The complexity of R&D for orphan medicines

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This article is part of our special report Reviewing orphan drugs law: A tough equation.

There are multiple challenges inherent to drug development for rare diseases, all consequences of the small number of patients. For most of these diseases, the body of pre-existing knowledge is extremely limited with a lack of crucial information such as its determining factors, since in most of the cases there are no consolidated outcome measures to assess clinically meaningful improvements.

Diego Ardigò is the Head of Global Rare Diseases, Research & Development at Chiesi.

This absence of background information on the disease impacts the foundational knowledge upon which the clinical development of new drugs is based. Besides the need to generate from scratch a relevant amount of observational data, this lack of information significantly increases the risk of producing incomplete or inconsistent results in clinical trials. In addition, the size and utility of observational and investigational studies is severely impacted by the difficulty (sometimes even the impossibility) of recruiting a sufficient number of patients to obtain fully-powered and informative results.

Sometimes even the diagnosis of the disease is an undefined and intricate process. The identification of patients and their subsequent referral to treatment centers (or network of centers) is now increasing, thanks to the efforts of the European Reference Networks and some influential patient associations, but most patients are still not diagnosed or are unknown to the specialized medical community. This makes the patient journey a long and arduous experience with an unpredictable outcome even when safe and effective treatments are available.

Finally, the costs incurred in rare disease development could be less than those of products targeting large populations, but are still highly significant and should by no means be minimized: the quality and non-clinical development is largely independent from the size of patient pool and the clinical studies might be smaller than those of mass market drugs but the cost-per-patient is orders of magnitude greater. In these conditions, the risk of financial unsustainability is high for developers in the absence of incentives and compensation systems. This is particularly true for ultra-orphan conditions where there are only several hundred or fewer of patients, globally.


How are R&D decisions are taken? Based on what criteria?

In general, drug development decisions are based on the possibility to fulfil significant medical/ patient needs (i.e. whether a new drug is meaningful to patients and to the health care system), on being able to demonstrate this relevant benefit through clinical trials (i.e. whether a new drug generates compelling clinical data), and considering the complexity and challenges and risks of investment in R&D and manufacturing.

This general framework is true also for rare diseases, with greater risks and uncertainties related to the viability due to the disproportionally lower number of patients to be treated in the future commercial setting compared to the costs and risks. Over the years, an increased pressure on industry has arisen to develop new treatments for a limited number of rare diseases, characterized by a manageable balance between up-front costs and possibility of future, although highly uncertain, returns.

The existing incentives for orphan drug development, as well as the progressive evolution of the regulatory system toward a sensible flexibility, have helped industrial sponsors maintain the possibility of developing new drugs for rare disease characterized by relevant medical needs. Legislative or policy changes that lead to a less favourable balance between inherent risks and future potential returns will likely move the decisions of pharmaceutical companies away from rare diseases.


Do you feel that the industrial strategy and the expected pharmaceutical strategy will have a positive or negative effect on the industry? Where do you see opportunities and potential risks?

The renewed industrial strategy and the expected pharmaceutical strategy are a landmark opportunity to ensure that the European life science industry will be able to compete at a global level, while ensuring access to innovative treatments to European patients. On the strategy itself, the renewed commitment to strengthen smart IP policies is a very positive, necessary, message. The pharmaceutical strategy would be a chance to open a constructive discussion on how we can strengthen the competitiveness of our regulatory framework: making it fast, flexible, and effective, so that it will deliver both safe and efficacious products to patients as well as attract innovative developers. This is a key driver when it comes to deciding where to carry out R&D activities at global level -an area where Europe has constantly lost ground in the last 20 years. We think that whatever strategy is proposed it should aim to benefit people living with diseases, and this means incentivizing research rather than merely focusing on increasing manufacturing capacity.


The success of the orphan regulation is widely recognised. However, EU member states worry about pricing issues and lack of investment in certain areas where there is unmet medical need. How would you respond to these? How can they be addressed if not by amending the regulation?

For society to work well, we believe it is important that a serious, clear and continual dialogue is maintained across different stakeholders, while respecting their own competencies. Everyone has their own role to play, and ultimately everyone should ensure that their actions generate societal benefits.

To this end, mixing pricing concerns with R&D incentives and related regulations lead to a very dangerous path that can be really detrimental for EU patients and EU pharmaceutical R&D operations. As a mid-size European pharmaceutical group operating at a global level with a strong commitment in the rare diseases area, we hope that the new EU mandate will aim at maintaining incentives to ensure a proper level of investment for areas of high unmet need, as is the case for ultra-orphan conditions where traditional business models don’t apply. On the access front, we fully understand that it is not acceptable to have a European Union that operates at different speeds when it comes to access to treatments. That’s why we think that it is time to reflect with all stakeholders on new models to finance innovation to ensure access for all EU patients and drive sustainability for health systems.

At a societal level, the impact of the cost of orphan drugs is limited, and will continue to be so when compared to treatments for much bigger patient populations. Many other components of healthcare systems spending are significantly more inefficient than the 5% of total pharmaceutical expenditure devoted to rare disease drugs in the EU.

Finally, a continued focus on pricing by European authorities rather than the still very high need to incentivise research will likely push companies to other geographies such as the US and emerging countries, leaving the European patients at a net loss. This, we believe, is also a net loss for the European society, as it will likely induce European companies to intensify their activities (on research, clinical development, formulation development, commercialization) away from Europe.

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