Connecting the clinical, regulatory, and commercial dots for rare diseases

The path to rare disease product innovation involves interdependencies between clinical, regulatory, and commercial. Understanding these and the challenges and considerations along the way is integral to successfully bringing these therapies to patients in need.

To understand how all the pieces weave together, experts from different areas of the journey came together for an informed discussion with Dr Christian K Schneider. The experts in conversation with him included Dr Brad Carlin, senior advisor of data science and statistics; Dennis Earle, senior director of development consulting & scientific affairs; and Erika Wissinger, PhD, senior director within market access and healthcare consulting, all of Cencora.

Adopting the right approach to studies

In rare diseases, conducting randomised controlled trials is not always practical and, increasingly, there is an emphasis on non-interventional or observational studies - both natural history and patient registry studies. Several statistical tools can be leveraged to adjust for bias in the data from not having a randomised design.

Carefully applied versions of methods such as propensity score matching can give regulators and other interested parties in rare disease settings greater confidence in the data, Carlin noted. Examples where regulators have demonstrated flexibility with an orphan drug can be found with natural history and patient registry data.

“Sometimes patients have been enrolled in a patient registry for a long time and a new treatment becomes available,” Carlin 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.”

Rather than randomising the order in which the subject receives treatments, in a rare disease study everybody starts with their own natural history - their own placebo - and then switches to treatment.

However, when it comes to data rigor with non-interventional studies, there is wide variability, Earle said. “Some disease registries have data approximating clinical trial data in terms of rigor, and others are a lot looser.”

Having thorough data is important both from a regulatory as well as a reimbursement perspective.

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

Balancing clinical considerations

Important considerations in rare disease may focus on improving quality of life (QoL), rather than extending survival. An example might be a rare cancer in the brain, which results in strong intracranial pressure, and where a novel drug doesn’t extend survival, but might reduce pressure on the brain. That’s why it’s important to talk to the regulators, so this claim can be considered meaningful for the development programme.

While early planning and engagement are key from a regulatory perspective, they’re also important from a payer point of view.
“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, ability to return to the workforce,” Wissinger commented. “It’s really that specific value message around the benefit for the individual asset.”

Carlin added that going with the QoL endpoint can be problematic, simply because this wasn’t a concern 10 years ago, so there hasn’t been a lot of attention paid to it as an endpoint.

“Moreover, 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,” he said.

“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,” Earle noted. “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.”

Nevertheless, there is growing comfort among regulators with innovative trial design. For example, the US Food and Drug Administration (FDA) established the Complex Innovative Trial Design (CID) Meeting Program that offers sponsors using complex adaptive, Bayesian, and other novel designs more meetings with the agency. This is an opportunity to negotiate the nature of the design and review existing historical data.

“The CID program is just one example of 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,” Carlin said.

The European Medicines Agency (EMA) has published a reflection paper on the use of single armed trials in the rare and other disease spaces, which is another opportunity to leverage Bayesian methodologies to address gaps in data.

On the payer front, some health technology assessment (HTA) bodies have also clarified their positions on issues such as surrogate endpoints and single arm studies. Wissinger cited as an example Germany’s IQWiG (Institute for Quality and Efficiency in Health Care), which has guidance around what needs to be proven to demonstrate 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 also will resonate with payers,” she said.

A patient-first perspective

Ultimately, the focus must be on the patient, including finding ways to improve accessibility; for example, by leveraging telemedicine to bring the trial to the patient.

“There are a number of clinical evaluations, including limited history, adverse event assessments, and drug administration that can be done by remote nursing staff to reduce the burden on the patient,” commented Earle.

Regulators are also taking a patient-centric approach, with various innovative access pathways aimed at fostering advanced therapies. One example is the Innovation Accelerator service established by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA).

Crucially, patients also need to be at the centre of the discussion from an access perspective, including better understanding 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,” Wissinger said.

In addition to working with HTA bodies, companies should also consider patient support schemes, as well as managing logistical steps such as managing cold chain supply for patients outside of the main centres.

“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,” Wissinger concluded.

The information provided in this article does not constitute legal advice. Cencora, Inc. 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.