To successfully navigate a rare disease pathway, it is necessary to understand the interdependency of clinical, regulatory and commercial branches, as well as their different and sometimes competing challenges.

A panel of experts recently came together to share insights into this complex and evolving arena and discuss some of the ways forward. The panel included the author, Christian Schneider; Dennis Earle, Senior Director – Development Consulting & Scientific Affairs; Brad Carlin, Senior Advisor, Data Science and Statistics; and Erika Wissinger, Senior Director within Market Access and Healthcare Consulting, all at Cencora.

One of the challenges in the rare disease development space is convincing payers that the therapy meets an unmet need. Education of some healthcare providers may be required to demonstrate the effect a therapy will have on the care pathway for patients to secure their advocacy. This means closely examining the question: what is the symptom burden and actual impact of burden of the disease?

“That leads to quantifying the unmet need, which is important for payers, particularly with a new treatment for which there is no real standard of care, other than maybe symptomatic treatment,” Erika said.

Actively engaging patients in the pathway can also help boost their access to treatment, as they are best placed to provide a deeper understanding of the burden of rare disease. “Patient advocacy can also contribute to the generation of real-world evidence, which can be factored into the total package of evidence that’s put in front of payers,” Erika added.

It is also important to understand that the benchmark for rare disease therapies is not necessarily survival. In many cases, it is about improving the patient’s quality of life (QoL).

Being able, for example, to take a pill every second month instead of requiring intravenous treatment daily in an intensive care unit would be life-changing for patients, Christian noted, even though the drug may not provide a better survival outcome. “That’s why it’s important to talk to the regulators so this claim can be considered meaningful for the development programme, as it’s something you will need to know early on when you plan the clinical study.”

In such scenarios, therapy innovators need to include an endpoint of patient relevant outcome.

‘Actively engaging patients in the pathway can also help boost their access to treatment, as they [have] a deeper understanding of the burden of rare disease’

Where there is both a clinical and QoL endpoint, however, Brad’s experience has made him wary of choosing the latter. “While QoL may be very important to patients, drug developers may worry that doctors won’t prescribe their new therapy if its only significant benefit over the current standard of care is improved QoL. So, while this endpoint is increasingly important, it is on a case-by-case basis.”

It is worth noting the significance of QoL for payer reimbursement in some markets. “It’s the holistic view of the overall benefit to the patient, to the caregiver and, in some cases, the overall societal benefit, for example, the ability to return to the workforce,” Erika said.

“Any data that can supplement the full value story for the asset in addition to clinical trial data, that supports the messaging around clinical benefit for the patient, will be helpful in making a convincing story for the payer.”

Regulators are also taking a patient-centric approach, with a growing understanding that rare diseases do not lend themselves to randomised controlled trials with a diversity of patients.

“A lot of regulators are not just looking at the primary endpoint in isolation, but also at other evidence – pharmacodynamics, plausibility of effects, maybe even some exploratory endpoints, and so on,” Christian said. “There is also growing flexibility to employ novel statistical approaches.”

Non-interventional or observational studies, both natural history and patient registry studies, are playing an increasingly important role in the development of rare disease therapies.

“Sometimes patients have been enrolled in a patient registry for a long time and a new treatment becomes available,” Brad said. “If we then give this treatment to a subset of the patients, each can act as their own control just by looking at what happens before and after the intervention. Statisticians call that a crossover study.”

While the order in which the subject receives the treatment and placebo would normally be randomised, the rare disease space does not afford that luxury.  “Everybody’s starting on placebo (their own natural history) and then switching to treatment,” Brad noted. “That’s an example where regulators have been flexible and have allowed us to get the approvals and information we need on an orphan drug without a randomised design.”

Whether the data from non-interventional studies is sufficient to support the statistical objectives remains a concern, with Dennis noting a wide degree of variability.

“What is often clear when dealing with the intersection of clinical medicine and regulatory science is the need to establish that surrogate endpoints are definitively associated with improved clinical outcomes. And those instruments need to be validated,” he said. “That is a big clinical regulatory development challenge – and one that remains constant, despite the fact that there’s huge unmet medical need in a lot of these rare diseases.”

Regulators have shown a willingness to embrace innovative access pathways, with several authorities introducing programmes to facilitate the same.

The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) established the Innovation Accelerator to support developers of innovative products, while the US Food and Drug Administration (FDA) opened its doors to innovative sponsors via the Complex Innovative Trial Design (CID) meeting programme.

“The CID programme is just one example of the FDA’s recent encouragement to use Bayesian method, causal inference tools and other novel methods to try to bridge some of the gaps that arise when you can’t do traditional randomised trials,” Brad said.

The European Medicines Agency (EMA) has also outlined its response to innovative and complex therapies in the Regulatory Science to 2025 strategy, as the authority works toward a more adaptive regulatory system.

There is increased clarity, too, from some of the larger health technology assessment (HTA) bodies. Germany’s IQWiG (Institute for Quality and Efficiency in Health Care), for example, has provided guidance around the evidence required to show the quality of the relationship between a surrogate endpoint and a hard clinical endpoint.

“That’s why it’s important that early on, when you’re considering the regulatory strategy, you make sure the evidence will also resonate with payers,” Erika said.

While there has been some disquiet about Europe as a strong market for rare disease treatments, Christian argued that the level of experience in areas such as advanced therapy medicinal products (ATMPs) could not be discounted. “A key intention of the European Commission is to facilitate innovation and provide incentives by not over-regulating the industry,” he said.

‘Obligations to patients do not end once companies have cleared HTA hurdles, with the need to invest in patient support and access schemes’

With the Joint Clinical Assessment (JCA) coming into effect in January 2025, experts predict many changes ahead for HTAs. The JCA, which brings European Union members together to evaluate the clinical efficacy of new treatments, will be mandatory for new oncology drugs and advanced therapy medicinal products (ATMPs).

“The hope is that it will make the process smoother for the individual pricing negotiations because the clinical efficacy and potentially comparative efficacy [of the new treatment] against standard of care has already been addressed in the JCA,” Erika said. “There is cautious optimism at the moment.”

No matter the market, it is crucial that stakeholders work together to improve patient accessibility to rare disease therapies. This includes making better use of telemedicine, with Dennis noting the important role remote nurses can play in reducing the burden on patients.

“So, keeping it generally focused on patient-centricity, supplementing that with specific clinical operations initiatives and integrating that with some Bayesian methodologies really gives you an optimal chance of having a timely, well-executed, rare disease development programme,” he said.

Obligations to patients do not end once companies have cleared HTA hurdles either, with the need to invest in patient support and access schemes. “There are logistical aspects to commercialisation, such as managing cold chain supply for patients outside the main centres,” Erika said. “There are a lot of steps that need to be considered as early as possible to make sure that you get the product to the patient.”

References are available on request.
Disclaimer: The information provided in this article presentation does not constitute legal advice. Cencora strongly encourages readers to review available information related to the topics discussed herein and to rely on their own experience and expertise in making decisions related thereto.

Christian Schneider is Chief Medical Officer, Strategic Product Development Consulting, and Vice President & Head of Biopharma Excellence at PharmaLex, a Cencora company