Balancing expectations: An unmet need in the orphan disease arena

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There are between 6000 and 8000 rare diseases in the world, and one in ten people in Europe and the US have a rare disease; 75% of rare diseases affect children, and 30% of rare disease patients die before the age of 51. Over 95% of these rare diseases have no treatment options available—instilling a devastating burden on patients and their families2. While the pharmaceutical industry is focusing on innovation to address this significant unmet need among patients, such dedication is not entirely altruistic. Commercial opportunity in orphan medicinal products (OMPs) is estimated to reach $209bn by 2022 and constitute one of the largest growing parts within the prescription drug segment3, continuously drawing investment from small, medium and large companies alike.

As the influx of OMPs into the global market is expected to continue, public and private payer stakeholders face a dilemma. They must balance providing patients optimal access to high-price OMPs with their responsibility for adequate resource appropriations and sustainability of their entire healthcare system. The situation is accentuated when the clinical/humanistic/economic evidence associated with OMPs is still evolving, creating uncertainty of the product value proposition in relation to its price. This lack of evidence and uncertainty often results in the delay or lack of access to OMPs as the pharmaceutical company and payers deliberate on product value. The healthcare ecosystem is left strained by the competing expectations of the core stakeholders:

  • Patients - in achieving immediate access to innovative OMPs when one is available
  • Payers - in managing their drug budget impact and seeing adequate demonstration of product value proposition in relation to its price, and
  • Pharmaceutical company shareholders – in achieving in ROI and commercial success

These three stakeholder groups influence and/or benefit from OMP market access. An imbalance in the strategies executed to address their needs has the potential to jeopardise the sustainability of the healthcare ecosystem. The top-3 issues pharmaceutical companies must address to meet each of these stakeholder expectations are outlined below4.

Meeting patient expectations:

  • Focus on patient-centric outcomes:
    Trial design needs to incorporate endpoints that are relevant to patients, keeping the wholistic patient disease burden in mind so that improvements in clinical as well as humanistic burden can be demonstrated as a function of use of the OMP. Conducting a patient advocacy advisory board, in addition to payer/key opinion leader (KOL) advisory boards during the product development stages is warranted.Payers/HTA stakeholders on the other hand are increasingly involving patient stakeholders in their value assessments and decision-making. Statistics derived from Decision Resource Group indicate that the involvement of patient and professional-group in HTAs has increased from 18% in 2009 to 35% in 2017.
  • Responsible pricing:
    Responsible pricing strategy needs to be adopted and communicated to relevant patient advocacy groups, along with the articulation of the manufacturer’s commitment to patient-centricity.Stakeholder communications on justifying product pricing should encompass unmet needs in the disease area, product differentiation attributes addressing the unmet needs, price, R&D investments made to-date, future research commitments, and the general vision of patient-centricity.

    Along these lines, Novartis and Sanofi/Regeneron, in support of their launch of Kymriah® and Dupixent® respectively, publicly articulated their approach to responsible pricing (of their product) and engaged in key external stakeholders communications/engagements; this may serve as an example for best practice.

    R&D investments alone are not valid justification for high OMP price; ‘value’ delivered by the product should be the central theme. Value should encompass clinical value, and the value derived by patients, healthcare systems and the broader society.

  • Equitable access to medications:
    Under human rights principles, patients with rare diseases have equal rights to medicines as other patients with more prevalent diseases (e.g., hypertension). Patients are not to be disadvantaged in gaining benefits from medical advances because of the rarity of their illness or the inability of healthcare stakeholders to come to terms concerning just one product attribute, namely, its price.

 Meeting Payer Expectations:

  • Addressing unmet needs:
    Adequately articulate unmet needs and disease burden associated with current SOC, in the concerned disease area, and justify the market need for innovation.

Excerpts from European payer interviews reflecting these perspectives:

“The severity of the disease and the impact on public health are crucial. Generally, the commission prioritises fatal diseases, like SMA or DMD, over, for example, CF, which is not immediately lethal. Translarna in DMD is very interesting and actually the commission speeded up the process of approval.” - AIFA advisor, Italy

 “Innovation is a key factor for the new AIFA heads. There is a specific commission called Innovative Drugs and Therapies, and all innovative drugs will get significant priority for reimbursement and access to the market. I'm quite optimistic about Spinraza.” “In the case of Translarna, it seems there is a relatively easy access program regulated by 648 law because the clinical impact is so important for DMD patients.” - AIFA advisor, Italy

  • Product differentiation:
    Highlight product differentiation in comparison to relevant comparators, using relevant clinical trial design and endpoints and show unequivocal proof of patient benefit (with high quality evidence) and value for money using not only RCT data but also using RWE post-launch

Excerpts from European payer interviews reflecting these perspectives:

“The longer the better, but the magnitude of the efficacy is crucial, not just the duration of the trial.” “Kalydeco received a rating of significant added medical benefit in CF patients aged 12 or older with the G551D mutation, but just minor additional benefit in those aged 6-11 due to lack of data on improved QOL in the latter age-group.” - G-BA advisor, Germany
“Finding the proper comparator for an orphan drug is possibly the main problem, because it's very difficult to compare.” “A head-to-head study, which I know is very difficult to have, is best for a favorable HTA and to allow you to compete on price.” – AIFA’s CTS advisor, Italy
“Payers need a control group that convince them that the orphan drug will represent an incremental benefit for patients in the long term. Sometimes placebo is not the best comparator. There are drugs that are being used off-label in the Spanish market and the manufacturer should use this off-label drugs as the proper comparator. In some other cases, the SoC in Spain is quite different from the placebo that it's being used in clinical trials.” - CIPM advisor, Catalonia, Spain
“Currently, access to an orphan drug is easier in the south of Italy because there are less strict reviews in southern regions. I feel that if a manufacturer could provide very important, significant real world data, this could definitely be an important factor to get hospital approval.” - AIFA advisor, Italy
  • Flexible negotiations:
    Exercise flexibility in pricing negotiations and be prepared to provide ancillary discounts, engage in Managed Entry Agreements / Outcomes Based Contracts as well as clearly articulate stop/start criteria of the drug to facilitate appropriate drug utilisation, within the parameters of defined projected budget impact

Excerpts from European payer interviews reflecting these perspectives:

“Sometimes regional health authorities can decide not to reimburse.” “You need to convince payers by proving that you are saving money elsewhere. So, other than efficacy, PE data is very important, especially data demonstrating a reduction in hospitalisations, professional care at home, and reduction in the use of other drugs.” - CTS advisor, Italy
“Cost sharing and simple rebates are common, something like ‘10 vials, one for free.’ These deals are most frequently made with at the hospital level. At the national and regional levels, you can have some kind of proposal. If manufacturers were to cover the cost of biomarker testing, for example, this would be a very significant reimbursement lever.” - CTS advisor, Italy
“In general, regions want to be sure that any new drug they are including on their formulary represents value for money. Regional assessments are based on clinical data and economic data, but the attention is focused mainly on budget impact models.” - CIPM advisor, Catalonia, Spain
“A price discount is not mandatory, but drug companies often offer discounts through various ways of risk-sharing or patient access scheme, and this is very important because you have to provide affordability. We usually want very simple discounts like a rebate. Not volume-based because we think it's not ethical.” “In addition, while specific biomarkers help make the case for cost-effectiveness, if manufacturers were to cover the cost of testing, that would be taken as positive.” – CCG chief formulary pharmacist, United Kingdom

Meeting Company Shareholder Expectations:

  • Optimise commercial strategy and revenue growth:
    Strategise launch sequencing to minimise market access hurdles, international referencing pricing issues and accelerate commercialisation
  • Increase market share:
    Achieve optimal market share via implementation of adequate strategies supporting accelerated patient finding, early diagnosis and prompt channelling of patients into the healthcare system to address their unmet needs
  • Portfolio management:
    Maintain focus on progression of pipeline, portfolio diversification (to minimise risk), as well as investing in continued evidence generation to support the current (OMP) product’s value proposition


Demonstrating value is paramount to commercial success of OMPs and increasing the shareholder value. Pharmaceutical organisations may see OMPs as cash cows with strategic pricing, but that may not last long. Strategic considerations meeting multiple stakeholder expectations to achieve optimal access and, consequently, optimal commercial success is warranted.

With the flurry of curative gene therapy launches in rare disease arena looming on the horizon, market challenges and corresponding stakeholder expectations and demands are only likely to increase. The industry needs to embrace and prepare itself for a new paradigm in achieving and maintaining market access to their OMPs. As Yann Le Cam at EURORDIS said,

“Today’s challenges will not be solved by applying yesterday’s mindsets. If risks must be taken to deliver scientific breakthroughs and genuine innovation, risks must also be taken to make sure that tomorrow’s processes and policies are more adequate and also fairer than today’s.”5

Author Bios:


Siva Narayanan

Siva currently serves as the Head of Global Scientific and Commercial Strategy, Global Access at DRG. His work centres around being a catalyst to globally enable healthcare industry players and payers to arrive at an optimal solution for patient access.


Yulia Privolnev

Yulia is a manager on the Global Market Access Insights team at Decision Resources Group, primarily focusing on European market access. She is responsible for monitoring, analysing, and reporting on global market access through the production of DRG’s Global Market Access Solution (GMAS) and Access & Reimbursement products.


  1. EURORDIS Fact Sheet on Rare Diseases
  2. Rare Diseases: Facts and Statistics
  3. Evaluate Pharma. Orphan Drug Report 2017. 4th Edition, February, 2017
  4. Payer stakeholder comments on concerned OMP market access topics extracted from Decision Resource Group’s “Rare Diseases and Orphan Drugs - Access and Reimbursement Report” are also depicted to contextualise relevant issues.
  5. Andersen, T and Le Cam., Y. Breaking the Access Deadlock to Leave No One Behind. A position paper by EURORDIS and its members. January 2018.