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Success in Rare Diseases, Part V: Working with Payers in the Rare Disease Ecosystem

Posted by Dr. Shradha Das, Ivan Hsiao-Suignard, Alejandro Lopez, and Yan Xue, Ph.D. on March 1st, 2021.

Throughout this series, we’ve covered a wide range of areas that biopharma companies must address if they are to succeed in the rare disease (RD) ecosystem including clinical trial design, clinical trial implementation, and ongoing evidence generation.  In this installment, we cover the important topic of market access.

To help drive commercial success, a therapy must have a sound pricing and market access (PMA) strategy resulting in a sustainable price that captures the value of the asset and supports broad access.  To inform such a strategy, early engagement with payers is typically required to understand their expectations and ensure that clinical programs generate data that will be relevant to them.

Building the PMA strategy can be complex and difficult for any therapy, but it’s even more so for rare disease products, given the complex and varied challenges they face.  In this article, we outline a high-level framework that biopharma companies can use to help guide their efforts.

We organize the factors that impact payer decision making into the “3 Ds”, outlining questions and key considerations for each:

  1. Disease
  2. Design
  3. Data

Key Questions and Considerations for Companies

RD companies with development-stage assets have a range of questions to answer as they design their clinical programs, including those related to access and reimbursement. Below we outline some of those questions and shed some light on key considerations related to them.


Three important questions for any therapy are:

  1. What are payers’ perceptions of the disease burden, including the impact on patients’ and caregivers’ quality of life, as well as the costs to the healthcare system and society?
  2. How rare is the disease based on the established definitions for the market(s) in question?
  3. What are payers’ perceptions regarding the level of unmet need?

As a biopharma company answers those questions, there are a few considerations to keep in mind.

In general, a payer’s stance regarding a new therapy will hinge on its assessment of the therapy’s effectiveness coupled with the degree of unmet need.

An effective therapy with a high perceived level of unmet need has a greater likelihood of launching into  a more favorable payer environment.  For many RDs, however, payers might not have a deep understanding of the level of unmet need for patients and caregivers, which means the biopharma companies will need to invest more in educating them.

Typically, the rarer the disease, the less familiar payers are likely to be with it.

When developing therapies for diseases that are unfamiliar to payers, biopharma companies should consider collaborating with patient advocacy groups (PAGs) to raise awareness early on to help educate payers and other stakeholders.  In addition, natural history of disease studies can be used to demonstrate the quantitative impact of the disease over time.

The activities of patients and/or advocacy groups have been effective in raising the profiles of some RDs.  Amyotrophic lateral sclerosis (ALS) provides an example of this, as the “ice bucket challenge” effectively affirmed the magnitude of the disease burden and made stakeholders more aware of its impact.

In addition, strong patient advocacy in one disease–even if it’s not “rare”–can raise the profile of other, rarer diseases that are similar to the one receiving advocacy attention.  It’s sort of like a “rising tide lifts all boats” phenomenon.  Patient advocacy in Parkinson’s disease, for example, raised awareness of a number of other neurodegenerative disorders ranging from associated disorders (e.g., neurogenic orthostatic hypotension) to Parkinson-plus syndromes (e.g., multiple system atrophy).

Historically, payers were often less likely to push back on price for rare disease therapies due to their lower total budget impact, but that is changing.

With the emergence of more and more RD therapies, especially advanced therapy medicinal products (ATMPs) that hold the promise of disease modification, RD therapies are increasingly on payers’ “radars”.  As a result, there is a trend towards more scrutiny and tighter cost controls. The burden remains on the biopharma company to make a compelling case for a therapy’s value. Bluebird Bio’s betibeglogene autotemcel provides a recent example of payer pushback leading to limitations on patient access and company valuation.

Payers are also seeking ways of adapting their processes to better manage RD therapies. For example, orphan disease status in Germany currently allows for “additional benefit” as long as annual sales generated through the therapy are less than €50 million.  However, there are efforts to abolish this, so it’s worthwhile to stay abreast of legislative developments.  In upcoming papers, we will take a more in-depth look at how the payer landscape is evolving.


Clinical trials must be designed to secure regulatory approval and simultaneously address the needs and expectations of payers, among other stakeholders.  To that end, companies must address a number of important questions when it comes to clinical trial design.  Two of those are:

  1. How can we design registrational studies that meet payer needs?
  2. Are the endpoints relatively obvious (or are innovative approaches required to develop them) and will they be relevant to payers?

For any given therapy, the answers to these questions can vary considerably.  Companies must engage early with payers and other stakeholders to answer them well in advance of designing pivotal studies.  For example, in Germany, the G-BA (Federal Joint Committee) offers official meetings with companies to discuss which comparator they should use in their studies to help ensure the study design and resultant data will be accepted.  Some key considerations regarding trial design are below.

Single-arm trials can have a role, but they’re not a panacea.

Conducting randomized controlled trials in rare diseases is difficult.  There are recruiting challenges in ultra-rare patient populations, there are ethical concerns for patients given the lack of therapeutic options, and there are other obstacles, too.  As a result, regulators and healthcare providers are willing to consider single arm trials if natural history studies or real world data can be presented for the “control” arm.

For example, Brineura® was approved for Batten disease based on a single-arm dose escalation study.  Zolgensma® was approved for spinal muscular atrophy (SMA) based on a single-arm study compared with the natural history of the disease.

On the other hand, there might be resistance from payers given that most are not convinced about the robustness of data due to the heterogeneity of the real-world population in many diseases.  To a certain extent, a biopharma company can navigate through these challenges through thoughtful early engagement with not only payers, but also key opinion leaders and patient advisory groups.  This engagement requires a strategic approach though, as the level of influence these stakeholders vary considerably by country.  We will provide a more detailed look at real-world evidence / data (RWE/RWD) in an upcoming paper.

Innovative—but validated—endpoints might be required.

For many rare diseases, established endpoints are not available and thus haven’t been used by payers in prior assessments.  While designing endpoints it is important to understand the course of the disease and the impact of the disease on patients and caregivers’ lives in order to choose the most patient-relevant metrics.

Although composite endpoints might be accepted by physicians, it can lead to significant confusion if different composite endpoints are used across trials. It could be difficult to demonstrate value of the product with payers through composite endpoints, as the link between clinical outcomes and impact on daily living, quality of life and overall disease burden might be unclear, especially since the disease might not be on their radar in the first place.  It will also be important to validate any new scale and/or composite endpoints through investigator-initiated studies.

In addition, some payers will be looking for the product’s impact on the quality of life (QoL) for patients and caregivers. Validated patient reported outcomes (PRO) tools, incorporation of digital patient monitoring, and the impact on patients’ or caregivers’ productivity are some key secondary endpoints that can be considered to facilitate buy-in from payers. Linking QoL related endpoints to the primary endpoint can further enhance the value perception of the product.

A prime example of this approach involves Luxturna® for inherited retinal disease. Spark Therapeutics collaborated with academic investigators to validate a novel metric to measure functional vision, the multi-luminescence mobility test (MLMT).  It measures a patient’s ability to navigate a course effectively at different levels of light in the environment. This is an impactful and patient-relevant measurement.

ALS provides another example.  In the US market, patient research directionally indicated that they may be more interested in preservation of limb strength, mobility, and independence than in overall survival.  So, we saw a shift from measuring the time to tracheostomy or death to the difference vs. placebo in decline in the ALSFRS-R score in a certain time frame as a primary endpoint.  The ALSFRS-R is a validated test that measures the progression of disability in patients with ALS.

Many assume that increasing survival by some period of time would be the most meaningful to payers because that’s what’s expected in a wide range of diseases (many cancers, in particular).  The example above shows that assumption is not always valid, and that stakeholder input is required to determine what endpoints will be relevant.


Obviously, a trial’s design leads to the type of data collected.  Leveraging stakeholder input, companies should answer:

  1. What are payers’ expectations around durability of benefit / long-term outcomes?
  2. Along with the study endpoints, what other data points will help communicate the therapy’s value to payers?
  3. When long-term data are limited or non-existent, what’s the best way to navigate around that challenge?

The duration of a therapy’s benefit can impact how payers perceive its value.

Radicava® (edaravone) for ALS was approved in the US but was declined in the EU for a few reasons, one of which was the duration of benefit.  The CHMP suggested an additional study of survival for Radicava® to be considered for regulatory approval in the EU.  While the preceding example relates to a regulatory issue, it can offer a lesson that’s relevant to access and reimbursement: if there is any question regarding the duration of benefit and how that will impact payers’ perceptions of its value, then it would be wise to collect direct input from them as early as possible.

When long-term efficacy data are unavailable, creative approaches are needed.

Reducing uncertainties for payers is one of the key challenges for products in rare diseases. Since long-term outcomes are generally unavailable at the time of market authorization, payers are reluctant to pay a premium price for a product that they’re not sure about long-term.  At the same time, they are aware that it is unethical to make patients wait for treatment until that long-term outcomes data becomes available, especially when there is a lack of therapeutic options.  There are some early access programs available to address this.  However, innovative pricing agreements also play a role in reducing payers’ risk.

Most of these innovative agreements should consider—or be based upon—the therapy’s performance, its budget impact, and the business needs of the manufacturer.  Novartis’ Kymriah® provides a well-known example.  It was approved in 2017 and US payers were concerned about its high cost ($475,000), given its uncertain outcomes.

However, it was a potentially curative cancer therapy and needed coverage. The agreement was structured so that the manufacturer would only receive payment for patients who showed significant improvement within a month after the infusion.  The Centers for Medicare and Medicaid Services (CMS) would later provide coverage based on its effectiveness.  In Germany, interim agreements were made for Kymriah® and Yescarta® (another Novartis T-cell-based cancer therapy) that included rebates based on outcomes.

The other way to navigate is through early access programs.  These programs ensure access to therapies for patients before reimbursement negotiations are finalized.  They also give the opportunity to generate additional long-term data for the company and embed experience of use within healthcare providers. For example, Evrysdi® and Spinraza® were made available to select patients in the UK through EAMS, the Early Access to Medicines Scheme . Evrysid (for SMA type 1 patients), Spinraza (for SMA type 1 & 2 patients), Kymriah® and Yescarta® were made available in France through Temporary Use Authorizations (ATU).

In addition to demonstrating a clinically meaningful benefit, it can be a value-add to show patient-relevant benefits for compliance and persistence.

If the benefit is statistically significant vs. the control, it will likely be considered good enough if there isn’t an alternative or if it’s competing against a not-so-efficacious therapeutic alternative.  Showing a patient-relevant benefit that positively affects compliance and persistence (e.g., an oral vs. IV route of administration or 1x/day vs. 3x/day dosing) can be relevant to some payers.


Clearly, securing the desired levels of pricing and market access are challenging for rare disease therapies.  However, there is an increasingly robust array of creative tools, programs, and approaches that biopharma companies can use to achieve success.

Reimbursement and payment models will continue to evolve almost as rapidly as new innovative therapies are developed.  Biopharma companies must adopt a strategic approach to understanding how payers perceive the disease, what clinical trial designs will be required, what data that will be compelling enough to secure access at a reasonable price.