Key Considerations in Accelerating Rare Disease Drug Development


Building partnerships and relationships between physicians, site staff, patients and families.

There are more than 7,000 rare diseases, according to the National Institutes of Health (NIH). Effective treatments are available for fewer than ten percent. Drug development for rare diseases is complex and presents specific challenges such as a limited, geographically dispersed pool of patients, many of which are children. Therefore, selecting a development partner with strong patient recruitment and global operational capabilities is extremely important for success. A panel of experts, hosted by Applied Clinical Trials and sponsored by Parexel® Biotech, discussed key considerations for conducting and accelerating rare disease studies. The discussion included building partnerships and relationships among physicians, site staff, patients and families. The panel also covered accelerated pathways to marketing authorization for rare disease compounds.

Participants in the roundtable were:

  • Lisa Dilworth, Vice President, Integrated Strategic Solutions, Parexel (Moderator)
  • Lucas Kempf, MD, Vice President of Regulatory Consulting, Parexel
  • Leanne Larson, Senior Vice President, Real-World Evidence and Access, Parexel
  • Rosamund Round, Vice President, Patient Innovation Center, Parexel

LISA: Which stakeholders do you suggest sponsors engage with when working in the rare diseases space?

Rosamund: Patients and their caregivers are experts in their disease. Therefore, it is critical to engage with them early in the planning stages to better understand their challenges and specific needs. In addition, tap into patient advocacy groups and online communities. Some patients prefer to speak more informally to others through these communities, and they help geographically dispersed patients feel connected with others going through a similar experience. Study details and information can be shared with these groups— which we see as trusted partners. Another group with which to partner is the site staff that provides so much support to patients.

LISA: Can you share any best practices for engaging with the various stakeholders?

Lucas: When I was at the US Food and Drug Administration (FDA), we recommended that companies engage with patient groups and key opinion leaders (KOLs) as early as possible. One mistake we often saw was drug companies making assumptions about the disease based upon little snippets of information they found in articles or medical books. These limited disease features do not truly encapsulate the full experience that patients are having or what they consider the most meaningful. Moreover, rare diseases are somewhat heterogenic, so patients experience the diseases quite differently. That’s why it’s so important to engage with KOLs, patients, and their caregivers early in the process.

Rosamund: I agree that early connections with patients and KOLs are very important. At Parexel, we do “digital ethnography” work with patients and caregivers using digital diaries. This approach enables those designing trials to see firsthand how the patients experience daily life and develop simple, patient-friendly protocols. The patient and caregiver insights are important in the endpoint selection as well. What we may have assumed to be very important may not be as important to the patient.

Lisa: That’s such a critical point. There is a distinction between a clinically meaningful outcome and what matters to the patients in the trial. We must address this in protocol design.

Rosamund: We learn something new whenever we do these projects. Sometimes, major barriers are raised that were previously not on our radar. For example, several years ago, we looked at a challenging pediatric population in one rare disease study. When we asked parents about what would prohibit their child from participating, 75% of them said childcare for their other children because the protocol had a heavy visit burden. We never imagined childcare would be the biggest recruitment barrier, but that’s something that you can address proactively once you know about it.

LISA: Yes, the siblings of the patients are indeed important stakeholders to consider. And if you’re studying a genetic disease, the sibling could be afflicted with the same indication as well.
As we discuss how important it is to understand the disease and the impact on the various stakeholders, I can’t help but think how important natural history studies are in rare disease drug development for identifying patients and describing populations. Are there other benefits to natural history studies or observational research in rare diseases?

Leanne: Natural history studies have long been a key opportunity to understand the disease better. In some cases, the study populations are incredibly small. In one natural history study that I worked on, only 47 patients were identified in the world. A natural history study can be a critical part of finding the patients and helping us better understand them on many levels. It provides an opportunity to use existing medical record data sets or larger aggregations of patient population data to help find patients to include in the studies. In addition, real-world evidence (RWE) offers some excellent opportunities to help us find patients in very small patient populations.

Opportunities for natural history studies to inform and supplement the drug development process generally fall into these buckets:

  • Informing drug developers product development strategy.
  • Helping developers better understand the patient populations they’re working with and how the product will be used.

Natural history studies can also evolve to take on a different form or role after the drug is approved, such as to help sponsors understand how a drug is performing and its impact on patients. Natural history studies can help us learn much more about the burden of illness and the costs of treating these conditions.

In today’s healthcare systems, the cost and burden of illness are critical. We’re dealing with products that can be expensive, such as gene therapies, and we have to inform the payment mechanism as well. It’s not just about getting the drug approved; it’s also about ensuring that patients have access to it. So, the reimbursement puzzle is critical for patient access, and that’s where these studies can be so important. The payer stakeholders need to understand that information, and, frankly, our payment systems need to evolve along the way to help us with that.

LISA: You hit on such a great point about payers and regulators. Lucas, could you talk about any guidances in this area?

Lucas: In March 2019, the FDA published the Rare Diseases: Natural History Studies for Drug Development draft guidance. This guidance aimed to set a foundation for using a natural history study for regulatory purposes, such as the special circumstance for creating a candidate pool of patients for an external control arm. The intent was to clarify to drug developers and all other stakeholders who are initiating these natural history studies what data they should be collecting, how they should be collecting it, and the possible uses of the data. This is important because people often want to collect as much data as possible, but they don’t have a systematic way of doing it. So, the FDA guidance talks about how natural history studies should be protocol- driven, and there should be a systematic way of collecting the data. Furthermore, a statistician should be consulted about the data elements being collected, how they will be analyzed, and whether the data will be informative.

Sites also need to standardize how they are providing clinical care and offer a clear protocol about how they’re assessing and what is being assessed. Organizing this information in a standard protocol enables clinicians and investigators to know what they are measuring and how to measure it. Natural history studies and RWE may also help develop endpoints, which is challenging in rare diseases. Sometimes, these studies may even be used as an external control arm in a trial, reducing the number of patients recruited and who must receive a placebo.

In addition, several guidance documents on RWE have been published by various regulatory agencies worldwide. For instance, the FDA, the European Medicines Agency (EMA), UK’s National Institute for Health and Care Excellence (NICE) and the Chinese National Medical Products Administration (NMPA) are developing guidelines on the use of RWE and real-world data:

  • US 21st Century Cures Act: Framework Dec 2018, final guidance to be released by the end of 2021
  • Chinese NMPA: RWE Guidance released January 2020
  • NICE: Statement on RWE released January 2020

LISA: What are some of the most exciting innovations you see in RWE?

Leanne: RWE is an exciting and innovative space because everyone recognizes how important it is and that some of the more traditional models and approaches do not work well in this space. We are continually looking for ways to do this better. We have found some of those opportunities in RWE. Although the industry has been using RWE for some time, we are just beginning to think about how RWE can change the drug development landscape, with specific benefits in rare diseases. It’s also getting focus from regulators and payers.

An area that’s become a hot topic is external control arms. Rare diseases are an area where external controls have the most attention. External controls allow us to create a control arm that does not require patient enrollment or randomize patients to placebo. Patients don’t want to face the risk of being randomized to a placebo or to what they perceive might be a less effective treatment. In some cases, randomizing patients to a placebo might even be unethical. Allowing patients to participate in an actively treated arm can make enrollment easier and faster. It can also accelerate the time to approval.

External Control Arm studies are an exciting advancement. At Parexel, we’ve been a part of several of these regulatory reviews and approvals for products in recent years, and it’s great to see this more creative and accelerated way of bringing important therapies to patients. It’s a learning and an evolutionary environment, so working with the agencies upfront in how you want to use RWE in your drug development process and your applications for a particular product is critical.

LISA: Given that roughly half of the patients diagnosed with rare diseases are children and that three out of 10 of them will not live to see their fifth birthday, what are some special considerations for pediatric rare disease trials?

Lucas: There are specific laws to protect children. The FDA has a group of pediatric ethicists who review individual protocols that affect children before approving them. Within the FDA in the US, ethics rules for children fall under Subpart D, which explains that when any child is exposed to an investigational drug or device, the prospect of a direct benefit to the patient must be established.

For example, to generate that information, drug developers must first do an adult program to show that the drug is safe and has some efficacy before they shift down to the younger age ranges. This can be difficult in some rare genetic disorders where the patients may not survive into adulthood. So, frequently with rare diseases, you have the flexibility to generate some of that data from animal models to show that your drug is effective in the animal model, and it makes sense to go directly into pediatric patients.

The guidance also specifies that the dose for pediatric patients should have some evidence of efficacy; you can’t start at a subtherapeutic dose and then inch your way up over time. You start at a dose you believe will help that child from the beginning and then move from there.

Rosamund: There are also practical considerations around the family unit, including travel time and financial impact, which can be significant. Decentralized trials can make a massive difference to families, enabling simpler visits that can be done at home.

Consent discussions with these groups of patients can be challenging because consent support needs to be easy to understand and age-appropriate. We provide consent videos that explain the main things parents and children need to know.

Decentralized trials are especially appropriate and helpful with pediatric patients. We should always think about what we can do to make the patient’s life easier. This includes things like telehealth and home nurse visits.

Lucas: Some of these new tools can even remove variance. When conducting a decentralized trial using televisits with the same physician using the same questionnaire and interacting with the patient in the same way every time, those sources of variance are no longer part of the equation and can improve the trial’s sensitivity for detecting a clinical response.

LISA: We know that approval doesn’t imply access for patients. What are your thoughts about ensuring access to patients once we have approval?

Lucas: This is an important topic today. Traditionally, the FDA has limited its focus to safety and efficacy without regard to access. We are starting to see that some access issues can stem from the way labels are written or how the reviews were written. The FDA is starting to look at improving how reviewers write their labels. For example, you may have an expanded access program and find patients improving, but their outcomes may not be in the labeling because they were not part of the trial. It’s important to have early conversations with the agency to define your indication statements and labels.


With more than 7,000 identified rare diseases that span all therapeutic areas and all regions of the world, collaboration and the sharing of insights are critical. This roundtable discussion provided timely information from Parexel® Biotech on current clinical trials and real-world evidence solutions for rare diseases. Parexel® Biotech has deep experience in rare disease clinical research—including trials for cell and gene therapies—that have contributed to multiple FDA drug approvals. To learn more about Parexel® Biotech and to see examples of our rare disease insights, visit

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