but they can be addressed, at least in part, through big data sources, such as patient registries.

Between 5000 and 8000 rare diseases are known, and around 250–280 more are described each year [3, 4]. More than 70 percent of these are genetic disorders (and 70 percent of these genetic disorders have exclusively pediatric onset), affecting 3–4 percent of all births. Although the number of individuals suffering from a single rare disease is by definition small, the total number of individuals that rare diseases impact is significant, at approximately 25 million people in the United States (almost one in ten), 30 million in Europe, and a total of 400 million worldwide.

It is difficult to estimate the number of patient advocacy groups (PAGs) in the rare disease space. One database identified over 1200 that had received money from biopharmaceutical companies [5], but this number is probably an underestimate because, as other groups who have surveyed PAGs that have received no money have discovered, groups in our survey that received no industry funding seemed to be for diseases that drug companies have little opportunity to profit by [6]. Anecdotally, I’ve been told that less than half of the rare diseases identified to date are represented by a PAG. Regardless of the actual number, it is clear that many patients with rare diseases lack patient advocacy representation.

Prior to the passage of the Orphan Drug Act of 1983, many of the more prevalent rare diseases, such as muscular dystrophy and certain childhood cancers, were only represented by a PAG. These groups worked tirelessly on behalf of their patients to vie for government dollars to study their diseases, determine its mechanism of action or genetic features, and attempt to identify approaches to target those mechanisms to modify or perhaps cure the disease.

According to PhRMA’s (phrma.​org) Fact Sheet entitled Spurring Innovation in Rare Diseases (posted February 28, 2019), in the decade prior to passage of the Orphan Drug Act, only ten rare diseases had approved therapies.

According to the Health Promotion and Disease Prevention Amendments of 1984 (Pub. L. No. 98–551, 98 Stat. 2815 (Oct. 30, 1984):

A rare disease is defined by the Amendment to the Orphan Drug Act of 1983 as a condition affecting fewer than 200,000 Americans or a disease with a greater prevalence but for which no reasonable expectation exists that the costs of developing or distributing a drug can be recovered from the sale of the drug in the United States.

Since then there has been a marked increase in rare disease research funding and development efforts, thanks to regulatory changes, multiple international initiatives, and development incentives. Today, more than 300 rare diseases have approved therapies. In 2019 alone, 22 of 48 novel drug approvals by the Food and Drug Administration (FDA) were for rare or orphan diseases, involving a total of 76 orphan indications [7, 8]. At present, almost 600 companies are developing novel rare disease therapies, and 729 gene therapies are being studied in 1855 clinical trials [9].

According to the FDA’s Rare Diseases at FDA website (www.​fda.​gov/​patients/​rare-diseases-fda), the Orphan Drug Act is a law that incentivizes the development of drugs used to treat rare diseases. Companies and other drug developers can request orphan drug designation if the drug meets certain criteria. Orphan designation qualifies sponsors for various incentives, including:

Tax credits for qualified clinical (in humans) testing

Waiver of the Prescription Drug User Fee (currently at almost $3m for a new drug)

Potential for 7 years of market exclusivity after approval (which serves as additional patent protection)

Along with regulatory incentives, there have been major advances in science, helping elucidate many more targets for rare disease therapies. Following a long unproductive spell, there have been some recent successes in the cell and gene therapy space. For the first time in decades, there is potential for a cure for many of the rare diseases that involve a single-gene mutation. Scientific progress, coupled with regulatory incentives and the promise of favorable pricing, has led to burgeoning of rare disease drug development.

Rare diseases represent one of the fastest growing areas for biopharmaceutical R&D investment [10], yet the inherent challenges pose significant risks that sponsors must anticipate and navigate to be successful. These include the extreme heterogeneity among rare diseases; the many unknowns about rare disease pathophysiology and natural history; the very long, often frustrating, and emotionally wrenching diagnostic journey many patients and their families must travel; complex and changeable global regulatory frameworks; uncertain reimbursement landscapes; and the limited availability of rare disease research expertise and patients to participate in clinical trials.

Worldwide orphan drug sales are forecast to grow at a compound annual growth rate of 12.3% from 2019 to 2024, which is approximately double the rate forecast for the non-orphan drug market [11]. By 2024, orphan drug sales are expected to reach $242bn and capture one-fifth of the worldwide prescription sales.

Introduction to Rare Disease Drug Development

Rare disease drug development is all about the patient.

All rare disease drug development should begin and end by thoughtfully and meaningfully incorporating feedback from rare disease patients. For patients who cannot communicate adequately, due to either their rare disease or a concurrent comorbidity, the voice of their caregivers and loved ones should be sought and incorporated.

To obtain a cure – the ultimate goal of rare disease drug development – we need to conduct well-designed clinical trials. We need to, first, identify patients with rare disease and, second, provide them with a compelling reason to consider enrolling in a particular clinical trial (after understanding and balancing the potential risks and benefits involved).

Absent a cure, we need to seek ways to treat, and care for, patients with rare diseases based on their priorities. To determine if candidate therapies are working, especially for disease-modifying treatments, we need to either:

1.

Identify a surrogate (or biomarker) that, if modified, should, by extrapolation, correspond to a clinical improvement.

2.

Determine if the rare disease product will alter the natural course of the disease when compared with lack of any treatment or treatment with the current standard of care.

Side Bar 1: Patient- Focused Drug Development Meeting with the FDA [12]

Thankfully, regulatory agencies are increasingly supporting the patient voice in rare disease drug development. My daughter, Meredith Lindsay Huml, and I provided feedback to the FDA on June 29, 2020, during a patient-focused drug development (PFDD) meeting jointly sponsored by the FDA and the Facioscapulohumeral Muscular Dystrophy (FSHD) Society. At the time, this was one of the only three PFDD meetings held by the FDA during the COVID-19 pandemic – and provided testimony that the patient voice cannot wait until it is over.

Based on over 20 years of combined experience, Meredith and I provided feedback to the FDA that:

FSHD is more common than originally thought – and may even be the most common type of muscular dystrophy, though not the most well-known or understood.

The severity of the clinical signs of FSHD is probably underreported in the literature, meaning that it is more severe than originally thought (especially in regard to the use of – and time to use of – wheelchairs and the probability that certain surgeries, such as back surgery to correct scoliosis, is needed more often than reported).

The meeting also highlighted that the fatigue, anxiety, and depression that often accompany a rare disease diagnosis are important clinical signs that need to be addressed – as well as the ability to slow down the progression of the disease until a cure is developed.

Incorporation of the patient voice should occur from inception of the idea of the candidate therapy, to address the particular culture and market, including prevailing or developing standards of care, and the type of patient that the therapy is intended to treat. For many rare diseases, including the muscular dystrophies, subtypes of patients may only be amenable to certain approaches (e.g., exon skipping therapies) or the condition may comprise a syndrome of diseases, as with the limb girdle muscular dystrophies (LGMDs), where the various proteins of subtypes targeted for correction may differ (e.g., sarcoglycan vs. dysferlin). The patient voice certainly needs to be incorporated prior to the recruitment phase. As an example, some leading entities in the muscular dystrophy space (e.g., CureDuchenne, Sarepta, and PTC Therapeutics) used a Web-based portal, such as DuchennXchange.com, to solicit both patient and caregiver feedback prior to finalizing and implementing a protocol.

This risk/benefit analysis needs to be understood by the patient, their caregiver(s), and their entire healthcare team. Every barrier to successful enrollment (typically defined by the inclusion/exclusion criteria or the schedule of protocol assessments in a clinical protocol), whether identified through artificial intelligence methods, competitive intelligence methods, clinical experience, or historical site performance, should make sure that every procedure in the protocol’s schedule of events is matched with either a primary or secondary endpoint in the trial design. We need to keep in mind that if the proposed procedure does not add or contribute to the proposed study, it should be considered an unnecessary burden and removed.

The recruitment phase, when patients may first become aware of the proposed clinical trial, may also require education on why the candidate therapy may work (e.g., promising preclinical data), what the risks entail (to determine the risk/benefit balance), and if the participant can take the product again following the trial. It is important to note that some approaches, such as the gene therapies utilizing adeno-associated virus (AVV) vector technology, currently employ a one and done strategy – meaning that a patient can only participate in a single such trial.

The patient voice continues to be needed after the approval of a drug to make sure that the diversity of patients that require the medication can afford and obtain access to the medication. This is especially important for highly expensive drugs, such as the gene therapies, which may limit access for certain patients.

Once a product is approved for the treatment of a rare disease, the product life cycle continues until patent expiration and beyond. Some products may receive a tentative regulatory approval based on results from only a small number of patients, and contingent on conducting a larger confirmatory clinical trial. For others, such as the gene therapies, sponsors may be required to monitor patients for up to 15 years or even longer to better understand the long-term safety (and possibly efficacy) consequences of taking an RNA- or DNA-altering product via a vehicle, such as a cold virus.

The Rare Disease Journey: Diagnosis

The rare disease patient journey may begin with a diagnostic test at birth due to genetic screening or, much more commonly, after an untoward clinical event occurs that mandates physician intervention. My daughter Meredith first exhibited a speech development problem when she was in the third grade (about 8 years old). This lessened as she grew older, probably due to her growing and increasing in size, but it was initially thought to have been resolved due to intervention by a speech pathologist, provided as part of public school services.

We did not realize that her speech pathology was due to weakening facial muscles until, retrospectively, when she had problems with her dance routines. Her impaired coordination, combined with her inability to lift her arms above her shoulders, initiated a greater than 1-year odyssey that led to multiple incorrect tentative diagnoses, including Marfan syndrome, until she was finally clinically diagnosed with facioscapulohumeral muscular dystrophy (FSHD) at age 13 at Duke University Hospital’s MDA Care Center. There were no genetic tests available at that time to confirm her clinical diagnosis.

For many folks with rare diseases, the diagnostic odyssey – whether clinical or molecular – may take weeks, months, or even decades. For example, when preparing to give a talk at the First National Limb Girdle Muscular Dystrophy (LGMD) Conference in Chicago in August 2019, I discovered that many patients with LGMD did not obtain the correct diagnosis until decades after their initial symptoms appeared. It is hoped that, with newer genetic tests, this prolonged time to correct diagnosis can be avoided.

See Chap. 4, The Caregiver Perspective by Pat Furlong, for more information about the environment surrounding an initial diagnosis if not provided at birth.

Joining a Patient Advocacy Group and Enrolling in a Registry

After diagnosis of a rare disease, the patient or caregiver will often seek to identify a PAG. These groups can be of enormous help with education about the disease, identifying available treatments (if any) and navigating the clinical trial landscape. In some cases, where a PAG does not exist, it is possible to join an umbrella organization, such as the National Organization for Rare Disorders (NORD) or the Muscular Dystrophy Association (MDA). There is also the option of setting up a new PAG.

Side Bar 2: The FSHD Society

I joined the FSHD Society as soon as Meredith was diagnosed with FSHD in 2003. I first met Carol Perez, who used to answer the phone at the time. Carol, a person with FSHD and mother of a child of FSHD, unfortunately, has since passed. I spent many hours with her on the phone discussing how one deals with such a diagnosis of FSHD. We also discussed my concerns that my daughter might have the infantile onset form (which is more severe when compared with the two other known types: FSHD 1 and FSHD 2) and if my son might have the same affliction (he was diagnosed with FSHD in 2013 at the University of North Carolina Hospital’s MDA Care Center). Having the disease herself, Carol was kind, compassionate, courageous, and incredibly supportive.

I then met Carol’s son, Daniel (Dan), founder of the FSHD Society and former CEO and Chairman, who is also afflicted with FSHD. I first thought Dan was a physician, as he knew so much about clinical, medical, and scientific muscular dystrophy issues (he is not). We became friends, even coauthoring the chapter on FSHD for the Springer book on all MDs. Dan testified almost 50 times before Congress and was well connected with others in the various muscular dystrophy communities and is conversant about almost every issue facing folks with FSHD as well as the many commonalities that folks with other rare diseases face on a daily basis.

When my good friend, Carl Hellman’s wife, Shannon – who had increasing motor and cognitive clinical symptoms – was diagnosed with early-onset Alzheimer’s disease when she was 37 years old, everyone was shocked. Shannon passed on Easter Sunday in 2017. The head of the Alzheimer’s disease PAG at the time was June Kinoshita. Carl told me how compassionate and smart June was, and I read about her long before I met her. I was delighted when June later joined the FSHD Society and is currently serving as Director of Research and Patient Engagement. June is the author of Chap. 2 of this book, on the rare disease patient perspective.

Recognizing the need to expand nationally, and with strong support from June and Dan, the FSHD Society asked me and Meredith to start a chapter of the Society in North Carolina (NC). The group was first formed in 2013 with the idea that folks with FSHD and their loved ones and caregivers could meet and discuss the issues most pressing to them. Later, the meetings became more formal, and Meredith was selected as the Chapter Director of the NC Chapter of the FSHD Society in 2018.

Meredith and I invited numerous physicians, some from the MDA Care Centers, as well as PhD scientists, MDA representatives, physical therapists, and occupational therapists, to our statewide meetings. Other members also solicited experts to come to our group. When Mark Stone, the current CEO who took over from Dan Perez in 2018, joined, he evolved the focus of the chapter to include fundraising. He also identified a goal – commensurate with the fundraising and consistent with my aspiration identified in my Springer book discussing the muscular dystrophies – of championing advancement of an FSHD disease-modifying drug to the market by 2025. See:

2015 Huml RA (Editor). Muscular Dystrophy: A Concise Guide; ISBN 978-3-319-17,361-0; 186 pp., Springer, Copyright 2015

When the members of the NC Chapter of the FSHD Society asked Meredith and me to provide an updated overview of FSHD (in addition to the information on the FSHD Society’s website), we collaborated with neurologist Dr. Lucie Undus to publish the following overview:

Huml RA, Undus L, Dean M, Huml ML. Facioscapulohumeral Muscular Dystrophy: Clinical, Therapeutic and Regulatory Updates. Journal for Clinical Studies, Volume 9; Issue 3, pp. 12–14, 16, and 18. Published online June 5, 2017

When the members of the NC Chapter of the FSHD Society asked Meredith and me to summarize the state of the FSHD product pipeline, we again solicited the help of Dr. Undus to publish the following:

Huml RA, Undus L, Smith G, Huml ML, Dean M. Potential Therapies in the R&D Pipeline for Facioscapulohumeral Muscular Dystrophy. Journal for Clinical Studies. Published online September 21, 2017

In 2018, the NC Chapter of the FSHD Society was discussing the lack of animal models to advance FSHD therapies and the increasing role of respiratory issues associated with FSHD. To provide the global community with an update on FSHD, I solicited the help of additional colleagues, including a neurologist and a PhD-candidate summer intern from North Carolina State University, to publish the following article on FSHD:

Huml RA, Uspenskaya-Cadoz O, Dawson J, Slifer Z. Updating the Clinical Picture of Facioscapulohumeral Muscular Dystrophy: Ramifications for Drug Development with Potential Solutions, DIA’s Therapeutic Innovation & Regulatory Science, 7pp. https://​doi.​org/​10.​1007/​s43441-019-00038-w. Published online January 10, 2019; published in print January 06, 2020

Patient Registries

Patient registries – defined by the Agency for Healthcare Research and Quality (AHRQ) as organized systems that use observational research methods to collect data for the scientific assessment of patient outcomes [13] – are potentially important sources of big data.

Patient advocacy groups typically enroll the patients they work with in registries that can vary from an MS Excel spreadsheet to a sophisticated registry such as that of the Cystic Fibrosis Foundation (CFF) or the patient databases of the Muscular Dystrophy Association (MDA). Simple registries may be accessible only to a small group of physicians, while highly complex databases covering several diseases may be accessible online across multiple institutions. Currently, however, many registries are only offered in one geographic area or for just a select number of diseases.

Ultra rare disease registries may contain only a handful of patients, whereas larger databases, such as the MDA’s MOVR hub (Side Bar 3), ultimately seek to register all neuromuscular disease patients that receive treatment at the 200+ MDA Care Centers. Sometimes misunderstood due to its original moniker, the MDA not only covers all of the types of muscular dystrophies but also currently represents 43 different neuromuscular diseases [14].

Registries can be useful to identify patients for global trials, protect patients’ rights, meet patient expectations, and expedite drug development. They can support efforts to develop treatments not only for the most severe or most common types of rare disease but also, perhaps more importantly, for those diseases that are not supported by well-financed advocacy groups.

Rapid identification of patients with rare diseases is important not only for trial recruitment but also for broader engagement with these individuals and their families, to inform and support the overall research effort and empower advocacy activities.

New technologies are making it easier to create registry programs that aggregate clinically rich data from electronic health record systems and other sources (e.g., patient-reported outcomes [PROs], mobile devices). However, the complexity of integrating data from numerous hospitals and providers makes it difficult to justify the investment for a single study or rare disease. By banding together, stakeholders can develop a common platform for collecting and managing data while maintaining governance over sponsor-specific needs related to individual diseases of interest.

Big data are defined by the European Medicines Agency as "extremely large datasets which may be complex, multi-dimensional, unstructured, and heterogeneous, which are accumulating rapidly and which may be analyzed computationally to reveal patterns, trends, and associations [15]." Such data are increasingly helping to identify individuals with rare diseases [16] and improve clinical trial recruitment. In healthcare, sources of big data include electronic health records, medical claims data, prescription data, clinical trial data, and laboratory data – each governed differently in different countries and subject to varying measures to protect individual patient privacy.

The healthcare sector has historically generated large amounts of data as hard copy, driven by record keeping, compliance, regulatory requirements, and routine patient care [17]. The current trend is toward digitization [18], which can potentially make data sharing easier.

Big data requires technological resources and complex analytical approaches for processing and analysis. Yet, the benefits are enormous as these could provide very significant information for the understanding and validation of statistical and medical assumptions about a particular patient population of interest, such as details about the disease characteristics, clinical trial design operational characteristics, dropout rates, response rates, endpoints used, and study duration.

For rare disease studies, increasingly sophisticated approaches are needed to track down and select eligible patients – who may be even more elusive if the study is focusing on a specific patient subset such as those with a mutation that qualifies for a gene therapy. The use of master protocols – intended to simultaneously evaluate more than one investigational drug and/or more than one disease subtype within the same overall trial structure – combined with enriched adaptive designs has proven to be of great value in achieving this goal.

Beyond conventional tactics, such as discussions with patient advocacy groups, leading academic centers and specialist centers focused on a particular disease (or set of diseases), a new strategy involves the identification of a digital footprint that mirrors or follows the patient. In pursuit of that goal, data analytics could include a review of electronic health records, prescription data, laboratory data, medical imaging data, and ICD-10 codes (if available; and especially if unique [e.g., not clumped with other sets of similar diseases as occurs in the muscular dystrophies: Duchenne and Becker MD are clumped together in one ICD-10 code]).

Applying these approaches to a delivery strategy can help to ensure an optimal country mix, identify the most appropriate patients and sites, minimize risks to quality, and increase the chance of meeting project timelines.

Side Bar 3: The MDA’s NeuroMuscular ObserVational Research (MOVR) Data Hub

When Quintiles announced a partnership with the MDA regarding the association’s registry in 2013 [19], I was an employee of Quintiles and volunteered to help with the registry. As I learned more about the potential for a state-of-the-art registry, I became increasingly aware of how a registry could be used to help populate a natural history study and how ultimately it could be leveraged to create a clinical trial-ready network. To help socialize this idea – and promote the need for a more modernized and unified national registry – Meredith and I wrote the following paper:

Huml RA, Huml ML, Dawson J. The Growing Case for the Rapid Identification of Patients with Muscular Dystrophy for Clinical Trials. Journal for Clinical Studies, Vol 8, Issue 2, pp. 48–51, 2016

We sent the paper to everyone at the MDA, including the entire Board of Directors (numbering 30 individuals at the time) and President and CEO, Steve Derks (tenure from 2012 to 2017). When Steve and I discussed Quintiles hosting the MDA’s 2017 board meeting, I was delighted, as it would provide me with the opportunity to meet everyone in person. By the time the board meeting was actually held, Steve had stepped down as CEO, and Kristine Welker (Director), a longtime board member, was serving as the interim CEO. I provided a parent/caregiver perspective on the need for a modernized registry to address the growing number of clinical trials in the neuromuscular clinical development pipeline, and a colleague described the information technology that would be required. Without exception, everyone on the board was supportive of expanding and modernizing the MDA neuromuscular disease registry. When several board members asked me how exactly this would be accomplished, I summarized our top-level views and later published the following article, along with the help of several very knowledgeable colleagues:

Huml RA, Campion DM, Lucove J, Blackburn S, Kelly BJ. Accelerating Therapeutic Advancements in Muscular Dystrophies through Shared Registry Platforms. Journal for Clinical Studies, Volume 10 Issue 3, pp. 60–65. Published online May 29, 2018

Unfortunately, the paper was not published until after the MDA announced that they would build MOVR [20], but I was pleased to see that our paper (and the MOVR idea) made the front cover of the Journal for Clinical Studies as an innovative idea. Meredith and I were happy to hear that Lynn O’Connor Vos, who was chosen as the new MDA President and CEO, was highly supportive of the MOVR idea and other innovative initiatives.

Since 2018, I have collaborated with the MDA and was invited as a guest to the 2019 MDA Clinical and Scientific Conference in Orlando, Florida. I attended many sessions to learn more about the various neuromuscular diseases, but the highlight of my trip was sharing the stage with John Crowley, CEO of Amicus (Note: John’s family was the basis for the movie entitled Extraordinary Measures, starring Brendan Fraser and Harrison Ford). During a special dinner held during the conference, Lynn encouraged us to tell our parent and patient stories. Humbled to share the stage with John, despite my biggest fears about his celebrity status, I found that he was a kind, compassionate, and wicked smart (to borrow a phrase from a British friend) person driven to help folks with rare diseases, not just those with Pompe disease, the rare disease that had afflicted his family. Along with Sir Dennis Gillings, Tom Pike, Pat Furlong, Dan Perez, Dr. Robert Lark, Dr. Edward (Eddie) Smith, Dr. Kathryn Wagner, Dr. Jill Dawson, Tara Britt, and Lynn O’Connor Vos, John ranks among my most admired rare disease advocates. Despite his numerous duties as CEO of Amicus, John was gracious enough to provide the Foreword for this book.

Lessons Learned from Muscular Dystrophy Patient Advocacy Groups

Based on my experience in MD drug development and biopharmaceutical investing over the last 18 years, as well as my close association with the MD PAGs, I’ve learned multiple lessons that can accelerate rare disease drug development. Some of these ideas were expressed in the book that my daughter and I wrote on the muscular dystrophies. We felt compelled to get the word out about the muscular dystrophies, especially after witnessing multiple MD diagnoses and accompanying tears – at our local MDA Care Center at Duke University Hospital. We were pleased the MDA advertised the book in one of its Quest Magazine articles (in 2016) [21]. According to the Springer Book Reports, this was one of the top 25% most downloaded eBooks in the relevant SpringerLink eBook Collection in 2016 (and 2017) and one of the top 50% most downloaded eBooks in 2018.

More recently, my son and I started writing rare disease articles together. We first highlighted the use of big data (based partly on us both working at IQVIA in the summer of 2019) to aid rare disease patient recruitment. Later, we highlighted accomplishments of the larger MD PAGS that could be leveraged for advocates/groups representing nonmuscular dystrophy rare diseases. Two recent articles are:

1.

Huml RA, Dawson J, Lipworth K, Rojas L, Warren J, Manaktala C, Huml JR. Use of Big Data to Aid Patient Recruitment for Clinical Trials Involving Biosimilars and Rare Diseases. DIA’s Journal of Therapeutic Innovation & Regulatory Science, 8 pp. Published online December 11, 2019

2.

Huml RA, Dawson J, Bailey M, Nakas N, Williams J, Kolochavina M, Huml JR. Accelerating Rare Disease Drug Development: Lessons Learned from Muscular Dystrophy Patient Advocacy Groups. DIA’s Journal for Therapeutic Innovation & Regulatory Science, 8 pp. Published online September 25, 2020

The second article highlighted the coauthorship clan’s experience of working with the MD PAGs and identified a playbook of key strategies that have been successfully employed to advance treatments:

Working with other PAGs to better understand and define the patient journey

Working with patients to include their voice into all aspects of drug development

Creating a national or international registry

Better understanding the barriers to identifying patients with certain subtypes of muscular dystrophy to participate in clinical trials

Partnering with the biopharmaceutical industry

Collaborating with the regulators

Incorporating market access and use insights early in clinical development.

While clearly helpful within the MD community, these tactics could also be employed by PAGs representing other types of rare diseases. The MD PAGs, in fact, have highlighted a path that others with rare diseases can use to get the word out about their particular disease and, most importantly, a path that will allow scientists and drug developers to identify products to treat, and hopefully cure, these diseases.

A new muscular dystrophy-oriented book also worth mentioning was written by a healthcare provider of my son, Jon, and a staunch advocate of all families dealing with the muscular dystrophies. Another important note is that she helped write the MD book that I published via Springer in 2015. See Dr. Kathryn R. Wagner’s book entitled:

100 Questions and Answers About Muscular Dystrophy – a joint project supported by the MDA, Parent Project Muscular Dystrophy (PPMD), and the FSHD Society, Jones & Bartlett Learning, ISBN: 978-1-284-20,166-6, Copyright 2021

Further elaboration of registries and natural history studies is provided in Chap. 8, a snapshot of the evolving regulatory space is captured in Chap. 18, integrated life cycle management is described in Chap. 23, and a summary of how real-world evidence is utilized in the rare disease space is provided in Chap. 24.

Jill Dawson, PhD

I meet Jill almost 10 years ago. Officially, we have coauthored over a half a dozen peer-reviewed articles together. We also worked together on multiple writing projects – some in a consultancy manner and many pro bono – including my books, many white papers, and several chapters in addition to countless emails, biosketches, slide presentations, and phone calls, helping me tackle the rare diseases. She was instrumental in helping Meredith, my daughter, and Jon, my son, get involved in writing. Unofficially, she serves as both my mentor and friend – always willing to help me get the word out about rare diseases. A professional medical writing consultant, her calm demeanor and friendly and optimistic attitude have been a great help to me as I continue to try to identify and overcome the innumerable challenges associated with rare disease drug development.

Conclusion

Although the number of individuals suffering from a single rare disease is small, the total number of individuals that rare diseases impact is significant, at approximately 400 million people worldwide. Up until the passage of the Orphan Drug Act, only a small number of rare diseases had approved therapies. Since then there has been a marked increase in rare disease research funding and development efforts, thanks to regulatory changes, multiple international initiatives, and development incentives. Today, more than 300 rare diseases have approved therapies.

Along with regulatory incentives, there have been major advances in science, helping elucidate many more targets for rare disease therapies. Following a long unproductive spell, there have been recent successes in the cell and gene therapy space. For the first time in decades, there is potential for a cure for many of the rare diseases that involve a single-gene mutation. Scientific progress, coupled with regulatory incentives and the promise of favorable pricing, has led to burgeoning of rare disease drug development.

Rare diseases represent one of the fastest growing areas for biopharmaceutical R&D investment, with worldwide orphan drug sales forecast to grow at a compound annual growth rate of 12.3% from 2019 to 2024, which is approximately double the rate forecast for the non-orphan drug market. By 2024, orphan drug sales are expected to reach $242bn and capture one-fifth of the worldwide prescription sales.

Despite the lure of lucrative markets, inherent challenges pose significant risks that sponsors must anticipate and navigate to be successful, including the extreme heterogeneity among rare diseases, the many unknowns about rare disease pathophysiology and natural history, the very long and often frustrating diagnostic journey many patients and their families must travel, complex and changeable global regulatory frameworks, uncertain reimbursement landscapes, and the limited availability of rare disease research expertise and – by definition – rare disease patients to participate in clinical trials.

This book benefits from the efforts of many dedicated patients, caregivers, physicians, scientists, healthcare providers, patient advocates, and patient advocacy groups to allow the reader to better understand the nuances of rare disease drug development. This book would not have been possible without these experts graciously being willing to serve as authors, sharing their time and expertise for the benefit of clinicians, medical experts, caregivers, disease drug developers, pharmaceutical executives, third-party capital providers, and, most importantly, the rare disease patients themselves.

It will take a village to address the myriad of challenges facing patients with rare diseases. We need to work together to support each other and apply the many lessons learned.

My personal journey has entailed, first, facing my children’s FSHD diagnoses and, later, helping others with muscular dystrophies. I’m fortunate that the muscular dystrophy PAGs are among the most active and influential in the rare disease drug development space. Notable achievements in the last decade include promulgating the first US clinical research guidance, setting up registries and natural history studies, and investing in companies – some of which have brought potentially disease-modifying products to the market. While some MD PAGs, such as the MDA, receive >$100m in funding on a yearly basis, enabling them to support larger projects such as the national registry, smaller groups such as the FSHD Society, which receives <$10m each year in funding, can provide equally important insights into trial design and patient needs. The MD PAGs have shown that it takes a collective to enable us all to better understand the disease and the research directions needed to advance optimal treatment options for patients. Based on the successful use by MD-related PAGs to advance therapies for patients, these tactics could also be applied by other rare disease PAGs to achieve the same goals.

As Head of the Rare Disease Consortium at Syneos Health, my role has expanded, and I have more opportunities than ever to learn from and contribute to rare diseases. I will continue to leverage my experience, which includes:

Twenty-one years of experience in the CRO industry while at Quintiles and, later, IQVIA

Thirteen years of experience in due diligence and biopharmaceutical investing experience from working with both PharmaBio and, later, NovaQuest

Eighteen years of experience of working in the rare disease space

I will continue to collaborate with experts around the globe in order to tackle the broad array of rare diseases. I also plan to take advantage of the drug development lessons contained in this book for the benefit of any sponsor wishing to market a new rare disease product.

My passion and optimism for new cures remains high. Working with experts both within Syneos Health and in the broader rare disease community, we can continue to identify new tactics and methods to make it easier to identify patients, enroll and retain them in trials, and, hopefully, find new disease-modifying treatments and cures for them all, including those we know and love.

References

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Huml RA, Dawson J, Bailey M, Nakas N, Williams J, Kolochavina M, Huml JR. Accelerating rare disease drug development: lessons learned from muscular dystrophy patient advocacy groups. J Ther Innov Regul Sci, 8pp. Published online September 25, 2020.

2.

Huml RA, Dawson J, Lipworth K, Rojas L, Warren J, Manaktala C, Huml JR. Use of big data to aid patient recruitment for clinical trials involving biosimilars and rare diseases. DIA’s J Ther Innov Regul Sci, 8pp. Published online December 11, 2019.

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Dawkins HJS, Draghia-Aki R, Lasko O, et al. Progress in rare diseases research 2010–2016; an IRDIRC perspective. Clin Transl Sci. 2018;11(1):11–20. https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​articles/​PMC5759730/​.Crossref

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Wakap SN, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Human Gen. 2019; https://​doi.​org/​10.​1038/​s41431-019-0508-0.

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KHN. Patient advocacy groups take in millions from drug makers; is there a payback? April 6, 2018. https://​khn.​org/​news/​patient-advocacy-groups-take-in-millions-from-drugmakers-is-there-a-payback/​.

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https://​www.​eurordis.​org/​orphan-drug-designations-marketingauthori​sations

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https://​www.​fda.​gov/​vaccines-blood-biologics/​development-approvalprocess-cber/​2020-biological-license-application-approvals

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https://​www.​pharmavoice.​com/​digital-edition/​february-2020/​#16

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Tufts Center for the Study of Drug Development. Growth in rare disease R&D is challenging development strategy and execution. Impact Report. 2019;21(4)

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Evaluate Pharma’s Orphan Drug Report 2019. 6th Edition, April 2019 at https://​www.​evaluate.​com/​thought-leadership/​pharma/​evaluatepharma-orphan-drug-report-2019

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Voice of the Patient Report, The FSHD Society at https://​www.​fshdsociety.​org/​fsh-events/​vopf/​. Accessed 6 Dec 2020.

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Gliklich RE, Levy D, Karl J, Leavy MB, Taylora T, Campion DM. Registry of patient registries (RoPR): project overview. Agency for Healthcare and Research Quality. May 2012.

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The Muscular Dystrophy Association’s Find a Neuromuscular Disease search engine @ https://​www.​mda.​org/​disease/​list, accessed November 7, 2020.

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Heads of Medicines Agencies (HMA)-European Medicines Agency (EMA) Joint Big Data Taskforce Summary Report. Accessed February 13, 2019.

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Hansen AJ. Health data provide insights into rare diseases, say panelists at big data in precision health. Scope, Stanford University, May 29, 2018.

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Raghupathi W. Data mining in health care. In: Kudyba S, editor. Healthcare informatics: improving efficiency and productivity; 2010. p. 211–23.Crossref

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Raghupathi W, Raghupathi V. Big data analytics in health care: promise and potential. Health Inf Sci Syst. 2014;2(1):3.Crossref

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Quintiles and MDA Partner to Develop US Neuromuscular Disease Registry, October 9, 2013. News Medical Life Sciences at https://​www.​news-medical.​net/​news/​20131009/​Quintiles-and-MDA-partner-to-develop-US-Neuromuscular-Disease-Registry.​aspx. Accessed 6 Dec 2020.

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Muscular Dystrophy Association (MDA) website: MDA Collaborates with IQVIA to Expand Disease Registry into the New MOVR Data Hub. 12 Mar 2018.

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Hagerty L. New resource a muscular dystrophy road map for families, Quest Magazine. One line on March 29, 2016 at https://​strongly.​mda.​org/​new-resource-a-muscular-dystrophy-road-map-for-families/​?​_​ga=​2.​94254109.​1632078619.​1604773133-1453067621.​1591881882

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021

R. A. Huml (ed.)Rare Disease Drug Developmenthttps://doi.org/10.1007/978-3-030-78605-2_2

2. The Patient Perspective

June Kinoshita¹  

(1)

Research & Patient Engagement, FSHD Society, Lexington, MA, USA

June Kinoshita

Email: [e-mail]

Keywords

Rare diseasePatient perspectivePatient voiceAdvocateUS Food and Drug Administration

Illustration 2

Illustration, from the EURORDIS Photo Contest 2014, courtesy of the artist.

This illustration received the Expert’s Choice Award. It is derived from a photo of 2-year-old Daniel from Russia who has Williams syndrome—a rare neurodevelopmental genetic disorder, featuring mild learning or developmental challenges and a markedly outgoing personality; people with the condition often have an unusual elfin appearance.

Rick Guidotti, judge of this category of the photo contest, commented, I selected the winner because we do not see limitations, challenges, or sadness when we look at the photo, but pure love and joy. We see this beautiful boy as his mom sees him. By seeing Daniel through her eyes, we are then given a powerful opportunity to celebrate the beauty of human diversity.

Reference: https://www.eurordis.org/news/eurordis-photo-contest-2014-and-winners-are

The Patient Perspective Is Essential for Drug Development

Tolstoy, in the opening to Anna Karenina, famously observed, All happy families are alike, but every unhappy family is unhappy in its own way. People living with rare diseases are not unlike Tolstoy’s unhappy families. Healthy individuals feel secure in the apparent predictability of their lives, whereas those with rare diseases are burdened by the isolating uniqueness and mystery of their condition. For them, the medical professionals offer scant guidance, and it is the patients who must patiently explain their symptoms and predicaments to their doctors.

In recent decades, patient advocates have driven a sea change in their relationship with medical research and drug development industries. Once seen as passive subjects and consumers, patients today demand to have a voice and role in the therapeutic development process, from clinical outcomes and the design of clinical trials to the assessment of risk benefit and, ultimately, access to therapies. This is especially true in the rare disease space. Here, patients and their families are unquestionably experts on their condition. They understand, as few can, the impact of their symptoms and what kinds of relief will improve the quality of their lives.

Responding to the advocates, governmental bodies, such as the US Food and Drug Administration and National Institutes of Health (and their counterparts in other nations), have integrated patients’ voices into disease research and drug development processes. NIH agencies regularly convene coordinating committees that include patient advocates. The FDA has instituted numerous programs, such as the patient-focused drug development meetings, to incorporate the patient voice into regulatory discussions. With regard to rare conditions, the FDA is working with the National Organization for Rare Disorders on listening sessions with patients, caregivers and advocates to enhance FDA’s clinical and regulatory understanding of diseases and conditions and provide a common understanding of the most urgent needs of patients, caregivers and advocates [1].

Biopharmaceutical companies have responded to the regulatory mandates by integrating patient engagement into their therapeutic programs, not only when a candidate drug approaches approval to go on the market but also often much earlier. Many companies initiate their outreach to patient communities as part of their due diligence before making a decision to enter a disease space. Indeed, the existence of strong patient advocacy organizations—with active community support and sophisticated understanding of their role in drug development—is part of the essential infrastructure for a successful therapy development program.

In Search of Patients Like Me

For individuals afflicted with a rare disease, it may take many years to get to a correct diagnosis, and many may feel relieved at finally having a name to attach to their mysterious symptoms. Yet that relief may be fleeting, as the future implications begin to sink in. Adding to their anxiety is the sense of being utterly alone and even invisible. Their world is populated by people who have never heard of the disease, much less comprehend what it portends.

For rare disease patients and their families, finding others who share their diagnosis is life changing. Thanks to the Internet, we live in an age when individuals with rare disease can find one another and form support communities as never before. They feel seen and validated when they find their tribe. Yet the experience can be double-edged. For newly diagnosed patients, meeting others, especially those whose symptoms have progressed, can be like looking into a crystal ball and seeing my future, as one individual told me. It is not uncommon for individuals to flee the community after such a terrifying experience and soldier on in solitude until, perhaps years later, they have progressed to a stage where they need help again.

Each patient lost to the community network is not just a loss for the fleeing individual, who will miss out on the knowledge and support of fellow patients, but also a loss to the advancement of the community. That individual is less likely to participate in research and therapy development efforts. Because of this all-too-understandable dynamic, it is important for patient advocacy organizations to move beyond the traditional support group model—sometimes derided by patients as pity parties—and consider community engagement tactics to retain as many members as possible. Such tactics are based on understanding what most individuals with rare diseases are seeking:

Hope—that a treatment or cure is possible

Advocacy—that someone is fighting for them

Collective intent—that all stakeholders are united in pursuit of treatment

Empowerment—that their own actions will make a difference

Medical professionals have a vital role to play in building patient networks. Although today there are few if any effective treatments for most rare diseases, telling a patient there’s nothing we can do is not only counterproductive (as the patient may decide there is no point in returning for follow-up and symptom management) but also incorrect. Patients can experience a sense of agency over their untreatable rare disease by joining an advocacy group and volunteering in research studies. Feeling that their actions will lead eventually to a treatment for their rare disease is in itself therapeutic.

Patient Perspectives on Clinical Trial Participation

Recruiting volunteers for clinical trials in sufficient numbers and on schedule is a concern for any drug development enterprise. A significant percentage of trials fail because they were unable to recruit enough volunteers [2]. In the rare disease space, however, there is cause for optimism. Because of the rarity of their condition, individuals may understand that they cannot assume others will step up to participate. In surveys, rare disease patients show a high degree of altruism, with a majority of respondents being willing to participate in a trial even if it doesn’t benefit them personally [3, 4].

Patient advocacy organizations are invaluable partners in recruiting volunteers for clinical studies and trials. Effective organizations have a research focus; continually educate their constituents about research, the clinical trial process, and the patients’ role; and are a trusted source of information. They communicate directly with many patients and family members and so hear about how their constituents perceive specific studies, drug candidates, companies, trial sites, and investigators. Clinical trial sponsors, contract research organizations (CROs), and trial sites can benefit greatly by tapping into such insights. However, to avoid the risk of unblinding a study, they must alert the patient advocacy organization to preserve the anonymity of patients who are participating in trials.

In the age of social media, people with rare diseases often are able to connect with other patients and form virtual support groups. Such social media groups present both opportunities and risks for drug